Current Pharmaceutical BiotechnologyCurrent Pharmaceutical BiotechnologyCurrent Pharmaceutical Biotechnology1389-20101873-4316Bentham Science64451710.2174/0113892010277933231122111244BiotechnologyResearch ArticleTherapeutic Potential of Capsaicin in Various Neurodegenerative Diseases with Special Focus on Nrf2 SignalingVarshneyVibhavinfo@benthamscience.netKumarAbhishekinfo@benthamscience.netParasharVikasinfo@benthamscience.netKumarAnkitinfo@benthamscience.netGoyalAhsasinfo@benthamscience.netGarabaduDebapriyainfo@benthamscience.netDepartment of Pharmacology, Institute of Pharmaceutical Research, GLA UniversityDepartment of Pharmacology, School of Health Sciences,, Central University of Punjab0107202425131693170707012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2010/article/view/644517

Neurodegenerative disease is mainly characterized by the accumulation of misfolded proteins, contributing to mitochondrial impairments, increased production of proinflammatory cytokines and reactive oxygen species, and neuroinflammation resulting in synaptic loss and neuronal loss. These pathophysiological factors are a serious concern in the treatment of neurodegenerative diseases. Based on the symptoms of various neurodegenerative diseases, different treatments are available, but they have serious side effects and fail in clinical trials, too. Therefore, treatments for neurodegenerative diseases are still a challenge at present. Thus, it is important to study an alternative option. Capsaicin is a naturally occurring alkaloid found in capsicum. Besides the TRPV1 receptor activator in nociception, capsaicin showed a protective effect in brain-related disorders. Capsaicin also reduces the aggregation of misfolded proteins, improves mitochondrial function, and decreases ROS generation. Its antioxidant role is due to increased expression of an nrf2-mediated signaling pathway. Nrf2 is a nuclear erythroid 2-related factor, a transcription factor, which has a crucial role in maintaining the normal function of mitochondria and the cellular defense system against oxidative stress. Intriguingly, Nrf2 mediated pathway improved the upregulation of antioxidant genes and inhibition of microglial-induced inflammation, improved mitochondrial resilience and functions, leading to decreased ROS in neurodegenerative conditions, suggesting that Nrf2 activation could be a better therapeutic approach to target pathophysiology of neurodegenerative disease. Therefore, the present review has evaluated the potential role of capsaicin as a pharmacological agent for the treatment and management of various neurodegenerative diseases via the Nrf2-mediated signaling pathway.

Capsaicinneurodegenerative diseasesNrf2oxidative stressParkinson&amprsquos diseaseAlzheimer&amprsquos disease.Mishra, A.; Mishra, P.S.; Bandopadhyay, R.; Khurana, N.; Angelopoulou, E.; Paudel, Y.N.; Piperi, C. Neuroprotective potential of chrysin: Mechanistic insights and therapeutic potential for neurological disorders. Molecules, 2021, 26(21), 6456. doi: 10.3390/molecules26216456 PMID: 34770864Armstrong, R. What causes neurodegenerative disease? Folia Neuropathol., 2020, 58(2), 93-112. doi: 10.5114/fn.2020.96707 PMID: 32729289Liu, Y.; Yu, C.; Zhang, X. Impaired long distance functional connectivity and weighted network architecture in Alzheimer’s disease. Cereb. Cortex, 