Catapol: a promising natural neuroprotective agent for neurologic disorders

Abstract

Neurologic disorders are the leading cause of illness and disability as a result of increased life expectancy and global population aging, highlighting the urgent need and great challenge for discovering neuroprotective agents with better efficacy and minimal side-effects. Catalpol, an iridoid glycoside derived from Rehmanniae Radix, has therapeutic potential in neurologic diseases due to its diverse biological activities. This review summarizes the research advances and therapeutic potential of catalpol for a wide range of neurologic disorders, including depression, cognitive impairment, stroke, Parkinson’s disease, and multiple sclerosis. A comprehensive discussion of experimental models used, dosages, duration of treatment, and mechanisms involved is provided. The common mechanisms underlying the neuroprotective effects of catalpol on these neurologic disorders are closely related to antioxidant, anti-neuroinflammatory, and anti-apoptotic properties, as well as the capacity to promote neuroplasticity and neurogenesis. Despite the promising results from experimental studies, there are still challenges to be addressed, such as identifying direct binding targets, assessing toxicologic effects, and understanding pharmacokinetics. Furthermore, well-designed and controlled clinical trials should be conducted to validate the efficacy and safety for treating various neurologic conditions. This review provides compelling evidence supporting catalpol as a promising natural neuroprotective agent.

Keywords

catalpol / Rehmanniae Radix / neurologic disorders / mechanisms / signaling pathways

References

[1] Feigin VL, Vos T, Nichols E, Owolabi MO, Carroll WM, Dichgans M, et al.: The Global Burden of Neurological Disorders: Translating Evidence into Policy. The Lancet Neurology 2020, 19: 255-265.

[2] Collaborators GUND, Feigin VL, Vos T, Alahdab F, Amit AML, Barnighausen TW, et al.: Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study. JAMA Neurology 2021, 78: 165-176.

[3] GBD 2021 Nervous System Disorders Collaborators: Global, Regional, and National Burden of Disorders Affecting the Nervous System, 1990-2021: A Systematic Analysis for the Global Burden of Disease Study 2021. The Lancet Neurology 2024, 23: 344-381.

[4] Svendsen SP, Svendsen CN: Cell Therapy for Neurological Disorders. Nature Medicine 2024, 30: 2756-2770.

[5] Wingo TS, Liu Y, Gerasimov ES, Vattathil SM, Wynne ME, Liu J, et al.: Shared Mechanisms Across the Major Psychiatric and Neurodegenerative Diseases. Nature Communication 2022, 13: 4314.

[6] Mishra A, Bandopadhyay R, Singh PK, Mishra PS, Sharma N, Khurana N: Neuroinflammation in Neurological Disorders: Pharmacotherapeutic Targets from Bench to Bedside. Metabolic Brain Disease 2021, 36: 1591-1626.

[7] Ravichandran KA, Heneka MT: Inflammasomes in Neurological Disorders - Mechanisms and Therapeutic Potential. Nature Reviews Neurology 2024, 20: 67-83.

[8] Hassan W, Noreen H, Rehman S, Kamal MA, da Rocha JBT: Association of Oxidative Stress with Neurological Disorders. Current Neuropharmacology 2022, 20: 1046-1072.

[9] Li J, Jia B, Cheng Y, Song Y, Li Q, Luo C: Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders. Oxidative Medicine and Cellular Longevity 2022, 2022: 3999083.

[10] Korczowska-Lacka I, Hurla M, Banaszek N, Kobylarek D, Szymanowicz O, Kozubski W, et al.: Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases. Molecular Neurobiology 2023, 60: 4132-4149.

[11] Zhang L, Dai L, Li D: Mitophagy in Neurological Disorders. Journal of Neuroinflammation 2021, 18: 297.

[12] Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson DM 3rd, et al.: Oxidative Stress and Impaired Oligodendrocyte Precursor Cell Differentiation in Neurological Disorders. Cellular and Molecular Life Sciences 2021, 78: 4615-4637.

[13] Cardozo PL, de Lima IBQ, Maciel EMA, Silva NC, Dobransky T, Ribeiro FM: Synaptic Elimination in Neurological Disorders. Current Neuropharmacology 2019, 17: 1071-1095.

[14] Martella G, Bonsi P, Johnson SW, Quartarone A: Synaptic Plasticity Changes: Hallmark for Neurological and Psychiatric Disorders. Neural Plasticity 2018, 2018: 9230704.

[15] Nimgampalle M, Chakravarthy H, Sharma S, Shree S, Bhat AR, Pradeepkiran JA, et al.: Neurotransmitter Systems in the Etiology of Major Neurological Disorders: Emerging Insights and Therapeutic Implications. Ageing Research Reviews 2023, 89: 101994.

[16] Suganya K, Koo BS: Gut-Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions. International Journal of Molecular Sciences 2020, 21: 7551.

[17] Andrzejewska A, Dabrowska S, Lukomska B, Janowski M: Mesenchymal Stem Cells for Neurological Disorders. Advanced Science 2021, 8: 2002944.

[18] Ling Q, Herstine JA, Bradbury A, Gray SJ: AAV-based In Vivo Gene Therapy for Neurological Disorders. Nature Reviews Drug Discovery 2023, 22: 789-806.

[19] Anthony K: RNA-based Therapeutics for Neurological Diseases. RNA Biology 2022, 19: 176-190.

[20] Camacho-Conde JA, Gonzalez-Bermudez MDR, Carretero-Rey M, Khan ZU: Brain Stimulation: A Therapeutic Approach for the Treatment of Neurological Disorders. CNS Neuroscience & Therapeutics 2022, 28: 5-18.

[21] Vendrik KEW, Ooijevaar RE, de Jong PRC, Laman JD, van Oosten BW, van Hilten JJ, et al.: Fecal Microbiota Transplantation in Neurological Disorders. Frontiers in Cellular and Infection Microbiology 2020, 10: 98.

