Aim: Mitochondria are essential for brain development, and the presence of different mitochondrial types is called mitochondrial heteroplasmy. Mitochondrial dysfunction is a central aspect of many people’s neurological diseases. Heteroplasmy is commonly observed in eukaryotes due to mitochondrial genome (mtDNA) mutation, paternal leakage, mitochondria transplantation/mitotherapy, and somatic cell nuclear transfer (SCNT). In this study, we developed two novel approaches to construct mitochondrial heteroplasmy cellular models.
Methods: Model 1: the yak cell line (Bos grunniens) was transfected with p-eGFP-neo plasmid while mammary alveolar cell-T (MAC-T) cell line from cattle cells (Bos taurus) was stained with MitoTracker Deep Red FM. The yak cell line was used as recipient cells which fused with enucleated cattle cells. Model 2: The cattle cell line was stained with MitoTracker Green FM while yak cells were stained with MitoTracker Deep Red FM. Cattle cells were used as recipient cells which fused with enucleated yak cells. Following fusions, the single cells exhibiting dual positive fluorescence signals were sorted into 96-well plate by fluorescence-activated cell sorting. Confocal fluorescence examination confirmed that the cells with mitochondrial heteroplasmy were sorted.
Results: The two methods can generate a variety of mitochondrial heteroplasmy cells of interest which can aid in understanding the patterns and influencing factors underlying heteroplasmy changes.
Conclusions: The mitochondrial heteroplasmy cellular model contributes to managing heteroplasmy mitochondrial changes and preventing the development of mitochondrial declines.
Epilepsy, a complex and widespread neurological disorder, has evolved in its understanding from ancient misconceptions to modern scientific advancements. This special issue highlights pivotal research and reviews on the mechanisms underlying epilepsy, innovative treatment strategies, and the psychosocial dimensions of living with this condition. Together, these contributions reflect the growing interdisciplinarity and depth in epilepsy research.
Intracranial artery dolichoectasia (IADE) is a vascular anomaly characterized by dilation and/or tortuosity of one or more intracranial arteries. While many cases are incidental findings on imaging, the associated ischemic neurological complications of IADE can be severe and must be promptly recognized. This study aims to increase awareness among general practitioners and neurologists regarding this rare and potentially life-threatening condition. We utilized reputable databases for this scoping review, including PubMed, Scopus, and Google Scholar, from database inception through September 2024, using a combination of terms such as “Dolichoectasia of Basilar Artery”, “Intracranial Dolichoectasia”, and “Ischemic Stroke”. Our scoping review revealed that IADE is a challenging and often underdiagnosed condition, with an estimated prevalence of less than 1% in the general population. Hypertension, atherosclerosis, and advanced age are well-documented risk factors. To minimize the risk of misdiagnosis, we briefly elucidated the pathophysiology of IADE, correlating it with clinical and radiological features. We discuss the diagnostic criteria for IADE based on radiological imaging, addressing the advantages and limitations of different techniques. Finally, we highlight the unmet clinical needs related to IADE management, which may involve pharmacological and surgical therapies tailored to individual cases, with careful consideration of safety and efficacy.
Intracellular amyloid β oligomers (AβOs) have been linked to Alzheimer’s disease (AD) pathogenesis and to the neuronal damage in this neurodegenerative disease. Calmodulin, which binds AβO with very high affinity, plays a pivotal role in Aβ-induced neurotoxicity and has been used as a model template protein for the design of AβO-antagonist peptides. The hydrophobic amino acid residues of the COOH-terminus domain of Aβ play a leading role in its interaction with the intracellular proteins that bind AβO with high affinity. This review focuses on Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ and their endogenous production in the brain, highlighting the role of the proteasome as a major source of this type of peptides. It is emphasized that the level of these hydrophobic endogenous neuropeptides undergoes significant changes in the brain of AD patients relative to age-matched healthy individuals. It is concluded that these neuropeptides may become helpful biomarkers for the evaluation of the risk of the onset of sporadic AD and/or for the prognosis of AD. In addition, Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ seem a priori good candidates for the development of novel AD therapies, which could be used in combination with other drug-based therapies. Future perspectives and limitations for their use in the clinical management of AD are briefly discussed.
Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are among the most significant health concerns worldwide, characterized by neuronal dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Epigallocatechin gallate, a green tea polyphenol, has been reported to possess multifaceted neuroprotective properties. It reduces oxidative stress through free radical scavenging, activation of antioxidant enzymes, and stabilization of mitochondrial function. It also inhibits neuroinflammation through modulation of key signaling pathways. It suppresses amyloid-beta aggregation in Alzheimer’s and alpha-synuclein fibrillation in Parkinson’s, thus attenuating toxic protein accumulation. Its activity in the induction of autophagy and promotion of synaptic plasticity supports neuronal survival and function. However, low bioavailability and metabolic instability hinder its translation into the clinic. Strategies including nanoparticle encapsulation, structural modifications, and combination therapies are being explored to overcome these challenges. Future research could establish epigallocatechin gallate as a viable candidate for managing neurodegenerative disorders.
The use of neurostimulation devices for the treatment of Alzheimer’s disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD.
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. It presents a significant challenge in terms of accurate diagnosis, disease progression monitoring, and the development of effective treatments. This article addresses the role of neuroimaging as an advancing tool for diagnosis, monitoring progression, and treatment of AD. A comprehensive review of existing literature on the use of neuroimaging in AD was conducted using various databases. The different imaging techniques, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), were examined in terms of their ability to detect amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), the hallmark pathological features of AD. Neuroimaging enables the visualization of Alzheimer-related biomarkers, such as Aβ plaques, tau protein tangles, neuro-inflammation, and synaptic dysfunction, providing valuable insights into disease pathophysiology and progression. These imaging techniques assist in the early detection of AD, distinguishing it from other conditions and evaluating the effectiveness of treatments. This has the potential to significantly transform the way AD is managed clinically. By providing insights into the molecular changes that occur in the brain during the course of the disease, neuroimaging can facilitate early diagnosis, monitor disease progression, and inform treatment decisions. Furthermore, neuroimaging holds great potential for accelerating drug development by allowing researchers to assess the efficacy of novel therapies in real time. Overall, the integration of neuroimaging into the clinical management of AD has the potential to revolutionize the way we approach diagnosis, treatment, and research in AD.
Purinergic signaling, mediated by ATP and adenosine receptors, plays a crucial role in cellular communication and homeostasis within the central nervous system (CNS), particularly by regulating synaptic activity, glial cell functions, and neuroplasticity. Glial cells, including astrocytes and microglia, contribute to both short-term processes, such as neurotransmission and neuroinflammation, and long-term functions, including synaptic remodeling, tissue repair, and behavioral adaptation. Dysregulation of purinergic signaling in these cells has been implicated in the pathogenesis of various neurodegenerative and neuropsychiatric disorders. This article explores the evolving concept of the synapse, highlighting the active role of glial cells in synaptic modulation and emphasizing the significance of purinergic signaling in synaptic function and responses to conditions such as injury and neurotoxicity. Specifically, it examines the roles of ATP and adenosine receptors—such as P2X4, P2X7, P2Y1, and P2Y12—in mediating key astrocytic and microglial functions, including neuroinflammation, phagocytosis, synaptic plasticity, and neuronal damage. Furthermore, the article discusses the involvement of purinergic receptors in neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, Rett syndrome, and autism spectrum disorder, as well as potential therapeutic strategies targeting these receptors to mitigate inflammation, promote tissue repair, and improve clinical outcomes.