2014, 24(6), 1422-1435. doi: 10.1093/cercor/bhs410Goyal, A.; Verma, A.; Dubey, N.; Raghav, J.; Agrawal, A. Naringenin: A prospective therapeutic agent for Alzheimer’s and Parkinson’s disease. J. Food Biochem., 2022, 46(12), e14415. doi: 10.1111/jfbc.14415 PMID: 36106706Prusiner, S.B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet., 2013, 47(1), 601-623. doi: 10.1146/annurev-genet-110711-155524 PMID: 24274755Walker, L.C.; Jucker, M. Neurodegenerative diseases: expanding the prion concept. Annu. Rev. Neurosci., 2015, 38(1), 87-103. doi: 10.1146/annurev-neuro-071714-033828 PMID: 25840008Watts, J.C.; Giles, K.; Oehler, A.; Middleton, L.; Dexter, D.T.; Gentleman, S.M.; DeArmond, S.J.; Prusiner, S.B. Transmission of multiple system atrophy prions to transgenic mice. Proc. Natl. Acad. Sci. USA, 2013, 110(48), 19555-19560. doi: 10.1073/pnas.1318268110 PMID: 24218576Cova, I.; Markova, A.; Campini, I.; Grande, G.; Mariani, C.; Pomati, S. Worldwide trends in the prevalence of dementia. J. Neurol. Sci., 2017, 379, 259-260. doi: 10.1016/j.jns.2017.06.030 PMID: 28716255Das, S.K.; Ray, B.K.; Paul, N.; Hazra, A.; Das, S.; Ghosal, M.K.; Misra, A.K.; Banerjee, T.K.; Chaudhuri, A. Prevalence, burden, and risk factors of migraine: A community-based study from Eastern India. Neurol. India, 2017, 65(6), 1280-1288. doi: 10.4103/0028-3886.217979 PMID: 29133701Bala, A.; Gupta, B.M. Parkinson′s disease in India: An analysis of publications output during 2002-2011. Int. J. Nutr. Pharmacol. Neurol. Dis., 2013, 3(3), 254. doi: 10.4103/2231-0738.114849Pandit, L.; Kundapur, R. Prevalence and patterns of demyelinating central nervous system disorders in urban Mangalore, South India. Mult. Scler., 2014, 20(12), 1651-1653. doi: 10.1177/1352458514521503 PMID: 24493471Jellinger, K.A. Basic mechanisms of neurodegeneration: A critical update. J. Cell. Mol. Med., 2010, 14(3), 457-487. doi: 10.1111/j.1582-4934.2010.01010.x PMID: 20070435Lamptey, R.N.L.; Chaulagain, B.; Trivedi, R.; Gothwal, A.; Layek, B.; Singh, J. A review of the common neurodegenerative disorders: Current therapeutic approaches and the potential role of nanotherapeutics. Int. J. Mol. Sci., 2022, 23(3), 1851. doi: 10.3390/ijms23031851 PMID: 35163773Obermeier, B.; Daneman, R.; Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med., 2013, 19(12), 1584-1596. doi: 10.1038/nm.3407 PMID: 24309662Mishra, A.; Bandopadhyay, R.; Singh, P.K.; Mishra, P.S.; Sharma, N.; Khurana, N. Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside. Metab. Brain Dis., 2021, 36(7), 1591-1626. doi: 10.1007/s11011-021-00806-4 PMID: 34387831Vasconcelos, A.R.; dos Santos, N.B.; Scavone, C.; Munhoz, C.D. Nrf2/ARE pathway modulation by dietary energy regulation in neurological disorders. Front. Pharmacol., 2019, 10, 33. doi: 10.3389/fphar.2019.00033 PMID: 30778297Stephenson, J.; Nutma, E.; van der Valk, P.; Amor, S. Inflammation in CNS neurodegenerative diseases. Immunology, 2018, 154(2), 204-219. doi: 10.1111/imm.12922 PMID: 29513402Moratilla-Rivera, I.; Sánchez, M.; Valdés-González, J.A.; Gómez-Serranillos, M.P. Natural products as modulators of Nrf2 signaling pathway in neuroprotection. Int. J. Mol. Sci., 2023, 24(4), 3748. doi: 10.3390/ijms24043748 PMID: 36835155Saha, S.; Buttari, B.; Profumo, E.; Tucci, P.; Saso, L. A perspective on nrf2 signaling pathway for neuroinflammation: A potential therapeutic target in Alzheimer’s and Parkinson’s diseases. Front. Cell. Neurosci., 2022, 15, 787258. doi: 10.3389/fncel.2021.787258 PMID: 35126058Dexter, D.T.; Carter, C.J.; Wells, F.R.; Javoy-Agid, F.; Agid, Y.; Lees, A.; Jenner, P.; Marsden, C.D. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J. Neurochem., 1989, 52(2), 381-389. doi: 10.1111/j.1471-4159.1989.tb09133.x PMID: 2911023Pedersen, W.A.; Fu, W.; Keller, J.N.; Markesbery, W.R.; Appel, S.; Smith, R.G.; Kasarskis, E.; Mattson, M.P. Protein modification by the lipid peroxidation product 4‐hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol., 1998, 44(5), 819-824. doi: 10.1002/ana.410440518 PMID: 9818940Selley, M.; Close, D.R.; Stern, S.E. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol. Aging, 2002, 23(3), 383-388. doi: 10.1016/S0197-4580(01)00327-X PMID: 11959400Arlt, S.; Beisiegel, U.; Kontush, A. Lipid peroxidation in neurodegeneration: New insights into Alzheimerʼs disease. Curr. Opin. Lipidol., 2002, 13(3), 289-294. doi: 10.1097/00041433-200206000-00009 PMID: 12045399Sayre, L.; Smith, M.; Perry, G. Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr. Med. Chem., 2001, 8(7), 721-738. doi: 10.2174/0929867013372922 PMID: 11375746Rauf, A.; Badoni, H.; Abu-Izneid, T.; Olatunde, A.; Rahman, M.M.; Painuli, S.; Semwal, P.; Wilairatana, P.; Mubarak, M.S. Neuroinflammatory markers: Key indicators in the pathology of neurodegenerative diseases. Molecules, 2022, 27(10), 3194. doi: 10.3390/molecules27103194 PMID: 35630670Dadhania, V.P.; Trivedi, P.P.; Vikram, A.; Tripathi, D.N. Nutraceuticals against neurodegeneration: A mechanistic insight. Curr. Neuropharmacol., 2016, 14(6), 627-640. doi: 10.2174/1570159X14666160104142223 PMID: 26725888Selvi, S.; Polat, R.; Çakilcioğlu, U.; Celep, F.; Dirmenci, T.; Ertuğ, Z.F. An ethnobotanical review on medicinal plants of the Lamiaceae family in Turkey. Turk. J. Bot., 2022, 46(4) doi: 10.55730/1300-008X.2712Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J.; Mattson, M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal., 2010, 13(11), 1763-1811. doi: 10.1089/ars.2009.3074 PMID: 20446769Mattson, M.P.; Son, T.G.; Camandola, S. Viewpoint: Mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose Response, 2007, 5(3), 174-186. doi: 10.2203/dose-response.07-004.Mattson PMID: 18648607Gezer, C. Stress response of dietary phytochemicals in a hormetic manner for health and longevity; Gene expression and regulation in mammalian cells - transcription toward the establishment of novel therapeutics. Gene expression and regulation in mammalian cells - transcription toward the establishment of novel therapeutics, 2018. doi: 10.5772/intechopen.71867Mattson, M.P.; Cheng, A. Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci., 2006, 29(11), 632-639.Koppula, S.; Kumar, H.; More, S.V.; Lim, H.W.; Hong, S.M.; Choi, D.K. Recent updates in redox regulation and free radical scavenging effects by herbal products in experimental models of Parkinson’s disease. Molecules, 2012, 17(10), 11391-11420. doi: 10.3390/molecules171011391 PMID: 23014498Van Kampen, J.M.; Baranowski, D.B.; Shaw, C.A.; Kay, D.G. Panax ginseng is neuroprotective in a novel progressive model of Parkinson’s disease. Exp. Gerontol., 2014, 50(1), 95-105. doi: 10.1016/j.exger.2013.11.012 PMID: 24316034Ríos, J.L.; Onteniente, M.; Picazo, D.; Montesinos, M.C. Medicinal