[22] Strawn JR, Mills JA, Poweleit EA, Ramsey LB, Croarkin PE: Adverse Effects of Antidepressant Medications and their Management in Children and Adolescents. Pharmacotherapy 2023, 43: 675-690.

[23] McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, et al.: Memantine for Dementia. The Cochrane Database of Systematic Reviews 2019, 3: CD003154.

[24] Pirker W, Katzenschlager R, Hallett M, Poewe W: Pharmacological Treatment of Tremor in Parkinson’s Disease Revisited. Journal of Parkinson’s Disease 2023, 13: 127-144.

[25] McFarland D, Merchant D, Khandai A, Mojtahedzadeh M, Ghosn O, Hirst J, et al.: Selective Serotonin Reuptake Inhibitor (SSRI) Bleeding Risk: Considerations for the Consult-Liaison Psychiatrist. Current Psychiatry Reports 2023, 25: 113-124.

[26] Chi X, Wang S, Baloch Z, Zhang H, Li X, Zhang Z, et al.: Research Progress on Classical Traditional Chinese Medicine Formula Lily Bulb and Rehmannia Decoction in the Treatment of Depression. Biomedicine & Pharmacotherapy 2019, 112: 108616.

[27] Pan J, Lu Y, Wang S, Ma T, Xue X, Zhang Z, et al.: Synergistic Neuroprotective Effects of Two Natural Medicinal Plants Against CORT-induced Nerve Cell Injury by Correcting Neurotransmitter Deficits and Inflammation Imbalance. Phytomedicine 2023, 121: 155102.

[28] Chi X, Xue X, Pan J, Wu J, Shi H, Wang Y, et al.: Mechanism of Lily Bulb and Rehmannia Decoction in the Treatment of Lipopolysaccharide-induced Depression-like Rats Based on Metabolomics Study and Network Pharmacology. Pharmaceutical Biology 2022, 60: 1850-1864.

[29] Zhang H, Xue X, Pan J, Song X, Chang X, Mao Q, et al.: Integrated Analysis of the Chemical-material Basis and Molecular Mechanisms for the Classic Herbal Formula of Lily Bulb and Rehmannia Decoction in Alleviating Depression. Chinese Medicine 2021, 16: 107.

[30] Mao Q, Zhang H, Zhang Z, Lu Y, Pan J, Guo D, et al.: Co-decoction of Lilii Bulbus and Radix Rehmannia Recens and Its Key Bioactive Ingredient Verbascoside Inhibit Neuroinflammation and Intestinal Permeability Associated with Chronic Stress-induced Depression via the Gut Microbiota-brain Axis. Phytomedicine 2024, 129: 155510.

[31] Zhou XD, Shi DD, Wang HN, Tan QR, Zhang ZJ: Aqueous Extract of Lily Bulb Ameliorates Menopause-like Behavior in Ovariectomized Mice with Novel Brain-uterus Mechanisms Distinct from Estrogen Therapy. Biomedicine & Pharmacotherapy 2019, 117: 109114.

[32] Zhou XD, Shi DD, Zhang ZJ: Ameliorative Effects of Radix Rehmanniae Extract on the Anxiety- and Depression-like Symptoms in Ovariectomized Mice: A Behavioral and Molecular Study. Phytomedicine 2019, 63: 153012.

[33] Jia J, Chen J, Wang G, Li M, Zheng Q, Li D: Progress of Research into the Pharmacological Effect and Clinical Application of the Traditional Chinese Medicine Rehmanniae Radix. Biomedicine & Pharmacotherapy 2023, 168: 115809.

[34] Wang Z, Wang X, Mou X, Wang C, Sun Y, Wang J: Rehmannia Glutinosa DC.- Lilium lancifolium Thunb. in the Treatment of Depression: A Comprehensive Review and Perspectives . Frontiers in Pharmacology 2024, 15: 1471307.

[35] Zhang B, Zhou N, Zhang Z, Wang R, Chen L, Zheng X, et al.: Study on the Neuroprotective Effects of Eight Iridoid Components Using Cell Metabolomics. Molecules 2024, 29: 1497.

[36] Wang RJ, Chen HM, Yang F, Deng Y, Ao H, Xie XF, et al.: Iridoids from the Roots of Valeriana jatamansi Jones . Phytochemistry 2017, 141: 156-161.

[37] Tan Y-Z, Yong Y, Dong Y-H, Wang R-J, Li H-X, Zhang H, et al.: A New Secoiridoid Glycoside and a New Sesquiterpenoid Glycoside from Valeriana jatamansi with Neuroprotective Activity. Phytochemistry Letters 2016, 17: 177-180.

[38] Dinda B, Dinda M, Kulsi G, Chakraborty A, Dinda S: Therapeutic Potentials of Plant Iridoids in Alzheimer’s and Parkinson’s Diseases: A Review. European Journal of Medicinal Chemistry 2019, 169: 185-199.

[39] Wang C, Gong X, Bo A, Zhang L, Zhang M, Zang E, et al.: Iridoids: Research Advances in Their Phytochemistry, Biological Activities, and Pharmacokinetics. Molecules 2020, 25: 287.

[40] Bhattamisra SK, Yap KH, Rao V, Choudhury H: Multiple Biological Effects of an Iridoid Glucoside, Catalpol, and Its Underlying Molecular Mechanisms. Biomolecules 2019, 10: 32.

[41] Kou Y, Li Z, Yang T, Shen X, Wang X, Li H, et al.: Therapeutic Potential of Plant Iridoids in Depression: A Review. Pharmaceutical Biology 2022, 60: 2167-2181.

[42] Chen H, Deng C, Meng Z, Meng S, Pan W: Effects of Catalpol on Alzheimer’s Disease and Its Mechanisms. Evidence-Based Complementary and Alternative Medicine 2022, 2022: 1-12.