Aim: Alzheimer’s disease (AD) is associated with several electrophysiological biomarkers. These biomarkers are associated with global decline in cognition and a diagnosis of AD. However, a specific electrophysiological biomarker is not characterized as normal-functioning older adults convert to AD. The longitudinal retrospective study was conducted to describe an electrophysiological biomarker indicator for AD as normal-functioning older adults convert to a diagnosis in the AD continuum over a 2-year period.
Methods: The study was conducted with 54 community-residing older adults, ranging from normal functioning to a diagnosis of AD. All initial and follow-up electrophysiological evaluations were completed in the New York University Brain Research Laboratories, and overall decline assessments with the Global Deterioration Scale (GDS) were completed in the New York University Aging and Dementia Research Center. Data included measurements from the GDS and raw resting-state electroencephalogram (rsEEG), which was transformed into quantitative EEG (qEEG) data. Data analysis consisted of descriptive statistics and a Kruskal-Wallis test. The level of significance was 0.05 with a moderate effect size. Topographic brain images displayed electrophysiological biomarkers.
Results: A consistently increasing rsEEG theta frequency (P ≤ 0.01) occurred as normal-functioning older adults converted to AD across all GDS stages from the frontal to posterior regions with the progressive global decline. No discernible consistent electrophysiological changes were observed for rsEEG delta, alpha, or beta frequencies over all GDS stages. The GDS stages differed at baseline and follow-up (P ≤ 0.01). The rsEEG theta frequency increased with the progressive global decline across the GDS stages.
Conclusions: The consistently increasing rsEEG theta frequency may be an electrophysiological biomarker indicator for AD from normal functioning to a diagnosis within the AD continuum. This biomarker will enhance the assessment of the risk, onset, and progression of AD and potentially inform the treatment of AD.
The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on a global scale. One of the main molecular mechanisms responsible for the development of Neuro-PASC, in individuals of all ages, is the formation and inadequate proteolysis/clearance of phase-separated amyloid crystalline aggregates—a hallmark feature of aging-related neurodegenerative disorders. Amyloidogenesis during viral infection and persistence is a natural, inevitable, protective defense response that is exacerbated by SARS-CoV-2. Acting as chemical catalyst, SARS-CoV-2 accelerates hydrophobic collapse and the heterogeneous nucleation of amorphous amyloids into stable β-sheet aggregates. The clearance of amyloid aggregates is most effective during slow wave sleep, when high levels of adenosine triphosphate (ATP)—a biphasic modulator of biomolecular condensates—and melatonin are available to solubilize amyloid aggregates for removal. The dysregulation of mitochondrial dynamics by SARS-CoV-2, in particular fusion and fission homeostasis, impairs the proper formation of distinct mitochondrial subpopulations that can remedy challenges created by the diversion of substrates away from oxidative phosphorylation towards glycolysis to support viral replication and maintenance. The subsequent reduction of ATP and inhibition of melatonin synthesis during slow wave sleep results in incomplete brain clearance of amyloid aggregates, leading to the development of neurological manifestations commonly associated with age-related neurodegenerative disorders. Exogenous melatonin not only prevents mitochondrial dysfunction but also elevates ATP production, effectively augmenting the solubilizing effect of the adenosine moiety to ensure the timely, optimal disaggregation and clearance of pathogenic amyloid aggregates in the prevention and attenuation of Neuro-PASC.
Neuropathic pain (NP) is a significant global health challenge, affecting an estimated 7–10% of the population. Painful diabetic neuropathy (PDN), a severe complication of diabetes, impacts approximately one in every three diabetic patients. With the rising global prevalence of diabetes, PDN is projected to become an increasingly urgent health concern. Current treatments for PDN often provide inadequate pain relief and are associated with adverse side effects, emphasizing the need for safe and effective therapeutic options. This review examines the limitations of existing pharmacological therapies for PDN and presents the sigma-1 receptor (S1R) as a promising therapeutic target. We explore the biological role of S1R, its implication in NP and PDN, its structural biology, and the expanding preclinical and clinical evidence supporting its potential. Furthermore, we present evidence for various S1R antagonists in addressing NP and PDN, with a particular focus on E-52862 and [18F]FTC-146. These compounds represent first-in-class ligands for therapeutic and diagnostic applications, respectively, marking significant advances in the development of S1R antagonists. This review underscores the potential of S1R antagonism as a strategy for developing more effective treatments for PDN, with the ability to significantly improve patient outcomes.
Glioma is a highly aggressive brain cancer associated with significant mortality. Despite advances in diagnostic and therapeutic strategies, the prognosis for glioma patients remains poor due to limited diagnostic accuracy and monitoring capabilities. Translocator protein (TSPO) is a mitochondrial protein implicated in various cancers, including glioma, where it plays a significant role in cell survival, proliferation, and chemo-resistance. This review article aimed to comprehensively analyze the role of TSPO in glioma, particularly its potential applications in enhancing diagnostic methods and therapeutic strategies. Molecular imaging techniques have emerged as promising tools for non-invasive diagnosis, disease progression monitoring, and treatment selection of gliomas. A comprehensive literature review was conducted to explore TSPO’s expression patterns, biological functions, and applications in molecular imaging. Studies utilizing positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and other imaging modalities were included. TSPO is overexpressed in glioma cells, particularly in high-grade tumors, correlating with tumor aggressiveness and patient prognosis. TSPO-targeted imaging agents demonstrate high specificity and sensitivity for glioma detection, positioning TSPO as a promising marker for accurate diagnosis and therapeutic monitoring. Future studies should focus on optimizing TSPO imaging protocols, validating their clinical utility, and exploring combined imaging modalities to improve diagnostic precision.
Alzheimer’s disease (AD), the term “dementia”, describes a specific neuropathology together with the development and progression of age-related cognitive and functional loss. Formononetin is naturally occurring isoflavone recognized for its potential health benefits, anti-oxidant, anti-inflammatory, anti-cancer, and anti-apoptotic properties. Neurodegenerative disorders arise from the gradual loss of function and eventual death of nerve cells in the brain or peripheral nervous system. Astragalus membranaceus is a traditional plant with a variety of pharmacological and biochemical properties, including antiviral, anti-hyperglycaemic, and immunomodulatory effects. Moreover, the expression of membrane-bound and soluble receptor for advanced glycation end products (RAGE) is enhanced in the AD brain due to increased levels of soluble and insoluble amyloid-beta (Aβ) peptides. Additionally, in inflammatory circumstances, leukocytes’ firm attachment and transmigration to endothelial cells are regulated by intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Formononetin also possesses anti-bacterial, anti-inflammatory, anti-cancer, anti-oxidant, and estrogenic activity. Formononetin has emerged as a promising agent in the modulation of mediators involved in neurodegenerative disease. Formononetin might modulate nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway to potentiate the anti-Alzheimer’s activity. Additionally, formononetin might inhibit the Aβ/RAGE interaction which further inactivates the activity of extracellular signal regulated kinase (ERK), Janus kinase (JNK) signaling pathway that results in the reduction of nuclear translocation of nuclear factor kappa B (NF-κB) and also reduces the cytokines level to ameliorate AD. It might inhibit the ICAM, VCAM, and THP-1 proteins. Therefore, this compound offers potential therapeutic benefits by reducing cytokine levels to ameliorate AD. This review article is designed to explore the mechanistic interplay underlying the anti-Alzheimer’s effect of A. membranaceus, especially formononetin.
“Functional” gut disorders are clinical conditions frequently encountered in clinical practice, often characterized by abnormalities of the intestinal sensory and motor functions. Although traditionally believed not harboring organic abnormalities, some of these disorders have been demonstrated to have more or less subtle involvement of the enteric nervous system. This involvement has been especially documented for enteric glial cells, even though other elements may be involved. Given the pivotal role of enteric glial cells in gut pathophysiology and their evident abnormalities in some disorders of gut-brain interaction, it may be time to reconsider their role and recognize them as an important pathophysiological factor in these conditions. Thus, due to the prominent neuronal and glial involvement in some clinically severe forms, it is proposed that at least some of the “functional” gut disorders should be reclassified as enteric neuro-gliopathies.