plants and natural products as potential sources for antiparkinson drugs. Planta Med., 2016, 82(11/12), 942-951. doi: 10.1055/s-0042-107081 PMID: 27224274Bi, Y.; Qu, P.C.; Wang, Q.S.; Zheng, L.; Liu, H.L.; Luo, R.; Chen, X.Q.; Ba, Y.Y.; Wu, X.; Yang, H. Neuroprotective effects of alkaloids from Piper longum in a MPTP-induced mouse model of Parkinson’s disease. Pharm. Biol., 2015, 53(10), 1516-1524. doi: 10.3109/13880209.2014.991835 PMID: 25857256Sun, Y.; Yang, T.; Leak, R.K.; Chen, J.; Zhang, F. Preventive and protective roles of dietary Nrf2 activators against central nervous system diseases. CNS Neurol. Disord. Drug Targets, 2017, 16(3), 326-338. doi: 10.2174/1871527316666170102120211 PMID: 28042770Jadeja, R.N.; Upadhyay, K.K.; Devkar, R.V.; Khurana, S. Naturally occurring Nrf2 activators: Potential in treatment of liver injury. Oxid Med Cell Longev., 2016.Balos, M.M. Determination of weeds and their floristic investigation in vineyards in some districts of Şanlıurfa. Int J Nat Lif Sci, 2023, 7(2), 1-17.Çakılcıoğlu, U.; Türkoğlu, I. Plants used for hemorrhoid treatment in elaziǧ central district. Acta Hortic., 2009, 826(826), 89-96. doi: 10.17660/ActaHortic.2009.826.11Babbar, S.; Marier, J.F.; Mouksassi, M.S.; Beliveau, M.; Vanhove, G.F.; Chanda, S.; Bley, K. Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain. Ther. Drug Monit., 2009, 31(4), 502-510. doi: 10.1097/FTD.0b013e3181a8b200 PMID: 19494795Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J. Med. Res., 2010, 131, 682-691. PMID: 20516541Rollyson, W.D.; Stover, C.A.; Brown, K.C.; Perry, H.E.; Stevenson, C.D.; McNees, C.A.; Ball, J.G.; Valentovic, M.A.; Dasgupta, P. Bioavailability of capsaicin and its implications for drug delivery. J. Control. Release, 2014, 196, 96-105. doi: 10.1016/j.jconrel.2014.09.027 PMID: 25307998Chittepu, VCSR; Kalhotra, P Revilla, GIO Emerging Technologies to Improve Capsaicin Delivery and its Therapeutic Efficacy. Capsaicin and its Human Therapeutic Development InTech, 2018. doi: 10.5772/intechopen.77080Ran, F.; Yang, Y.; Yang, L. Capsaicin prevents contrast-associated acute kidney injury through activation of Nrf2 in mice. Oxid. Med. Cell. Longev., 2022, 2022, 1763922. doi: 10.1155/2022/1763922Hayes, J.D.; Dinkova-Kostova, A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci., 2014, 39(4), 199-218. doi: 10.1016/j.tibs.2014.02.002 PMID: 24647116Joung, E.J.; Li, M.H.; Lee, H.G. Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid. Redox Signal., 2007, 9(12), 2087-2098.Lv, Z.; Xu, X.; Sun, Z.; Yang, Y.X.; Guo, H.; Li, J.; Sun, K.; Wu, R.; Xu, J.; Jiang, Q.; Ikegawa, S.; Shi, D. TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca2+/CaMKII/Nrf2 signaling pathway. Cell Death Dis., 2021, 12(6), 504. doi: 10.1038/s41419-021-03792-8 PMID: 34006826Kwon, Y. Estimation of dietary capsaicinoid exposure in korea and assessment of its health effects. Nutrients, 2021, 13(7), 2461. doi: 10.3390/nu13072461 PMID: 34371974Díaz-Laviada, I.; Rodríguez-Henche, N. The potential antitumor effects of capsaicin. Prog. Drug Res., 2014, 68, 181-208. doi: 10.1007/978-3-0348-0828-6_8 PMID: 24941670Pasierski, M.; Szulczyk, B. Capsaicin inhibits sodium currents and epileptiform activity in prefrontal cortex pyramidal neurons. Neurochem. Int., 2020, 135, 104709. doi: 10.1016/j.neuint.2020.104709 PMID: 