[43] Jesulola E, Micalos P, Baguley IJ: Understanding the Pathophysiology of Depression: From Monoamines to the Neurogenesis Hypothesis Model - Are We There Yet? Behavioural Brain Research 2018, 341: 79-90.

[44] Duman RS, Aghajanian GK, Sanacora G, Krystal JH: Synaptic Plasticity and Depression: New Insights from Stress and Rapid-acting Antidepressants. Nature Medicine 2016, 22: 238-249.

[45] Wang Q, Timberlake II MA, Prall K, Dwivedi Y: The Recent Progress in Animal Models of Depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2017, 77: 99-109.

[46] Song J, Kim YK: Animal Models for the Study of Depressive Disorder. CNS Neuroscience & Therapeutics 2021, 27: 633-642.

[47] Wang J, Chen R, Liu C, Wu X, Zhang Y: Antidepressant Mechanism of Catalpol: Involvement of the PI3K/Akt/Nrf2/HO-1 Signaling Pathway in Rat Hippocampus. European Journal of Pharmacology 2021, 909: 174396.

[48] Wu X, Liu C, Wang J, Guan Y, Song L, Chen R, et al.: Catalpol Exerts Antidepressant-Like Effects by Enhancing Anti-oxidation and Neurotrophy and Inhibiting Neuroinflammation via Activation of HO-1. Neurochemical Research 2022, 47: 2975-2991.

[49] Wang J-M, Yang L-H, Zhang Y-Y, Niu C-L, Cui Y, Feng W-S, et al.: BDNF and COX-2 Participate in Anti-depressive Mechanisms of Catalpol in Rats Undergoing Chronic Unpredictable Mild Stress. Physiology & Behavior 2015, 151: 360-368.

[50] Liang X, Zhao Y, Xu T, Wang W, Sun W, Wang R: Catalpol Alleviates Depression by Inhibiting NLRP3 Inflammasome via TLR4/MAPK/NF-Kb Pathway. Iranian Journal of Public Health 2023, 52: 722-731.

[51] Wang Y-L, Wu H-R, Zhang S-S, Xiao H-L, Yu J, Ma Y-Y, et al.: Catalpol Ameliorates Depressive-like Behaviors in CUMS Mice via Oxidative Stress-mediated NLRP3 Inflammasome and Neuroinflammation. Translational Psychiatry 2021, 11: 353.

[52] Wu X, Liu C, Wang J, Zhang Y, Li Y, Wang Y, et al.: The Role of TrkB Signaling-mediated Synaptic Plasticity in the Antidepressant Properties of Catalpol, the Main Active Compound of Rehmannia Glutinosa Libosch. Journal of Ethnopharmacology 2024, 333: 118448.

[53] Wu X, Zhang Y, Wang J, Qin L, Li Y, He Q, et al.: Role of SIRT1-mediated Synaptic Plasticity and Neurogenesis: Sex-differences in Antidepresssant-like Efficacy of Catalpol. Phytomedicine 2024, 135: 156120.

[54] Song L, Wu X, Wang J, Guan Y, Zhang Y, Gong M, et al.: Antidepressant Effect of Catalpol on Corticosterone-induced Depressive-like Behavior Involves the Inhibition of HPA Axis Hyperactivity, Central Inflammation and Oxidative Damage Probably via Dual Regulation of NF-κB and Nrf2. Brain Research Bulletin 2021, 177: 81-91.

[55] Wu X, Wang J, Song L, Guan Y, Cao C, Cui Y, et al.: Catalpol Weakens Depressive-like Behavior in Mice with Streptozotocin-induced Hyperglycemia via PI3K/AKT/Nrf2/HO-1 Signaling Pathway. Neuroscience 2021, 473: 102-118.

[56] Li B, Zhou X, Zhen L, Zhang W, Lu J, Zhou J, et al.: Catapol Reduced the Cognitive and Mood Dysfunctions in Post-stroke Depression Mice via Promoting PI3K-mediated Adult Neurogenesis. Aging 2023, 15: 8433-8443.

[57] Wang J, Cui Y, Feng W, Zhang Y, Wang G, Wang X, et al.: Involvement of the Central Monoaminergic System in the Antidepressant-like Effect of Catalpol in Mice. BioScience Trends 2014, 8: 248-252.

[58] Guo N, Wang X, Xu M, Bai J, Yu H, Le Z: PI3K/AKT Signaling Pathway: Molecular Mechanisms and Therapeutic Potential in Depression. Pharmacological Research 2024, 206: 107300.

[59] Yang K, Cao F, Qiu S, Jiang W, Tao L, Zhu Y: Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway. Frontiers in Pharmacology 2022, 13: 829830.

[60] Zhou W, Hong J, Liu T, Li M, Jin H, Wang X, et al.: Polygonatum Polysaccharide Regulates Macrophage Polarization and Improves LPS-Induced Acute Lung Injury through TLR4-MAPK/NF-κB Pathway. Canadian Respiratory Journal 2022, 2022: 1-11.

[61] Wu X, Guan Y, Wang J, Song L, Zhang Y, Wang Y, et al.: Co-catalpol Alleviates Fluoxetine-Induced Main Toxicity: Involvement of ATF3/FSP1 Signaling-mediated Inhibition of Ferroptosis. Phytomedicine 2024, 126: 155340.

[62] Czeh B, Fuchs E, Wiborg O, Simon M: Animal Models of Major Depression and Their Clinical Implications. Progress in Neuro-psychopharmacology & Biological Psychiatry 2016, 64: 293-310.

[63] Lima S, Sousa N, Patricio P, Pinto L: The underestimated sex: A review on female animal models of depression. Neuroscience and Biobehavioral Reviews 2022, 133: 104498.