Aim: Cognitive complaints are frequent among cancer patients. These issues can significantly affect the patient’s quality of life and are linked to a higher risk of developing dementia. However, their occurrence does not consistently correlate with measurable objective cognitive dysfunction, which contributes to their negligence in oncological care. Thus, this study aimed to examine the relationship between subjective and objective measures of cognitive function in patients without CNS involvement in a developing context.
Methods: A cross-sectional study was conducted with 50 patients aged 18 and above shortly after diagnosis of non-CNS cancer but before any systematic treatment at a tertiary hospital in Gauteng. The patients completed a self-perceived cognitive impairment (PCI) assessment, and the mini-Montreal Cognitive Assessment (mini-MoCA) as an objective measure of cognition. Correlational analyses were conducted to examine the relationship between self-perceived cognitive problems and performance on the mini-MoCA.
Results: The results of the study revealed the presence of both self-perceived cognitive problems and objective cognitive impairments among the study cohort. There was a small non-significant association between self-PCI and the objective measure of cognitive impairment on the mini-MoCA, rs(43) = 0.220, P = 0.147. Notably, only the memory sub-domain showed a significant but moderate positive association with self-PCI, rs(43) = 0.325, P = 0.029.
Conclusions: This study offers initial evidence of both subjective and objective cognitive impairment in non-CNS cancer patients before treatment in a resource-constrained setting. While there was a small non-significant association between global objective cognitive impairment and patients’ PCIs, a significant moderate association was revealed between the memory sub-domain and PCI. These results underscore the need for thorough cognitive assessment before treatment, as both the presence of cognitive impairment and patients’ perceptions of it can influence treatment compliance and everyday functioning.
Aim: This study is to better understand how the transient ion transport activity of touch receptors could change the graded potential to stimulate an action potential firing.
Methods: The latest transmembrane-electrostatically localized protons/cations charges (TELC) theory is employed for numerical analysis to calculate the neural touch signal transduction responding time required to fire an action potential spike.
Results: A neural action potential spike was constructed successfully using newly developed time-dependent TELC-based neural transmembrane potential integral equations (Equations 5, 6, and 7). The results explicated that the TELC curve has an inverse relationship with neural transmembrane potential since its curve appears as an inverse mirror image to the action potential spike. Based on the TELC density at resting membrane potential of –70 mV calculated to be 3,900 (excess protons + cations) per μm2 and that at the stimulation threshold level (–55 mV) calculated to be 3,100 (excess protons + cations) per μm2 on extracellular membrane surface, the neural touch signal transduction responding time from PIEZO channel ion conduction to reduce the TELC density to the stimulation level of 3,100 TELC per μm2 has now, for the first time, been calculated for action potential firing.
Conclusions: The activity of a single or a few PIEZO channels may be sufficient to generate a “graded potential” to trigger an action potential spike firing. With a high number (200–300) of PIEZO channels activated by touch, it can generate the required “graded potential” to reach the stimulation threshold level (–55 mV) within a neural touch signal transduction time as fast as 0.3 ms. The calculated neural touch signal transduction responding time (e.g., 0.3 ms) may have fundamental implications not only for neuroscience but also for other science and technology fields such as bioengineering and sports physiology.
Neuropathic pain, defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory system”, has an estimated prevalence of 7–9.2% in the general population and is associated with poorer health-related quality of life than other types of pain. Diagnosis can be improved by the use of diagnostic algorithms, but treatment remains rather unsatisfactory, with only 30–40% of patients achieving an acceptable response. Some authors have suggested that the poor results in the treatment of neuropathic pain may be related to the different mechanisms present in each patient and have tried to correlate them with clinical characteristics in order to evaluate possible targeted treatments. This approach has been used in some studies evaluating the response to specific pharmacotherapies in clusters of patients, with encouraging results but still limited applicability to clinical practice. In this narrative review, we attempt to analyse the literature suggesting possible pathogenetic mechanisms manifested along the nociceptive pathway due to a lesion or disease of the nervous system; aware of the limitations of exploring such a wide field, we look for conditions that could be targeted by the available pharmacological or interventional treatment options. Functional changes may occur in the nociceptive system from the periphery to the cerebral cortex, in particular in the nociceptive terminals, along the first-order neuron and the dorsal root ganglion, at the first synapses, or at supraspinal levels. Clinical assessment is the first step in the study of anatomical and functional changes; the diagnostic hypothesis should be confirmed, if possible, by instrumental studies or diagnostic blocks or procedures to guide an individualised therapeutic algorithm from less to more invasive treatments.
Aim: To report the incidence, characteristics, and prognosis of spontaneous intracerebral hemorrhage (ICH) in North Karelia Central Hospital Primary Stroke Center (PSC).
Methods: All patients admitted with ICH to North Karelia Central Hospital between January 1, 2021, and August 8, 2023, were identified from the center’s prospectively updated stroke care database. Post-hospital care data on outcomes were retrospectively updated between May 27 and June 5, 2024.
Results: During the entire study period, we identified altogether 56 ICH patients, of whom two thirds were men. The mean annual incidence of 2021–2022 was 12.3/100,000, and in the population 19–49 years of age, 1.8/100,000. Three months after the stroke, 50% of the patients were functionally independent. In-hospital mortality was 5%, and altogether 11 patients (20%) died during the follow-up (mean 1.72 years). In multivariate analyses, diabetes was associated with mortality [hazard ratio: 3.50, 95% confidence interval (CI): 1.02–11.95], and age was associated with functional outcome in three-month follow-up (odds ratio: 1.060, 95% CI: 1.015–1.107). New-onset epilepsy was diagnosed in three patients (6%) during the follow-up (mean: 1.84 years).
Conclusions: Short-term functional outcome of ICH was mostly favorable, continuing long-term trends of improving outcomes after stroke. Efficacy of multiple interventions care bundle in the treatment of ICH in a PSC-level hospital, a shift of using direct oral anticoagulants (DOACs) instead of warfarin, and improved health status of elderly citizens could be contributing to the better outcome.
CD36 is a transmembrane protein that plays a role in various biological processes, including oxidized low-density lipoprotein and fatty acid uptake as well as regulatory control for inflammation signaling. Its robust expression in monocytes and macrophages associated with its ability to translocate fatty acids linked this scavenger receptor to foam cell formation and atherosclerosis. In the context of ischemic stroke, CD36 has been shown to contribute to brain injury and inflammation. Preclinical studies have demonstrated that CD36 expression increases in the brain after stroke and that inhibiting CD36 can reduce infarction size and improve neurological outcomes in animal models. These findings suggest that CD36 may be a potential therapeutic target for ischemic stroke. However, no clinical trials addressing CD36 and acute ischemic stroke are registered in the American or European databases. This review will discuss the relationship between CD36 and ischemic stroke and present some clinical findings in patients with single nucleotide polymorphisms of the CD36 gene.
The choroid plexus, pivotal for cerebrospinal fluid (CSF) regulation and blood-CSF barrier function, becomes a focal point for primary central nervous system lymphoma (PCNSL). This article delves into a case of this uncommon presentation, highlighting diagnostic challenges, treatment complexities, and post-treatment outcomes. A 30-year-old Lebanese patient with mild headaches and vomiting was initially diagnosed with vasculitis but later confirmed through endoscopic biopsy to have diffuse large B-cell lymphoma of the choroid plexus. Treatment with intravenous methotrexate, intrathecal cytarabine, rituximab, and radiotherapy led to gradual neurological improvement. Treatment strategies, aligned with PCNSL standards, include intravenous methotrexate, intrathecal cytarabine, rituximab, and radiotherapy, leading to gradual neurological improvement post-treatment. Prognostic factors, such as age and specific brain area involvement, guide tailored treatment plans. This report emphasizes the need for a multidisciplinary approach, increased awareness, and ongoing research for optimal outcomes in PCNSL cases involving the choroid plexus.
