A review: Research progress on multi-target neuroprotective effects of n-butylphthalide extracted from Apium graveolens seeds

Abstract

Apium graveolens, an annual herb belonging to the family of Apiaceae, is widely distributed in North and South America, Southern Europe, Africa and Asia. Apium graveolens seeds have a rich history in traditional Chinese medicine for treating hypertension, headaches, vertigo and epilepsy. N-butylphthalide, originally extracted from Apium graveolens seeds, represents a first-in-class drug developed independently in China. Its broad pharmacological activities on nervous system disorders have garnered significant attention from researchers globally. This review focuses on the pharmacological research of n-butylphthalide on central nervous system diseases, including ischemic stroke, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. The purpose is to pave the way for future study on the mechanistic targets of n-butylphthalide.

Keywords

Apium graveolens seeds / n-butylphthalide / central nervous system diseases

References

[1] Jin T, Gu JC, Li ZS, et al. Recent Advances on Extracellular Vesicles in Central Nervous System Diseases. Clin Interv Aging, 2021, 16: 257-274.

[2] Stam CJ. Modern network science of neurological disorders. Nat Rev Neurosci, 2014, 15: 683-695.

[3] Wang YQ, Jia RX, Liang JH, et al. Dementia in China (2015-2050) estimated using the 1% population sampling survey in 2015. Geriatr Gerontol Int, 2019, 19: 1096-1100.

[4] Scarian E, Viola C, Dragoni F, et al. New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases. Int J Mol Sci, 2024, 25: 2698.

[5] Fornari Laurindo L, Aparecido Dias J, Cressoni Araújo A, et al. Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression. Front Immunol, 2024, 14: 1305933.

[6] Tripathi K, Ben-Shachar D. Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation. Cells, 2024, 13: 410.

[7] Yang JH, Du CC, Li YH, et al. Contrasting Iron Metabolism in Undifferentiated Versus Differentiated MO3.13 Oligodendrocytes via IL-1β-Induced Iron Regulatory Protein 1. Neurochem Res, 2024, 49: 466-476.

[8] Tian J, Du E, Guo L. Mitochondrial Interaction with Serotonin in Neurobiology and Its Implication in Alzheimer’s Disease. J Alzheimers Dis Rep, 2023, 7: 1165-1177.

[9] Wang JN, Dai LJ, Deng M, et al. SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy. Mol Neurobiol, 2023, 61: 2446-2458.

[10] Kvistad CE, Kråkenes T, Gavasso S, et al. Neural regeneration in the human central nervous system—from understanding the underlying mechanisms to developing treatments. Where do we stand today? Front Neurol, 2024, 15: 1398089.

[11] Zhan GL, Wei L, Peng JW. Chemical Composition and Ability of Scavenging DPPH Radical of Essential Oil and Residue from the Celery Seed. Adv Mater Res, 2011, 1154: 18-21.

[12] Shayani Rad M, Moohebati M, MohammadEbrahimi S, et al. Safety evaluation and biochemical efficacy of celery seed extract (Apium Graveolens) capsules in hypertensive patients: a randomized, triple- blind, placebo-controlled, cross-over, clinical trial. Inflammopharmacology, 2022, 30: 1669-1684.

[13] Tan SW, Xie T, Malik TH, et al. Advances of neurovascular protective potential of 3-N-butylphthalide and its derivatives in diabetic related diseases. J Diabetes Complications, 2022, 36: 108335.

[14] Xiao HY, Yang SX, Han W, et al. Research progress on pharmacology of butylphthalide and its derivatives. Zhongguo Zhongyao Zazhi, 2022, 47: 3425-3431.

[15] Chen XQ, Qiu K, Liu H, et al. Application and prospects of butylphthalide for the treatment of neurologic diseases. Chin Med, 2019, 132: 1467-1477.

[16] Correction to: Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation, 2017, 136: e196.

[17] Chapman SN, Mehndiratta P, Johansen M, et al. Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke. Vasc Health Risk Manag, 2014, 2014: 75-87.

[18] Yang H, Xu S, Li J, et al. Potassium 2-(1-hydroxypentyl)-benzoate inhibits ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathways. Naunyn Schmiedebergs Arch Pharmacol, 2015, 388: 983-990.

[19] Zhang C, Cui LL, He WL, et al. Dl-3-n-butylphthalide promotes neurite outgrowth of primary cortical neurons by Sonic Hedgehog signaling via upregulating Gap43. Exp Cell Res, 2021, 398: 112420.

[20] Huang SS, Zhou B, Zeng GX, et al. Neuroprotective effect and mechanism of butylphthalide after cerebral ischemia-reperfusion injury in rats. Folia Neuropathol, 2021, 59: 131-142.

[21] Lu JD, Sun ML, Li P, et al. Butylphthalide protects against ischemia-reperfusion injury in rats via reducing neuron ferroptosis and oxidative stress. J Investig Med, 2023, 71: 623-633.

[22] Gao YR, Hu M, Niu XL, et al. Dl-3-n-Butylphthalide Improves Neuroinflammation in Mice with Repeated Cerebral Ischemia-Reperfusion Injury through the Nrf2- Mediated Antioxidant Response and TLR4/MyD88/NF- κB Signaling Pathway. Oxid Med Cell Longev, 2022, 2022: 8652741.

[23] Dong GX, Feng YP. Effects of NBP on ATPase and anti- oxidant enzymes activities and lipid peroxidation in transient focal cerebral ischemic rats. Zhongguo Yixue Kexueyuan Xuebao, 2002, 24: 93-97.