[64] Monteiro AR, Barbosa DJ, Remião F, Silva R: Alzheimer’s Disease: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Disease-modifying Drugs. Biochemical Pharmacology 2023, 211: 115522.

[65] Bai R, Guo J, Ye X-Y, Xie Y, Tian X: Oxidative Stress: The Core Pathogenesis and Mechanism of Alzheimer’s Disease. Ageing Research Reviews 2022, 77: 101619.

[66] Ionescu-Tucker A, Cotman CW: Emerging Roles of Oxidative Stress in Brain Aging and Alzheimer’s Disease. Neurobiology of Aging 2021, 107: 86-95.

[67] Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM: Alzheimer’s Disease: Targeting the Cholinergic System. Current Neuropharmacology 2016, 14: 101-115.

[68] Wang Z-H, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al.: Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer’s Disease. Cell Reports 2019, 28: 655-669.

[69] Liao J, Chen C, Ahn EH, Liu X, Li H, Edgington-Mitchell LE, et al.: Targeting Both BDNF/TrkB Pathway and Delta-secretase for Treating Alzheimer’s Disease. Neuropharmacology 2021, 197: 108737.

[70] Tai LM, Maldonado Weng J, LaDu MJ, Brady ST: Relevance of Transgenic Mouse Models for Alzheimer’s disease. Progress in Molecular Biology and Translational Science 2021, 177: 1-48.

[71] Zhong MZ, Peng T, Duarte ML, Wang M, Cai D: Updates on Mouse Models of Alzheimer’s Disease. Molecular Neurodegeneration 2024, 19: 23.

[72] Henry JD: Prospective Memory Impairment in Neurological Disorders: Implications and Management. Nature Reviews Neurology 2021, 17: 297-307.

[73] Zhang X, Jin C, Li Y, Guan S, Han F, Zhang S: Catalpol Improves Cholinergic Function and Reduces Inflammatory Cytokines in the Senescent Mice Induced by D-galactose. Food and Chemical Toxicology 2013, 58: 50-55.

[74] Wan D, Xue L, Zhu H, Luo Y: Catalpol Induces Neuroprotection and Prevents Memory Dysfunction through the Cholinergic System and BDNF. Evidence-Based Complementary and Alternative Medicine 2013, 2013: 1-9.

[75] Wang J-H, Xie H, Zhao T-K, Kang B: Catalpol Regulates Cholinergic Nerve System Function Through Effect on Choline Acetyl-transferase not M Receptor Affinity. Biomedicine & Pharmacotherapy 2015, 69: 291-296.

[76] Zhang X, Jiang B, Li Z, Hao S, An L: Catalpol Ameliorates Cognition Deficits and Attenuates Oxidative Damage in the Brain of Senescent Mice Induced by D-galactose. Pharmacology Biochemistry and Behavior 2007, 88: 64-72.

[77] Huang J-Z, Wu J, Xiang S, Sheng S, Jiang Y, Yang Z, et al.: Catalpol Preserves Neural Function and Attenuates the Pathology of Alzheimer’s Disease in Mice. Molecular Medicine Reports 2016, 13: 491-496.

[78] Zhou H, Liu J, Ren L, Liu W, Xing Q, Men L, et al.: Relationship with Spatial Memory in Diabetic Rats and Protein Kinase Cγ, Caveolin-1 in the Hippocampus and Neuroprotective Effect of Catalpol. Chinese Medical Journal 2014, 127: 916-923.

[79] Wang C-F, Li D-Q, Xue H-Y, Hu B: Oral Supplementation of Catalpol Ameliorates Diabetic Encephalopathy in Rats. Brain Research 2010, 1307: 158-165.

[80] Zhang X-L, An L-J, Bao Y-M, Wang J-Y, Jiang B: D-galactose Administration Induces Memory Loss and Energy Metabolism Disturbance in Mice: Protective Effects of Catalpol. Food and Chemical Toxicology 2008, 46: 2888-2894.

[81] Du J, Liu J, Huang X, Li Y, Song D, Li Q, et al.: Catalpol Ameliorates Neurotoxicity in N2a/APP695swe Cells and APP/PS1 Transgenic Mice. Neurotoxicity Research 2022, 40: 961-972.

[82] Tian L, Li H, Xiong W, Li X, Duan S, Yang C, et al.: Proteomic Alteration in Catalpol Treatment of Alzheimer’s Disease by Regulating HSPA5/GPX4. European Journal of Pharmacology 2025, 987: 177075.

[83] Zhang A, Hao S, Bi J, Bao Y, Zhang X, An L, et al.: Effects of Catalpol on Mitochondrial Function and Working Memory in Mice After Lipopolysaccharide-induced Acute Systemic Inflammation. Experimental and Toxicologic Pathology 2009, 61: 461-469.

[84] Hu W, Zou L, Yu N, Wu Z, Yang W, Wu T, et al.: Catalpol Rescues LPS-induced Cognitive Impairment via Inhibition of NF-Kb-regulated Neuroinflammation and Up-regulation of TrkB-mediated BDNF Secretion in Mice. Journal of Ethnopharmacology 2024, 319: 117345.

[85] Wang Z, Liu Q, Zhang R, Liu S, Xia Z, Hu Y: Catalpol Ameliorates Beta Amyloid-induced Degeneration of Cholinergic Neurons by Elevating Brain-derived Neurotrophic Factors. Neuroscience 2009, 163: 1363-1372.

[86] Xia Z, Zhang R, Wu P, Xia Z, Hu Y: Memory Defect Induced by Beta-amyloid Plus Glutamate Receptor Agonist is Alleviated by Catalpol and Donepezil Through Different Mechanisms. Brain Research 2012, 1441: 27-37.

[87] Liu J, He Q-J, Zou W, Wang H-X, Bao Y-M, Liu Y-X, et al.: Catalpol Increases Hippocampal Neuroplasticity and Up-regulates PKC and BDNF in the Aged Rats. Brain Research 2006, 1123: 68-79.