Aim: Natural products possess diverse pharmacological properties that are effective and safe for treating and managing amnesia; however, there is little or no scientific proof for most of their claims. This study evaluates the efficacy of Lecaniodiscus cupanioide-supplemented diets (LCSD) and Alchornea cordifolia-supplemented diets (ACSD) on scopolamine-induced amnesia in male rats. Roots of L. cupanioide and A. cordifolia were obtained and used to formulate 10% and 20% supplemented diets.
Methods: Experimental animals were orally pre-fed LCSD and ACSD for 14 days before the induction of amnesia via single i.p. (intraperitoneal) administration of scopolamine (2 mg/kg body weight). Experimental animals were subjected to a Y-maze test to evaluate cognitive performance before experiment termination. The activities of hippocampal key enzymes linked to cognitive function were determined.
Results: The result of the Y-maze showed that the induction of amnesia significantly (p < 0.001) reduced spatial memory function, which was protected against LCSD and ACSD pre-treated rats. Also, pre-treatment with supplemented diets inhibited the significant (p < 0.01) aggravation of monoamine oxidase, arginase, tumor necrosis factor-α, malonaldehyde, myeloperoxidase, acetylcholinesterase, and butyrylcholinesterase concentrations, and the significant (p < 0.05) depletion of dopamine, nitric oxide, interleukin-6, total thiol, and non-protein thiol concentrations, in comparison with that observed with amnesic-induced untreated rats. Comparatively, LCSD was more effective in preventing neuronal enzymatic imbalances, while ACSD was more effective in avoiding antioxidant status depletion.
Conclusions: Conclusively, this study established that the supplemented diets possess potent anti-amnesic and neuroprotective abilities. Furthermore, this study recommends supplemented diets as a dietary intervention for preventing and managing amnesic conditions.
Ectonucleoside triphosphate diphosphohydrolases (ENTPDases), members of the cluster of differentiation 39 (CD39) family, are key regulators of purinergic signaling through the hydrolysis of tri and diphosphate nucleotides. These enzymes are expressed on the cell surface, extracellular environment, or within intracellular organelles such as the Golgi apparatus. ENTPDases play critical roles in modulating immune responses, inflammation, and neuroinflammation by controlling extracellular nucleotide availability in mammals. Moreover, they contribute to adenosine-mediated signaling in cooperation with 5’-nucleotidases (CD73). Pathogenic microorganisms also express ENTPDases, manipulating host purinergic signaling, suppressing adenosine triphosphate (ATP)-driven inflammation, and promoting immune evasion via increased adenosine production. Pathogenic parasites also express ENTPDases, manipulating host purinergic signaling, suppressing ATP-driven inflammation, and promoting immune evasion via increased adenosine production. Given their involvement in infection and inflammatory diseases, ENTPDases have emerged as promising pharmacological targets. This review comprehensively analyzes the ENTPDases from mammals and pathogenic parasites, emphasizing their role in purinergic signaling and their potential as therapeutic targets. While ENTPDase inhibitors hold promise for modulating inflammation and infection, their clinical translation faces challenges, including selectivity, off-target effects, and systemic alterations in purinergic homeostasis. Addressing these concerns through targeted drug delivery, allosteric modulation, and improved inhibitor specificity is crucial for therapeutic advancements.
All living beings, from microorganisms to plants, animals, and humans, require iron as an essential micronutrient for their lives. However, iron overload can constitute a scenario prone to damage to the organism, including oxidative stress, deterioration of cellular and subcellular membranes, and thus leading to cell death. This process involves unrestricted lipid peroxidation caused by the generation of reactive oxygen species (ROS) because of an abrupt increase in free Fe2+ in the cytoplasm, all of which leads to subsequent membrane damage and iron-dependent cell death, now known as “ferroptosis”. This process can be induced by convulsive stress, and conversely, inducing seizures, and in both situations under a context of neuroinflammation. In this critical review, we will highlight the most relevant aspects of this recently described mechanism, which has been studied little in epilepsy, its impact on the prognosis of the disease, and its effects on the development of central and/or peripheral comorbidities, including SUDEP (sudden unexpected death in epilepsy).
Alzheimer’s disease, the main cause of dementia worldwide, is a slowly progressive neurodegenerative disorder. This disease involves a diversity of etiophatogenic processes as it is not only a genetic but also a biological and environmental disease. Owing to that complexity, nowadays there is no efficacious treatment for this disorder. The major Alzheimer’s disease clinical indications include extracellular senile plaques of amyloid-β protein, intracellular hyperphosphorylated τ neurofibrillary tangles, uncommon neuroinflammatory response, oxidative stress, and synaptic and neuronal dysfunction. The evaluation of the neuroprotective potential of new compounds is imperative. As natural products, like phenolic compounds, exhibit several bioactivities, it is urgent to test them and evaluate their inhibition of each clinical indication of Alzheimer’s disease. If phenolic compounds target more than one Alzheimer’s disease pathogenic mechanism (multi-target drug ligands), they will have the potential of becoming a leading Alzheimer’s disease treatment. Thus, this review analyzes, for each Alzheimer’s disease clinical indication, the scaffolds of several phenolic compounds leading to the highest activity with the objective to find phenolic compounds active against all the clinical indications. It was concluded that compounds presenting scaffolds like rugosin E or isocorilagin show potential in combating Alzheimer’s disease.
Spinal myelopathies, characterized by neurological deficits due to spinal compression in the spinal column, are increasingly common in the aging population. Although spinal myelopathies commonly present with sensory and motor deficits, they also manifest with life-debilitating enteric dysfunction associated with increased gastroparesis, constipation, bloating, abdominal pain, neurogenic bowel disease, and bladder and bowel incontinence. That said, the effects of spinal myelopathies on enteric gastrointestinal (GI) function are still poorly understood. This review aims to summarize existing literature concerning spinal myelopathies and their effect on the GI system, including the relevant anatomy and physiology of the nervous systems, etiology of various spinal cord injuries, clinical manifestations, current diagnosis and treatment strategies, and ongoing research concerning the gut-brain-spinal axis. The autonomic nervous system contributes to GI innervation through enteric reflex arcs and communication with the central nervous system (CNS) via spinal nerves. When spinal cord damage occurs, enteric reflex arcs, autonomic regulation, and gut-brain-spinal axis can become impaired, leading to GI symptoms. Etiologies of spinal myelopathies occur at all spinal levels. Spinal myelopathy includes inflammatory processes, such as multiple sclerosis and infection, and non-inflammatory processes, such as spondylosis, degenerative disc disease, tumors, and traumatic spinal cord injuries. Diagnosis modalities include imaging, particularly MRI, and functional assessments, such as high-resolution anorectal manometry and colonic transit studies. Enteric dysfunction treatment includes non-pharmacological, pharmacological, neuromodulatory interventions, and surgery. These strategies encompass lifestyle modifications, laxatives, prosecretory agents, 5HT4 agonists, vagus nerve stimulation, sympathetic nerve stimulation, colostomy, and ileostomy. Despite these treatment options, ongoing research with pudendal nerve stimulation, transanal irrigation, mesenchymal stem cells, and the relationship between the gut microbiome and gut-brain-spinal nerve axis may be beneficial in understanding spinal cord myelopathy-related enteric dysfunction, diagnosis, and treatment, ultimately improving clinical outcomes and quality of life for those who are affected.