[24] Jia JJ, Deng JW, Jin H, et al. Effect of Dl-3-n-butylphthalide on mitochondrial Cox7c in models of cerebral ischemia/reperfusion injury. Front Pharmacol, 2023, 14: 1084564.

[25] Fang MC, Yuan JH, Jiang SH, et al. Dl -3- n - butylphthalide attenuates hypoxic-ischemic brain injury through inhibiting endoplasmic reticulum stress-induced cell apoptosis and alleviating blood-brain barrier disruption in newborn rats. Brain Res, 2020, 1747: 147046.

[26] Li JM, Li Y, Ogle M, et al. DL-3-n-butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathway. Brain Res, 2010, 1359: 216-226.

[27] Abyadeh M, Gupta V, Paulo JA, et al. Amyloid-beta and tau protein beyond Alzheimer’s disease. Neural regen res, 2024, 19: 1262-1276.

[28] Abdallah AE. Review on anti-alzheimer drug development: approaches, challenges and perspectives. RSC Adv, 2024, 14: 11057-11088.

[29] Lu J, Zhang JW, Wang XZ, et al. Dl-3-n-butylphthalide promotes microglial phagocytosis and inhibits microglial inflammation via regulating AGE-RAGE pathway in APP/PS1 mice. Brain Res Bull, 2024, 212: 110969.

[30] Chang YM, Yao Y, Ma R, et al. Dl-3-n-Butylphthalide Reduces Cognitive Deficits and A lleviates Neuropathology in P301S Tau Transgenic Mice. Front Neurosci, 2021, 15: 620176.

[31] Wang F, Chen H, Sun XJ, et al. Improvement of cognitive deficits in SAMP8 mice by 3-n-butylphthalide. Neurol Res, 2014, 36: 224-233.

[32] Ma SP, Xu SF, Liu B, et al. Long-term treatment of l-3- n-butylphthalide attenuated neurodegenerative changes in aged rats. Naunyn Schmiedebergs Arch Pharmacol, 2009, 379: 565-574.

[33] Peng Y, Xing C, Xu S, et al. L-3-n-butylphthalide im proves cogni ti ve i mpai rm ent induc ed by intracerebroventricular infusion of amyloid-beta peptide in rats. Eur J Pharmacol, 2009, 621: 38-45.

[34] Zhao Y, Yang WQ, Yu L, et al. Dl-3-n-butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal-enriched protein tyrosine phosphatase/ERK/ cAMP-response element-binding protein signaling pathway. Exp Ther Med, 2022, 23: 319.

[35] Lv C, Ma QY, Han B, et al. Long-Term DL-3-n- Butylphthalide Treatment Alleviates Cognitive Impairment Correlate With Improving Synaptic Plasticity in SAMP8 Mice. Front Aging Neurosci, 2018, 10: 200.

[36] Huang LJ, Wang S, Ma F, et al. From stroke to neuro- degenerative diseases: The multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives. Pharmacol Res, 2018, 135: 201-211.

[37] Peng Y, Hu Y, Xu S, et al. L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer’s transgenic mice. J Alzheimers Dis, 2012, 29: 379-391.

[38] Peng Y, Sun J, Hon S, et al. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid- beta in a transgenic model of Alzheimer’s disease. J Neurosci, 2010, 30: 8180-8189.

[39] Lei H, Zhang Y, Huang LJ, et al. L-3-n-Butylphthalide Regulates Proliferation, Migration, and Differentiation of Neural Stem Cell In Vitro and Promotes Neurogenesis in APP/PS1 Mouse Model by Regulating BDNF/TrkB/ CREB/Akt Pathway. Neurotox Res, 2018, 34: 477-488.

[40] Yang LC, Li J, Xu SF, et al. L-3-n-butylphthalide Promotes Neurogenesis and Neuroplasticity in Cerebral Ischemic Rats. CNS Neurosci Ther, 2015, 21: 733-741.

[41] Ali NH, Al-Kuraishy HM, Al-Gareeb Al, et al. BDNF/TrkB activators in Parkinson’s disease: A new therapeutic strategy. J Cell Mol Med, 2024, 28: e18368.

[42] Wang TT, Liu C, Zhang L, et al. Clinical effects of Madopar with pramipexole in the treatment of Parkinson’s disease. Asian J Surg, 2024, 47: 3780-3781.

[43] Nakaso K. Roles of Microglia in Neurodegenerative Diseases. Yonago Acta Med, 2024, 67: 1-8.

[44] Luo R, Zhu LH, Zeng ZH, et al. Dl-butylphthalide inhibits rotenone-induced oxidative stress in microglia via regulation of the Keap1/Nrf2/HO-1 signaling pathway. Exp Ther Med, 2021, 21: 597.

[45] Zhang L, Tang Y, Huang P, et al. Role of NLRP 3 inflammasome in central nervous system diseases. Cell Biosci, 2024, 14: 75.

[46] Que RF, Zheng JL, Chang ZH, et al. Dl -3- n - Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP 3 Inflammasome and Ameliorating Mitochondrial Impairment. Front Immunol, 2021, 12: 794770.

[47] Nguyen L. Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis. Cells, 2024, 13: 888.

[48] Arnold FJ, Putka AF, Raychaudhuri U, et al. Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration. Int J Mol Sci, 2024, 25: 5587.

[49] Feng XH, Peng Y, Liu MS, et al. DL-3-n-butylphthalide extends survival by attenuating glial activation in a mouse model of amyotrophic lateral sclerosis. Neuropharmacology, 2012, 62: 1004-1010.