[88] Xia Z, Wang F, Zhou S, Zhang R, Wang F, Huang JH, et al.: Catalpol Protects Synaptic Proteins from Beta-amyloid Induced Neuron Injury and Improves Cognitive Functions in Aged Rats. Oncotarget 2017, 8: 69303-69315.

[89] Lin J, Deng L, Qi A, Jiang H, Xu D, Zheng Y, et al.: Catalpol Alleviates Hypoxia Ischemia-Induced Brain Damage by Inhibiting Ferroptosis Through the PI3K/NRF2/system Xc-/GPX4 Axis in Neonatal Rats. European Journal of Pharmacology 2024, 968: 176406.

[90] Delage CI, Šimončičová E, Tremblay M-È: Microglial Heterogeneity in Aging and Alzheimer’s Disease: Is Sex Relevant? Journal of Pharmacological Sciences 2021, 146: 169-181.

[91] Navakkode S, Gaunt JR, Pavon MV, Bansal VA, Abraham RP, Chong YS, et al.: Sex-Specific Accelerated Decay in Time/Activity-dependent Plasticity and Associative Memory in an Animal Model of Alzheimer’s Disease. Aging Cell 2021, 20: 13502.

[92] Shehjar F, Maktabi B, Rahman ZA, Bahader GA, James AW, Naqvi A, et al.: Stroke: Molecular Mechanisms and Therapies: Update on Recent Developments. Neurochemistry International 2023, 162: 105458.

[93] Qin C, Yang S, Chu Y-H, Zhang H, Pang X-W, Chen L, et al.: Signaling Pathways Involved in Ischemic Stroke: Molecular Mechanisms and Therapeutic Interventions. Signal Transduction and Targeted Therapy 2022, 7: 215.

[94] Fang J, Wang Z, Miao CY: Angiogenesis After Ischemic Stroke. Acta Pharmacologica Sinica 2023, 44: 1305-1321.

[95] Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mărginean C, Istrate M, et al.: Vascular Endothelial Growth Factor (VEGF) - Key Factor in Normal and Pathological Angiogenesis. Romanian Journal of Morphology and Embryology 2018, 59: 455-467.

[96] Kumar A, Aakriti, Gupta V: A Review on Animal Models of Stroke: An Update. Brain Research Bulletin 2016, 122: 35-44.

[97] Sun S, Xu Y, Yu N, Zhang M, Wang J, Wan D, et al.: Catalpol Alleviates Ischemic Stroke Through Promoting Angiogenesis and Facilitating Proliferation and Differentiation of Neural Stem Cells via the VEGF-A/KDR Pathway. Molecular Neurobiology 2023, 60: 6227-6247.

[98] Wang H-J, Ran H-F, Yin Y, Xu X-G, Jiang B-X, Yu S-Q, et al.: Catalpol Improves Impaired Neurovascular Unit in Ischemic Stroke Rats via Enhancing VEGF-PI3K/AKT and VEGF-MEK1/2/ERK1/2 Signaling. Acta Pharmacologica Sinica 2021, 43: 1670-1685.

[99] Zhu H-F, Wan D, Luo Y, Zhou J-L, Chen L, Xu X-Y: Catalpol Increases Brain Angiogenesis and Up-Regulates VEGF and EPO in the Rat after Permanent Middle Cerebral Artery Occlusion. International Journal of Biological Sciences 2010, 6: 443-453.

[100] Zhang MF, Wang JH, Sun S, Xu YT, Wan D, Feng S, et al.: Catalpol Attenuates Ischemic Stroke by Promoting Neurogenesis and Angiogenesis via the SDF-1α/CXCR4 Pathway. Phytomedicine 2024, 128: 155362.

[101] Dong W, Xian Y, Yuan W, Huifeng Z, Tao W, Zhiqiang L, et al.: Catalpol Stimulates VEGF Production via the JAK2/STAT3 Pathway to Improve Angiogenesis in Rats’ Stroke Model. Journal of Ethnopharmacology 2016, 191: 169-179.

[102] Zhu H-F, Shao Y, Qin L, Wang J-H, Feng S, Jiang Y-B, et al.: Catalpol Enhances Neurogenesis And Inhibits Apoptosis Of New Neurons Via BDNF, But Not The BDNF/Trkb Pathway. Drug Design, Development and Therapy 2019, 13: 4145-4157.

[103] Wang J, Wan D, Wan G, Wang J, Zhang J, Zhu H: Catalpol Induces Cell Activity to Promote Axonal Regeneration via the PI3K/AKT/mTOR Pathway In Vivo and In Vitro Stroke Model. Annals of Translational Medicine 2019, 7: 756- 756.

[104] Liu K, Yao X, Gao J, Wang J, Qi J: A Study on the Mechanism of Beclin-1 m6A Modification Mediated by Catalpol in Protection Against Neuronal Injury and Autophagy Following Cerebral Ischemia. Molecular Medicine 2024, 30: 65.

[105] Xie S, Zhi Y, Zeng B: Protective Effects of Catalpol on Limb Motor Function and Ultrastructure of Hippocampal Neurons in Rats with Cerebral Ischemia. Molecular Biotechnology 2021, 64: 213-219.

[106] Wang J, Zhang Y, Zhang M, Sun S, Zhong Y, Han L, et al.: Feasibility of Catalpol Intranasal Administration and Its Protective Effect on Acute Cerebral Ischemia in Rats via Anti-Oxidative and Anti-Apoptotic Mechanisms. Drug Design, Development and Therapy 2022, 16: 279-296.

[107] Wang J, Zhang M, Sun S, Wan G, Wan D, Feng S, et al.: Network Pharmacology-Based Prediction of Catalpol and Mechanisms Against Stroke. Evidence-Based Complementary and Alternative Medicine 2021, 2021: 1-14.