Depression is associated with executive cognitive deficits which are not well explored and treated. Such deficits have a significant impact on remission and recurrence. To understand the neurocognitive mechanisms of executive processes, a literature search was conducted using bibliographic databases in neuroscience and cognitive sciences: PubMed, ScienceDirect, EBSCOhost, and PsyArxiv, combining search terms: “depression”, “executive functions”, and “specific brain event-related potentials”. The theoretical review focuses on experiments using electrophysiological techniques, non-invasive tools with high temporal resolution. Depression shows alterations in brain activity linked with cognition: P3 diminished amplitudes and prolonged latencies, indicating executive attentional dysfunction; similar activity characterizes mismatch negativity (MMN), reflecting difficulties for change detection, voluntary effort, and mental shifting. Besides, depression tends to increase N1 latencies related with discrimination, and amplitudes of loudness dependence of auditory evoked potentials (LDAEP), suggesting inhibitory control’s deficits. Regarding feedback processing, the alterations of error-related negativity (ERN), correct response negativity (CRN), and error positivity (Pe), at anterior cingulate cortex (ACC), and frontal regions, are related with troubles for error awareness, cognitive control, and error monitoring in depression. Lastly, the ability to interpret coherently the information value of negative feedback (NF), and a propensity to commit perseverative and non-perseverative errors, need further investigation. Depressive individuals commit both errors on more occasions than controls, what seems to relate with fronto-striatal networks’ alterations, producing visual attention deficits and difficulties for inhibiting incoming information. Results show a variety of brain and executive cognitive components that are impaired under depression, although further research may clarify controversies resulting from depression heterogeneity and methodology used.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common type of dementia, characterized by cognitive decline in later years of life. Among various hypotheses explaining AD pathology, the cholinergic hypothesis is one of the most studied. Though there are Food and Drug Administration (FDA) approved drugs (donepezil, galantamine, rivastigmine and tacrine) for AD treatment, their adverse effects make it urgent to develop new drugs with minimal side effects. This review focuses on the acetylcholinesterase (AChE) inhibitory potential of plant extracts and phytochemicals that could aid in preventing and mitigating AD. From the literature search, extracts of 28 species were found to have strong inhibition against AChE, with IC50 values ranging from 0.08 μg/mL to 10.0 μg/mL. The highest number of species with AChE inhibition belongs to the Amaryllidacea family, followed by Fabaceae, Lycopodiaceae, Amaranthaceae and Anacardiaceae. Several phytochemicals, including alkaloids, terpenoids and phenolics, show a multitarget approach in AD therapy, exhibiting more than one of the following activities such as inhibition of AChE, butyrylcholinesterase (BuChE), MAO-A, beta site amyloid precursor protein cleaving enzyme 1 (BACE-1), β-amyloid (Aβ) aggregation, tau phosphorylation, and an ability to cross blood-brain barrier (BBB). With a multitarget approach and minimal side effects, they could revolutionise the treatment of AD. Many phytochemicals and their derivatives are under clinical and pre-clinical trials, potentially serving as prospective therapeutic drug candidates for treating AD. This review briefly discusses the findings and advances in knowledge about plant-derived bioactive compounds as potential new drugs acting as AChE inhibitors.
Parkinson’s disease is typified by Lewy bodies and the selective death of dopaminergic neurons in the substantia nigra. α-Synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress are key components of its pathophysiology. The neuroprotective potential of natural substances with anti-inflammatory and antioxidant qualities has drawn attention in recent years. A naturally occurring isoflavone that is mostly present in red clover and other legumes, biochanin A has shown promise as a treatment option for Parkinson’s disease. Preclinical research has shown that biochanin A uses a variety of methods to provide notable neuroprotective benefits. By activating the Nrf2/ARE pathway, it scavenges reactive oxygen species (ROS), upregulates antioxidant defense enzymes, and inhibits pro-inflammatory mediators by modifying the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling cascade. Additionally, it has been demonstrated that biochanin A preserves neuronal integrity in Parkinson’s disease models by reducing dopaminergic neuronal death, inhibiting microglial activation, and mitigating mitochondrial dysfunction. Its potential as a neurotherapeutic agent is increased by its capacity to pass the blood-brain barrier. To investigate its safety, bioavailability, and effectiveness in people, more translational and clinical research is necessary. Biochanin A’s incorporation with neuroprotective techniques may pave the way for novel supplementary treatments for Parkinson’s disease. Therefore, the current review aims to present a thorough investigation of the molecular basis of biochanin A’s anti-Parkinson properties in Parkinson’s disease, building on the body of existing research that explains these properties.
Aim: Mutations in the EFHC1 gene have been identified in patients with various epilepsies, including juvenile myoclonic epilepsy (JME). Mice with Efhc1 deficiency also exhibit epileptic phenotypes. The protein myoclonin1, encoded by EFHC1, is not expressed in neurons but in cells with motile cilia, including choroid plexus and ependymal cells lining of brain ventricles. However, the molecular mechanisms by which EFHC1 mutations cause epilepsy remain unclear. Because of the involvement of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in epileptic phenotypes and the involvement of myoclonin1 in calcium ions (Ca2+) signaling, we investigated possible functional interplay between myoclonin1 and IP3R1.
Methods: We performed immunohistochemical staining of brain tissues and co-immunoprecipitation assay of myoclonin1 and IP3R1, and Ca2+ imaging analyses using human HeLa.S3, mouse embryonic fibroblasts, or glial cells derived from Efhc1 homozygous knockout (Efhc1–/–) and wild-type (WT) littermates.
Results: Myoclonin1 was revealed to be well co-expressed with IP3R1 at choroid plexus and ependymal cells, and these two proteins bound to each other. Endoplasmic reticulum (ER) of Efhc1-deficient mouse (Efhc1–/–) cells showed larger amounts of Ca2+ than that of WT mice, and IP3-induced Ca2+ release (IICR) from ER was higher in Efhc1–/– cells than that of WT. Furthermore, myoclonin1 was revealed to interact with beta subunit of glucosidase II (PRKCSH), also known as a protein kinase C substrate 80K-H, which interacts with IP3R1. Myoclonin1 further binds to IP3R2 and IP3R3.
Conclusions: These results indicate that myoclonin1 modulates ER-Ca2+ homeostasis through interactions with IP3Rs and PRKCSH, and suggest that myoclonin1 dysfunctions cause impaired intracellular Ca2+ mobilization. Its relevance to the epileptic phenotypes of patients with EFHC1 mutations is now of interest.
Congenital hydrocephalus (CH) is an extreme cerebrospinal fluid (CSF) condition that affects brain development. Current medical treatments, such as ventriculoperitoneal shunting and endoscopic third ventriculostomy, are invasive and susceptible to complications. The subventricular zone (SVZ) is involved in CH, but investigations are hindered by conventional models. Here, we introduce SVZonChip, a dynamic 3D microfluidic device simulating SVZ physiology and CSF dynamics, presenting a proof-of-concept system that could be applied for studying CH. This bioengineered device provides a translational bridge between disease modeling and therapeutic discovery, opening up avenues for non-invasive treatments.
Neurofibromatosis type 1 (NF1) is a hereditary, autosomal dominant condition marked by the development of tumors along the nervous system due to uncontrolled cell proliferation. The current case reports a 31-year-old male patient diagnosed with NF1 with the involvement of bilateral pheochromocytomas and colonic inflammatory polyps/leiomyoma. A genetic profile was explored through whole-exome sequencing to identify pathogenic variants, and segregation analysis was subsequently performed in the patient’s family. Sequencing analysis revealed a novel heterozygous frameshift variant, NF1 c.7301dupA (p.S2435Efs*11), which was identified as the pathogenic variant in the patient. Additionally, two identified variants, PMS2 c.2T>C (p.M1T) and MUTYH c.850-2A>G, may be associated with colonic tumor conditions in the patient. These findings provide insights into the molecular etiology underlying this rare presentation of multiple tumors in a Vietnamese male and may contribute to improved treatment planning and patient management.