[108] Li D-Q, Bao Y-M, Li Y, Wang C-F, Liu Y, An L-J: Catalpol Modulates the Expressions of Bcl-2 and Bax and Attenuates Apoptosis in Gerbils after Ischemic Injury. Brain Research 2006, 1115: 179-185.

[109] Liu Y-R, Li P-W, Suo J-J, Sun Y, Zhang B-A, Lu H, et al.: Catalpol Provides Protective Effects Against Cerebral Ischaemia/Reperfusion Injury in Gerbils. Journal of Pharmacy and Pharmacology 2014, 66: 1265-1270.

[110] Liu Y-R, Lei R-Y, Wang C-E, Zhang B-A, Lu H, Zhu H-C, et al.: Effects of Catalpol on ATPase and Amino Acids in Gerbils with Cerebral Ischemiareperfusion Injury. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2014, 35: 1229-1233.

[111] Li D-Q, Li Y, Liu Y, Bao Y-M, Hu B, An L-J: Catalpol Prevents the Loss of CA1 Hippocampal Neurons and Reduces Working Errors in Gerbils After Ischemia-reperfusion Injury. Toxicon 2005, 46: 845-851.

[112] Haast RAM, Gustafson DR, Kiliaan AJ: Sex Differences in Stroke. Journal of Cerebral Blood Flow & Metabolism 2012, 32: 2100-2107.

[113] Ahnstedt H, McCullough LD, Cipolla MJ: The Importance of Considering Sex Differences in Translational Stroke Research. Translational Stroke Research 2016, 7: 261-273.

[114] Zhang H, Lin S, Chen X, Gu L, Zhu X, Zhang Y, et al.: The Effect of Age, Sex and Strains on the Performance and Outcome in Animal Models of Stroke. Neurochemistry International 2019, 127: 2-11.

[115] Matur AV, Candelario-Jalil E, Paul S, Karamyan VT, Lee JD, Pennypacker K, et al.: Translating Animal Models of Ischemic Stroke to the Human Condition. Translational Stroke Research 2022, 14: 842-853.

[116] Pajares M, I Rojo A, Manda G, Boscá L, Cuadrado A: Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells 2020, 9: 1687.

[117] Gopinath A, Mackie P, Hashimi B, Buchanan AM, Smith AR, Bouchard R, et al.: DAT and TH Expression Marks Human Parkinson’s Disease in Peripheral Immune Cells. NPJ Parkinson’s Disease 2022, 8: 72.

[118] Dovonou A, Bolduc C, Soto Linan V, Gora C, Peralta Iii MR, Lévesque M: Animal Models of Parkinson’s Disease: Bridging the Gap Between Disease Hallmarks and Research Questions. Translational Neurodegeneration 2023, 12: 36.

[119] Lal R, Singh A, Watts S, Chopra K: Experimental Models of Parkinson’s Disease: Challenges and Opportunities. European Journal of Pharmacology 2024, 980: 176819.

[120] Mustapha M, Mat Taib CN: MPTP-induced Mouse Model of Parkinson’s Disease: A Promising Direction of Therapeutic Strategies. Bosnian Journal of Basic Medical Sciences 2020, 21: 422-433.

[121] Cerri S, Mus L, Blandini F: Parkinson’s Disease in Women and Men: What’s the Difference? Journal of Parkinson’s Disease 2019, 9: 501-515.

[122] Jiang B, Zhang H, Bi J, Zhang XL: Neuroprotective Activities of Catalpol on MPP+/MPTP-Induced Neurotoxicity. Neurological Research 2013, 30: 639-644.

[123] Xu G, Xiong Z, Yong Y, Wang Z, Ke Z, Xia Z, et al.: Catalpol Attenuates MPTP Induced Neuronal Degeneration of Nigral-striatal Dopaminergic Pathway in Mice Through Elevating Glial Cell Derived Neurotrophic Factor in Striatum. Neuroscience 2010, 167: 174-184.

[124] Raza C, Anjum R, Shakeel NUA: Parkinson’s Disease: Mechanisms, Translational Models and Management Strategies. Life Sciences 2019, 226: 77-90.

[125] Choi WS, Palmiter RD, Xia Z: Loss of Mitochondrial Complex I Activity Potentiates Dopamine Neuron Death Induced by Microtubule Dysfunction in a Parkinson’s Disease Model. The Journal of Cell Biology 2011, 192: 873-882.

[126] Wang L-Y, Yu X, Li X-X, Zhao Y-N, Wang C-Y, Wang Z-Y, et al.: Catalpol Exerts a Neuroprotective Effect in the MPTP Mouse Model of Parkinson’s Disease. Frontiers in Aging Neuroscience 2019, 11: 316.

[127] Dobson R, Giovannoni G: Multiple Sclerosis - A Review. European Journal of Neurology 2019, 26: 27-40.

[128] Correale J, Gaitán MI, Ysrraelit MC, Fiol MP: Progressive Multiple Sclerosis: From Pathogenic Mechanisms to Treatment. Brain 2017, 140: 527-546.

[129] Muñoz-Jurado A, Escribano BM, Túnez I: Animal Model of Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis. Methods in Cell Biology 2024, 188: 35-60.

[130] Zeydan B, Rangachari M, Kantarci OH: Editorial: Understanding Sex-specific Issues in MS and Its Animal Models: Natural History, Management and Mechanisms. Frontiers in Neurology 2024, 15: 1366126.

[131] McCombe PA, Greer JM: Effects of Biological Sex and Pregnancy in Experimental Autoimmune Encephalomyelitis: It’s Complicated. Frontiers in Immunology 2022, 13: 1059833.

[132] Ryan L, Mills KHG: Sex Differences Regulate Immune Responses in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. European Journal of Immunology 2021, 52: 24-33.