Mucopolysaccharidosis type IIIB (MPS IIIB), or Sanfilippo Syndrome type B, is a lysosomal storage disorder caused by mutations in the NAGLU gene, which encodes the enzyme alpha-N-acetylglucosaminidase, responsible for the degradation of heparan sulfate. Progressive accumulation of undegraded glycosaminoglycans primarily affects the central nervous system, resulting in severe neurodegeneration. Cellular findings reveal impaired intracellular trafficking, especially within the Golgi apparatus, linked to GM130 depletion and accumulation of GM2 and GM3 gangliosides. Endocytic vesicles fail to properly fuse with lysosomes due to genetic defects, disrupting lysosomal degradation. This contributes to oxidative stress, mitochondrial dysfunction, and mitophagy failure, which collectively drive neuronal apoptosis. MPS IIIB shares pathways with Alzheimer’s and Parkinson’s, suggesting cellular aging processes. Given the lack of specific treatment, modulation of inflammatory pathways such as TLR4 emerges as a potential therapeutic strategy.
Down syndrome (DS), caused by trisomy 21, is strongly associated with an increased risk of early-onset Alzheimer’s disease (AD). This work explores the cellular, genetic, epigenetic, and neuropsychological mechanisms that underlie the accelerated development of AD in individuals with DS. We review key contributors such as amyloid-β accumulation, mitochondrial dysfunction, oxidative stress, tau pathology, neuroinflammation, and chromosomal and epigenetic instability in the neuropathology of AD in DS. Particular attention is given to genes, microRNAs, and chromatin remodeling factors encoded by human chromosome 21 (Hsa21) that regulate these pathological processes. We also highlight the roles of non-coding RNAs and altered DNA methylation patterns in modulating gene expression and neuronal vulnerability. Additionally, the writing evaluates current pharmacological and non-pharmacological interventions and addresses the critical need for inclusive, person-centered health services. Integrating molecular biology with clinical perspectives, the review emphasizes the importance of early diagnosis and coordinated care strategies for individuals with DS at risk for AD.
Treatment resistant depression (TRD) is frequently encountered in clinical practice. The lack of response of the condition to conventional medications and augmentation strategies has spawned the search for novel treatment approaches. Psychedelic medications used in conjunction with intensive psychotherapy, so-called psychedelic-assisted psychotherapy (PAP), have been evaluated in a limited number of studies as an alternative tactic. This psychedelic renaissance has seen psilocybin, a naturally occurring, potentially hallucinogenic substance occurring in some species of mushrooms, used as one exemplar. The definition of “treatment resistance” varies between different authorities, but there is general agreement that a minimum standard is failure to respond to at least two pharmacological agents from different classes used at a therapeutic dose for an adequate length of time. In the studies to date, more stringent definitions have mostly been applied. Each of the clinical evaluations finds that the addition of a single dose of psilocybin to the psychotherapeutic regimen produces a rapid and clinically significant decline in depressive symptomatology, which is mostly retained in follow-up evaluations out to 12 weeks or longer. Psilocybin was well tolerated with mostly mild to moderate side effects of elevated blood pressure, fatigue, lack of concentration, headache, lethargy, vertigo, feeling of physical or emotional weakness, decreased appetite, nausea, feeling dull, and being easily exhausted, which were transient. Hallucinogen persisting perception disorder (HPPD) has occasionally been reported, while there were few reports of suicidal ideation and behaviour. Psilocybin appears to offer the promise of rapid alleviation of resistant depressive symptoms, but further controlled evaluations are necessary before the drug can be given routinely.
Recent progress in translational neuroscience has significantly advanced our understanding of neurological diseases. Research progress closely went in line with innovations in research methods, which have expanded our insights considerably beyond previous limits. However, despite the development of disease-modifying treatments, therapeutic options in brain diseases still lag behind fundamental discoveries in basic neuroscience. This perspective examines the factors that hinder clinical progress in translational neuroscience and provides solutions on how to overcome them. Editorial board members of Exploration of Neuroscience were interrogated about the most prominent challenges they see in translational neuroscience and about possible ways to overcome these issues. Key challenges were seen at the interface between experimental research and clinical studies by several members, both from the basic and applied neuroscience fields, which include the selection of appropriate study readouts and endpoints. The establishment of refined study endpoints, combined with biomarkers capable of predicting treatment responses in human patients, will be crucial for the successful clinical implementation of new therapies. Further obstacles were found in the standardization of experimental models, interventions, and assessments both in animals and humans, as well as in the development of personalized treatment strategies. These challenges can be addressed through more clearly defined experimental procedures that closely match clinical conditions and precision-based approaches that ensure efficient therapeutic responses. As a great opportunity, treatment options targeting pathophysiological processes in multiple brain diseases and disease processes in different organ systems were noted. Significant barriers remain in the funding of investigator-driven clinical trials through public research programs, as well as the education of translational and clinician scientists dedicated to clinical translation. Enhanced communication between experimental neuroscientists and clinicians, with a shared understanding and common language, will be essential for the success of future research endeavors.
Aim: This study aimed to assess the relationship between clinician adherence to International League Against Epilepsy (ILAE) management guidelines and seizure freedom in adult patients with epilepsy at a Mexican tertiary care center.
Methods: This retrospective cross-sectional study analyzed 404 adult outpatients with epilepsy from an institutional database (January–October 2013). Data were collected on demographic characteristics, seizure types, diagnostic workup completeness, treatment regimens, weight-adjusted dosing, self-reported adherence, and seizure freedom (defined as being seizure-free for at least 3 months). Statistical analysis included chi-squared tests (χ2) for categorical variables and multivariate logistic regression to identify independent predictors of seizure freedom.
Results: Of 404 patients analyzed (58.7% female, mean age 33 ± 13 years), 49.3% achieved seizure freedom. Generalized seizures (including primary and secondarily generalized seizures) were most common (66%), followed by focal seizures (30%). Diagnostic studies included an electroencephalogram in 80% and a magnetic resonance imaging scan in 75% of patients. Monotherapy was used in 50.7%, polytherapy in 44.6%, with weight-adjusted dosing achieved in 92%. Self-reported treatment adherence was 81%. Factors significantly associated with seizure freedom included treatment adherence (51.4% vs. 27.3% in non-adherent patients, χ2 = 13.56, p < 0.001), monotherapy vs. polytherapy (71.7% vs. 62.9%, χ2 = 46.07, p < 0.001), and adequate weight-adjusted dosing (44.9% vs. 32.3%, χ2 = 5.97, p = 0.01).
Conclusions: Adherence to ILAE management guidelines, particularly regarding monotherapy selection, weight-adjusted dosing, and treatment adherence, was significantly associated with improved seizure freedom rates. These findings underscore the importance of implementing evidence-based epilepsy management protocols systematically in clinical practice.
Aim: We previously observed oxidative stress and neuroinflammation caused behavioral and neurochemical changes in young Gabrb2 (gamma-aminobutyric acid type A receptor β2 subunit) knockout (KO) mice. Aging was moderated in a D-galactose-induced accelerated aging mouse model by an oral Chinese medicinal herbal formula BYPA consisting of Bupleurum chinense, Corydalis yanhusuo, Polygonum multiflorum, and Albizia julibrissin. The present study aimed to examine first whether Gabrb2-KO phenotypes observed in young adult mice would remain in aged mice, and whether BYPA may display a role of anti-aging in naturally aged mice.