[133] Ramien C, Taenzer A, Lupu A, Heckmann N, Engler JB, Patas K, et al.: Sex Effects on Inflammatory and Neurodegenerative Processes in Multiple Sclerosis. Neuroscience & Biobehavioral Reviews 2016, 67: 137-146.

[134] Umair M, Fazazi MR, Rangachari M: Biological Sex As a Critical Variable in CD4⁺ Effector T Cell Function in Preclinical Models of Multiple Sclerosis . Antioxidants & Redox Signaling 2022, 37: 135-149.

[135] Wu M, Kang Q, Kang Y, Tong Y, Yang T, Fan Y, et al.: Catalpol Regulates Oligodendrocyte Regeneration and Remyelination by Activating the GEF-Cdc42/Rac1 Signaling Pathway in EAE Mice. Evidence-Based Complementary and Alternative Medicine 2022, 2022: 7074157.

[136] Li Q, Yang T, Guo A-C, Fan Y-P: Role of Catalpol in Ameliorating the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Increasing the Level of Noradrenaline in the Locus Coeruleus. Molecular Medicine Reports 2018, 17: 4163-4172.

[137] Xu D-Q, Zhao L, Li S-J, Huang X-F, Li C-J, Sun L-X, et al.: Catalpol Counteracts the Pathology in a Mouse Model of Duchenne Muscular Dystrophy by Inhibiting the TGF-β1/TAK1 Signaling Pathway. Acta Pharmacologica Sinica 2020, 42: 1080-1089.

[138] Lim KRQ, Nguyen Q, Dzierlega K, Huang Y, Yokota T: CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy. Genes 2020, 11: 342.

[139] McGreevy JW, Hakim CH, McIntosh MA, Duan D: Animal Models of Duchenne Muscular Dystrophy: From Basic Mechanisms to Gene Therapy. Disease Models & Mechanisms 2015, 8: 195-213.

[140] Xu D, Zhao L, Jiang J, Li S, Sun Z, Huang X, et al.: A Potential Therapeutic Effect of Catalpol in Duchenne Muscular Dystrophy Revealed by Binding with TAK1. Journal of Cachexia, Sarcopenia and Muscle 2020, 11: 1306-1320.

[141] Kim M, Acharya S, Botanas CJ, Custodio RJ, Lee HJ, Sayson LV, et al.: Catalpol and Mannitol, Two Components of Rehmannia Glutinosa, Exhibit Anticonvulsant Effects Probably via GABAA Receptor Regulation. Biomolecules & Therapeutics 2020, 28: 137-144.

[142] Gao J, An L, Xu Y, Huang Y: Catalpol Exerts an Anti-Epilepticus Effect, Possibly by Regulating the Nrf2-Keap1-ARE Signaling Pathway. Medical Science Monitor 2018, 24: 9436-9441.

[143] Löscher W: Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochemical Research 2017, 42: 1873-1888.

[144] Reddy DS: The Neuroendocrine Basis of Sex Differences in Epilepsy. Pharmacology Biochemistry and Behavior 2017, 152: 97-104.

[145] Khellaf A, Khan DZ, Helmy A: Recent Advances in Traumatic Brain Injury. Journal of Neurology 2019, 266: 2878-2889.

[146] Abdul-Muneer PM, Chandra N, Haorah J: Interactions of Oxidative Stress and Neurovascular Inflammation in the Pathogenesis of Traumatic Brain Injury. Molecular Neurobiology 2015, 51: 966-979.

[147] Rubin TG, Lipton ML: Sex Differences in Animal Models of Traumatic Brain Injury. Journal of Experimental Neuroscience 2019, 13: 1179069519844020.

[148] Ni H, Rui Q, Kan X, Gao R, Zhang L, Zhang B: Catalpol Ameliorates Oxidative Stress and Neuroinflammation after Traumatic Brain Injury in Rats. Neurochemical Research 2022, 48: 681-695.

[149] Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E: The Neuropathic Pain: An Overview of the Current Treatment and Future Therapeutic Approaches. International Journal of Immunopathology and Pharmacology 2019, 33: 2058738419838383.

[150] Guida F, De Gregorio D, Palazzo E, Ricciardi F, Boccella S, Belardo C, et al.: Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain. International Journal of Molecular Sciences 2020, 21: 3396.

[151] Mogil JS, Parisien M, Esfahani SJ, Diatchenko L: Sex Differences in Mechanisms of Pain Hypersensitivity. Neuroscience & Biobehavioral Reviews 2024, 163: 105749.

[152] Wang Y, Zhang R, Xie J, Lu J, Yue Z: Analgesic Activity of Catalpol in Rodent Models of Neuropathic Pain, and Its Spinal Mechanism. Cell Biochemistry and Biophysics 2014, 70: 1565-1571.

[153] Regan SL, Williams MT, Vorhees CV: Review of Rodent Models of Attention Deficit Hyperactivity Disorder. Neuroscience & Biobehavioral Reviews 2022, 132: 621-637.

[154] Jung DH, Lee HJ, Choi YW, Shin HK, Choi BT: Sex-specific Responses to Juvenile Stress on the Dopaminergic System in an Animal Model of Attention-deficit Hyperactivity Disorder. Biomedicine & Pharmacotherapy 2023, 160: 114352.

[155] Yuan H, Ni X, Zheng M, Han X, Song Y, Yu M: Effect of Catalpol on Behavior and Neurodevelopment in an ADHD Rat Model. Biomedicine & Pharmacotherapy 2019, 118: 109033.

[156] Richter-Levin G, Stork O, Schmidt MV: Animal Models of PTSD: A Challenge to be Met. Molecular Psychiatry 2018, 24: 1135-1156.

[157] Shansky RM: Sex Differences in PTSD Resilience and Susceptibility: Challenges for Animal Models of Fear Learning. Neurobiology of Stress 2015, 1: 60-65.

[158] Jowf GIA, Ahmed ZT, Reijnders RA, Nijs LD, Eijssen LMT: To Predict, Prevent, and Manage Post-Traumatic Stress Disorder (PTSD): A Review of Pathophysiogy, Treatment, and Biomarkers. International Journal of Molecular Sciences 2023, 24: 5238.

[159] Sun L, Zhang W, Ye R, Liu L, Jiang L, Xi C: Catalpol Enhanced Physical Exercise-Mediated Brain Functional Improvement in Post-traumatic Stress Disorder Model via Promoting Adult Hippocampal Neurogenesis. Aging 2021, 13: 18689-18700.

[160] Xiang C, Lu Y, Hao R, Wei Y, Hu Y, Yu G: Catalpol Alleviates Amyloid- Generation and Neuronal Oxidative Stress Injury via Activating the Keap1-Nrf2/ARE Signaling Pathway in the Immortalized Lymphocytes from Patients with Late-onset Alzheimer’s Disease and SKNMC Cells Co-culture Model. Iranian Journal of Basic Medical Sciences 2024, 27: 1547-1557.

[161] Zhang H, Wu ZM, Yang YP, Shaukat A, Yang J, Guo YF, et al.: Catalpol Ameliorates LPS-Induced Endometritis by Inhibiting Inflammation and TLR4/NF-kappaB Signaling. Journal of Zhejiang University Science B 2019, 20: 816-827.

[162] She Y, Shao CY, Liu YF, Huang Y, Yang J, Wan HT: Catalpol Reduced LPS Induced BV2 Immunoreactivity Through NF-kappaB/NLRP3 Pathways: An In Vitro and In Silico Study. Frontiers in Pharmacology 2024, 15: 1415445.

[163] Hu L, Sun Y, Hu J: Catalpol Inhibits Apoptosis in Hydrogen Peroxide-induced Endothelium by Activating the PI3K/Akt Signaling Pathway and Modulating Expression of Bcl-2 and Bax. European Journal of Pharmacology 2010, 628: 155-163.

[164] Chen W, Li X, Jia LQ, Wang J, Zhang L, Hou D, et al.: Neuroprotective Activities of Catalpol Against CaMKII-dependent Apoptosis Induced by LPS in PC12 Cells. British Journal of Pharmacology 2013, 169: 1140-1152.

[165] Yang C, Shi Z, You L, Du Y, Ni J, Yan D: Neuroprotective Effect of Catalpol via Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Mechanisms. Frontiers in Pharmacology 2020, 11: 690.

[166] Lu R, Gu Y, Si D, Liu C: Quantitation of Catalpol in Rat Plasma by Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry and Its Pharmacokinetic Study. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2009, 877: 3589-3594.

[167] Wu L-n, Lu R, Gu Y, Liu C-x, Si D-y: Pharmacokinetics and Bioavalibability of Catalpol in Rats. Chinese Journal of Clinical Pharmacology and Therapeutics 2012, 17: 126-130.

[168] Ge X, Zheng Y, He Y, Chen C, Yang C, Lu S, et al.: Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [³H]Catalpol in Rats: The Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke . Current Drug Metabolism 2023, 24: 448-457.

[169] Wang Q, Xing M, Chen W, Zhang J, Qi H, Xu X: HPLC-APCI-MS/MS Method for the Determination of Catalpol in Rat Plasma and Cerebrospinal Fluid: Application to an In Vivo Pharmacokinetic Study. Journal of Pharmaceutical and Biomedical Analysis 2012, 70: 337-343.

[170] Feng Y, Liu Z, Peng Y, Zhang L, Ju P, Bi K, et al.: Validated LC-MS Method for Simultaneous Quantitation of Catalpol and Harpagide in Rat Plasma: Application to a Comparative Pharmacokinetic Study in Normal and Diabetic Rats After Oral Administration of Zeng-Ye-Decoction. Biomedical Chromatography 2013, 27: 1503-1510.

[171] Zhao M, Qian D, Liu P, Shang EX, Jiang S, Guo J, et al.: Comparative Pharmacokinetics of Catalpol and Acteoside in Normal and Chronic Kidney Disease Rats After Oral Administration of Rehmannia Glutinosa Extract. Biomedical Chromatography 2015, 29: 1842-1848.

[172] Peng L, Zhang XF, Guo DY, Zhai BT, Liang YJ, Chen ZZ, et al.: Evaluation of the Clinical Efficacy of the Classic Prescription “Baihe Dihuang Decoction” Based on Meta-Analysis. Evidence-based Complementary and Alternative Medicine: eCAM 2022, 2022: 8559176.

[173] Tian JS, Meng Y, Wu YF, Zhao L, Xiang H, Jia JP, et al.: A Novel Insight into the Underlying Mechanism of Baihe Dihuang Tang Improving the State of Psychological Suboptimal Health Subjects Obtained from Plasma Metabolic Profiles and Network Analysis. Journal of Pharmaceutical and Biomedical Analysis 2019, 169: 99-110.

[174] Fei B, Dai W, Zhao S: Efficacy, Safety, and Cost of Therapy of the Traditional Chinese Medicine, Catalpol, in Patients Following Surgical Resection for Locally Advanced Colon Cancer. Medical Science Monitor 2018, 24: 3184-3192.

[175] Dong W, Xu J, Chen L: Separation and Identification of Catalpol from Rehmannia and its Acute Toxicity Test. Journal of Fudan University (Natural Science) 2009, 48: 3.

[176] Jiang T, Zhang A, Zhao R, Jiang B: Protective Effect of Catalpol in Mice Injuries Induced by Rotenone and Evaluation of the Safety of Catalpol. Progress in Modern Biomedicine 2008, 8: 1039-1045.