Methods: A range of behavioral tests were performed on naturally aged Gabrb2-KO and wild-type (WT) mice treated with BYPA. Oxidation stress level was evaluated by MDA (malondialdehyde) test, and the expressions of antioxidant enzymes (superoxide dismutase and catalase) were measured using RT-qPCR (reverse transcription-quantitative polymerase chain reaction).
Results: Behavioral tests on aged Gabrb2-KO mice showed hyper-locomotor activity, social function deficit, decreased levels of anxiety and depression, consistent with a previous study on young Gabrb2-KO mice. Oral administration of BYPA ameliorated anxiety, activity, and depression. Remarkably, BYPA protected facial tissues with regrowth of significantly lost hairs and whiskers due to aging. It also reduced oxidative stress levels and enhanced the expression of antioxidant enzymes.
Conclusions: The present study showed that schizophrenia-like behavioral changes were exhibited by aged Gabrb2-KO mice, similar to what was reported earlier, suggesting that the observed behavioral changes did not result from any developmental delay, but a direct result of Gabrb2-KO, reconfirming the critical role of Gabrb2 in schizophrenia etiology. Since the BYPA herbal formula moderated the oxidative status and enhanced the expressions of antioxidant enzymes in D-galactose-accelerated aging as well as naturally aged mice, it might furnish a useful health supplement to both the schizophrenic and the aged populations, due to its significant antioxidation and anti-inflammation effects exerted in the brain.
Aim: Alzheimer’s disease (AD) is a chronic neurodegenerative brain dysfunction and the most common form of dementia, especially in the elderly, and is considered a serious problem for health systems worldwide. It is a multifactorial and progressive condition, characterized by memory loss, personality changes and decline in cognitive function, in addition to neuropsychiatric complications such as depression, anxiety, sleep disorders, and others, further reducing the quality of life of patients with AD. Since the introduction of galantamine in AD therapy, medicinal plants and herbal remedies are gaining increasing interest as complementary and alternative interventions and are a valuable source for the development of drug candidates for AD. This work aims to explore Tithonia diversifolia ethanol extract (EETD), which showed an acetylcholinesterase (AChE) inhibitory activity like rivastigmine, as a new candidate for molecular targets of AD.
Methods: Mice were submitted to intracerebroventricular (I.C.V.) streptozotocin (STZ)-induced AD (2.5 mg/mL) and separated into different groups: sham, vehicle, rivastigmine (0.6 mg/kg), and EETD (0.1, 1.0, and 3.0 mg/kg). After AD induction, the animals were treated for 24 days and submitted to behavioral tests of memory, anxiety and depression. After the tests, the animals were sacrificed and the hippocampus was removed for assays of oxidative stress, AChE activity and markers of neuroinflammation. In vitro studies evaluated the effect of the extract on tau hyperphosphorylation, beta-amyloid (Aβ), and nitric oxide (NO) production.
Results: EETD promoted a reduction in STZ-induced behavioral parameters of depression and anxiety, as well as reversed memory deficits. Biochemical assays revealed that EETD increased antioxidant defenses, as well as decreased levels of neuroinflammation markers. In addition, EETD partially inhibited Aβ production.
Conclusions: The results together suggest that the plant exhibits therapeutic relevance in AD. However, studies are needed to identify the phytoconstituents responsible for such effects.
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with declining memory and cognitive impairment, largely mediated by extracellular amyloid-beta (Aβ). Although the amyloid cascade and tau protein hypotheses have long served as established frameworks for AD pathology, recent evidence suggests that long-term infections, particularly with Chlamydia pneumoniae (C. pneumoniae), may contribute to disease progression. A systematic search strategy was used to identify relevant literature using PubMed, Scopus, Google Scholar, and Web of Science. Keywords and Boolean operators such as “Chlamydia pneumoniae and Alzheimer’s disease,” “neuroinflammation,” “amyloid-beta,” and “tau protein” were applied, with filters for peer-reviewed articles, human and experimental studies, and publications from the past 25 years. Epidemiological and background data were supplemented by official sources, including the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). This review examines the potential relationship of C. pneumoniae infection with AD pathogenesis. Studies have identified DNA and antigens of C. pneumoniae in AD-infected brain regions, often co-localized within Aβ plaques and neurofibrillary tangles (NFTs). Proposed mechanisms of CNS invasion include olfactory, hematogenous, and immune cell-mediated routes, leading to persistent glial activation, neuroinflammation, altered amyloid precursor protein processing, and tau protein hyperphosphorylation. Experimental models support these associations, with infected animals developing AD-like pathology. Diagnostic challenges persist due to the limitations of PCR and immunohistochemistry, though advanced approaches such as next-generation sequencing and TSPO-PET imaging are emerging. Potential therapeutic approaches include antimicrobial and immunomodulatory strategies, although human trials have shown mixed results. While current evidence suggests a possible link, causality remains unproven. Future research must prioritize large-scale, longitudinal, and mechanistic studies to clarify these relationships. Establishing a definitive role for C. pneumoniae in AD pathogenesis could reshape current understanding of disease etiology and inform the development of novel preventive and therapeutic strategies.
Schizophrenia (SZ) is a complex psychiatric disorder characterized by disruptions in cognition, perception, and behavior, contributing significantly to the global burden of psychiatric disorders and necessitating ongoing research into its pathophysiology, diagnosis, and treatment. This narrative review explores recent insights into SZ research, highlighting the genetic, neurochemical, and neurodevelopmental factors that contribute to the disorder. Emerging evidence underscores the dynamic interplay between neurotransmitter imbalances, particularly involving dopamine, glutamate, and gamma-aminobutyric acid (GABA), and neuroinflammation, oxidative stress, and immune dysregulation in the pathophysiology of SZ. Neuroimaging, clinical staging models, and multi-omics technologies have deepened our understanding of structural and functional brain abnormalities, identifying potential biomarkers for early detection and subtyping. This has refined diagnostic frameworks and informed precision psychiatry approaches. Advances in pharmacological treatments, including trace amine-associated receptor 1 agonists, glutamatergic modulators, psychedelics, and anti-inflammatory agents, offer new therapeutic possibilities beyond conventional dopamine antagonists. Novel targets, such as N-methyl-D-aspartate (NMDA) receptor modulation and neuroprotective strategies, are also being explored to address negative and cognitive symptoms. Additionally, non-pharmacological interventions, such as neuromodulation techniques, digital therapeutics, and psychosocial interventions, are promising complementary strategies. Digital phenotyping, machine learning (ML), and artificial intelligence (AI)-driven tools enable real-time symptom tracking, early risk prediction, and personalized care delivery. Despite these advancements, challenges remain in early diagnosis, treatment adherence, and equitable access to mental health care, particularly in low-resource settings. Therefore, addressing these barriers requires interdisciplinary collaboration, public health education, and the integration of scalable, culturally sensitive, and AI-based mental health innovations. Future research should prioritize multi-omics integration, longitudinal and transdiagnostic studies, biomarker validation, and the real-world implementation of personalized interventions to improve outcomes and quality of life for individuals living with SZ.
Cyclic vomiting syndrome (CVS) is a rare disorder in which stereotypical periods of intermittent nausea and vomiting last between hours and over a week. The disorder overlaps with migraine, and the current treatment recommendations follow those of migraine management. The current patient had experienced vomiting periods lasting up to a week since the age of two. Prophylactic amitriptyline had led to probably slightly longer intervals between CVS periods, while several medications had proven ineffective. At the age of 17, there was an excellent response to peroral olanzapine, which eventually proved sufficient to abort the vomiting periods in a single dose when taken at the beginning of one. In light of these and previously reported cases, early administration of olanzapine is suggested to treat CVS periods.
Guillain-Barré Syndrome (GBS) is a rare cause of acute, flaccid paralysis and affects populations around the world, usually in the setting of recent gastrointestinal infection. The myelin sheaths of affected patients are destroyed, and consequently, the disease can manifest variably with the most common complaints including weakness, disturbances in sensation, and pain. Multiple available pharmacotherapies are employed to address disease progression and promote the reversal of symptoms. However, there is no widely accepted guideline detailing tiers of pain management options, despite pain being a significant primary complaint during the acute phase of the disease. To address this, we searched the GBS literature for publications that specifically discussed patient pain, how the pain was managed by the clinician, and how patients responded to various modalities. We discuss the findings of the literature review we conducted, evaluate the expansive list of existing options for treating pain and how they fared in symptom resolution, and draw conclusions based on our observations of which interventions addressed patient pain effectively and which were less successful. While general management of GBS, including treatment and efforts towards symptom reversal, has been robustly discussed in the literature, our work stresses the lack of research towards pain management in GBS and emphasizes the need to fill the gap in patient care for patients with this disease.
Aim: This study investigated the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on post-stroke outcomes, including quality of life, physical fitness, cognitive function, depression, and overall disability.
Methods: The difference between Met carriers and non-Met carriers was analyzed for the entire sample and in pair-matched analysis, using age, sex, time since stroke, and race.
Results: We evaluated 89 stroke participants (mean age, 57 ± 10 years; 58% male; 54% White, and 49% Hispanic). Twelve participants (13%) had one copy of the BDNF Val66Met (Val/Met heterozygotes) and none had two copies (Met/Met homozygotes). Comparing Met (n = 12) and non-Met carriers (n = 77), no significant differences were observed in demographics or clinical characteristics, including motor or cognitive outcomes. In pair-matched analysis, a significant difference was observed for the Center for Epidemiological Studies Depression (CES-D) scale, where Met carriers had significantly greater CES-D scores than non-Met carriers (24 ± 16 vs. 9 ± 9, p = 0.011). Regardless of the chosen CES-D cut-off scores (≥ 16 vs. ≥ 20), more cases of depressive symptomatology were observed among those with the BDNF Val66Met polymorphism than those without it (p values < 0.05).
Conclusions: The BDNF Val66Met polymorphism may be associated with post-stroke depression but not motor or cognitive recovery.
Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes, representing less than one percent of all non-Hodgkin lymphomas and approximately four percent of primary brain tumors. When the disease is truly isolated to the central nervous system, with no evidence of systemic spread, it poses unique diagnostic and therapeutic challenges, particularly in immunocompetent patients. We reviewed nine recently published cases from 2021 to 2024 that described isolated primary central nervous system lymphoma without extracranial involvement. Patients ranged in age from forty-four to eighty-five years, with both immunocompetent and immunosuppressed individuals represented. Presenting symptoms include focal neurological deficits, seizures, progressive confusion, cranial neuropathies, and neurolymphomatosis. Magnetic resonance imaging findings were diverse, including intra-axial masses, leptomeningeal and cranial nerve enhancement, and mass effect. Cerebrospinal fluid analysis was variably positive for lymphoma cells. Histopathological analysis confirmed diffuse large B-cell lymphoma in all cases, although initial biopsies were sometimes inconclusive, underscoring the importance of repeat tissue sampling and expert pathology review. Treatment strategies most often included high-dose methotrexate-based chemotherapy, monoclonal antibody therapy, and radiotherapy, with some patients undergoing surgical decompression or diagnostic craniotomy. Follow-up data revealed variable survival outcomes, with a subset of patients achieving disease-free survival beyond one year. These cases highlight the wide clinical spectrum and diagnostic complexity of isolated primary central nervous system lymphoma and reinforce the need for a high index of suspicion, timely advanced imaging, multidisciplinary discussion, and appropriate tissue diagnosis to guide individualized management.
Neurological disorders constitute a major global health burden with limited effective treatments. Despite advances in molecular neuroscience, critical gaps persist in understanding intercellular communication systems underlying central nervous system homeostasis and neurodegeneration. Extracellular vesicles (EVs), nanoscale to microscale membrane-bound vesicles secreted by virtually all cell types, have emerged as pivotal mediators of intercellular communication in neurological pathologies. This review examines molecular mechanisms governing EV biogenesis, cargo selection, and pathological functions in neurological disorders, emphasizing the emerging role of ubiquitin-like protein 3 (UBL3) as a novel regulator of EV-mediated protein sorting. Neural cell populations produce specialized EV subtypes containing distinct molecular cargo reflecting their physiological states. UBL3, a membrane-anchored post-translational modifier, operates through geranylgeranylation-dependent mechanisms to promote selective protein incorporation into small EVs (sEVs), with knockout studies demonstrating approximately 60% reduction in EV protein content. Proteomic analyses reveal UBL3 interacts with over 1,200 proteins, with ~30% classified as EV cargo proteins. Critically, UBL3-mediated sorting influences disease-associated protein trafficking, including α-synuclein in Parkinson’s disease and mutant huntingtin in Huntington’s disease, suggesting involvement in prion-like spreading mechanisms. EVs’ dual nature as pathological mediators and therapeutic vehicles represents a paradigm shift in neurological medicine. EVs offer advantages as natural drug delivery systems capable of crossing the blood-brain barrier, accessible biomarkers for noninvasive disease monitoring via liquid biopsies (achieving diagnostic accuracies exceeding 0.88 ROC-AUC), and engineered therapeutic platforms for delivering CRISPR-Cas9 systems and neuroprotective factors. However, clinical translation requires addressing challenges, including standardizing isolation protocols, elucidating cell-type-specific cargo sorting mechanisms, and defining optimal administration routes. Understanding UBL3-mediated cargo sorting mechanisms presents promising therapeutic opportunities by selectively modulating pathogenic protein trafficking. EVs, positioned at the intersection of pathogenesis and therapy, represent attractive targets for precision medicine approaches in neurological conditions, with UBL3 emerging as a novel molecular handle for manipulating EV composition and function.
Although addiction is a complex and contextually embedded disorder that extends beyond individual pathology and neurobiological dysfunction, prevailing computational and clinical models often reduce addiction to a chronic brain disease. While such frameworks have shaped dominant approaches to treatment and theory, they remain poorly aligned with the lived experience and behavioral phenomena of addiction, ignoring its psychological, social, and systemic dimensions. This paper examines the limitations of various disease and compulsion models both critically and in-depth, highlighting their empirical and conceptual shortcomings. In doing so, it argues for the development of context-sensitive and psychologically grounded computational models, ones capable of capturing the nuanced realities of addiction and informing more effective, personalized interventions.
Neurogenetic disorders remain genetically uncharacterized in many populations, including Libya. We report three Libyan patients from two consanguineous families with pathogenic variants in sodium channel genes. Two adult sisters (Patients 1 & 2) presented with global developmental delay and progressive spastic paraparesis without epilepsy. Whole exome sequencing identified the same heterozygous SCN8A variant (c.142G>A; p.Asp48Asn) in both sisters, classified as a variant of uncertain significance (VUS). Its occurrence in two affected siblings with a consistent phenotype and the absence of other explanatory variants provide supporting evidence for its potential pathogenicity. These cases represent the first documented instances of a suspected SCN8A-related disorder in Libya. A third, unrelated 10-year-old boy (Patient 3) with a phenotype consistent with Dravet syndrome, including refractory seizures and neurodevelopmental regression, was found to harbor a likely pathogenic heterozygous SCN1A variant (c.2113del; p.Glu705Lysfs*10). This report expands the genetic and phenotypic spectrum of neurological disorders in Libya and underscores the critical role of genetic testing, while also highlighting the need for segregation studies to achieve a definitive molecular diagnosis.