32105721Onizuka, S.; Yonaha, T.; Tamura, R.; Hosokawa, N.; Kawasaki, Y.; Kashiwada, M.; Shirasaka, T.; Tsuneyoshi, I. Capsaicin indirectly suppresses voltage-gated Na+ currents through TRPV1 in rat dorsal root ganglion neurons. Anesth. Analg., 2011, 112(3), 703-709. doi: 10.1213/ANE.0b013e318204ea5b PMID: 21156986Anand, P.; Bley, K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth., 2011, 107(4), 490-502. doi: 10.1093/bja/aer260 PMID: 21852280McCarty, M.F.; DiNicolantonio, J.J.; O’Keefe, J.H. Capsaicin may have important potential for promoting vascular and metabolic health: Table 1. Open Heart, 2015, 2(1), e000262. doi: 10.1136/openhrt-2015-000262 PMID: 26113985Xu, X.; Wang, P.; Zhao, Z.; Cao, T.; He, H.; Luo, Z.; Zhong, J.; Gao, F.; Zhu, Z.; Li, L.; Yan, Z.; Chen, J.; Ni, Y.; Liu, D.; Zhu, Z. Activation of transient receptor potential vanilloid 1 by dietary capsaicin delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Stroke, 2011, 42(11), 3245-3251. doi: 10.1161/STROKEAHA.111.618306 PMID: 21852608Liu, L.; Oortgiesen, M.; Li, L.; Simon, S.A. Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons. J. Neurophysiol., 2001, 85(2), 745-758. doi: 10.1152/jn.2001.85.2.745 PMID: 11160509Wang, C.; Huang, W.; Lu, J.; Chen, H.; Yu, Z. TRPV1-mediated microglial autophagy attenuates alzheimer’s disease-associated pathology and cognitive decline. Front. Pharmacol., 2022, 12, 763866. doi: 10.3389/fphar.2021.763866 PMID: 35115924Baek, J.; Jeong, J.; Kim, K.; Won, S.Y.; Chung, Y.; Nam, J.; Cho, E.; Ahn, T.B.; Bok, E.; Shin, W.H.; Jin, B. Inhibition of microglia-derived oxidative stress by ciliary neurotrophic factor protects dopamine neurons in vivo from MPP+ neurotoxicity. Int. J. Mol. Sci., 2018, 19(11), 3543. doi: 10.3390/ijms19113543 PMID: 30423807Jittiwat, J.; Suksamrarn, A.; Tocharus, C.; Tocharus, J. Dihydrocapsaicin effectively mitigates cerebral ischemia-induced pathological changes in vivo, partly via antioxidant and anti-apoptotic pathways. Life Sci., 2021, 283, 119842. doi: 10.1016/j.lfs.2021.119842 PMID: 34298038Xia, J.; Gu, L.; Guo, Y.; Feng, H.; Chen, S.; Jurat, J.; Fu, W.; Zhang, D. Gut microbiota mediates the preventive effects of dietary capsaicin against depression-like behavior induced by lipopolysaccharide in mice. Front. Cell. Infect. Microbiol., 2021, 11, 627608. doi: 10.3389/fcimb.2021.627608 PMID: 33987106Wang, J.; Sun, B.L.; Xiang, Y.; Tian, D.Y.; Zhu, C.; Li, W.W.; Liu, Y.H.; Bu, X.L.; Shen, L.L.; Jin, W.S.; Wang, Z.; Zeng, G.H.; Xu, W.; Chen, L.Y.; Chen, X.W.; Hu, Z.; Zhu, Z.M.; Song, W.; Zhou, H.D.; Yu, J.T.; Wang, Y.J. Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice. Transl. Psychiatry, 2020, 10(1), 230. doi: 10.1038/s41398-020-00918-y PMID: 32661266Du, Y.; Fu, M.; Huang, Z.; Tian, X.; Li, J.; Pang, Y.; Song, W.; Tian Wang, Y. Dong, Z. TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease. Aging Cell, 2020, 19(3), e13113. doi: 10.1111/acel.13113 PMID: 32061032Chung, Y.C.; Baek, J.Y.; Kim, S.R.; Ko, H.W.; Bok, E.; Shin, W.H.; Won, S.Y.; Jin, B.K. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson’s disease. Exp. Mol. Med., 2017, 49(3), e298. doi: 10.1038/emm.2016.159 PMID: 28255166Zhao, Z.; Wang, J.; Wang, L.; Yao, X.; Liu, Y.; Li, Y.; Chen, S.; Yue, T.; Wang, X.; Yu, W.; Liu, Y. Capsaicin protects against oxidative insults and alleviates behavioral deficits in rats with 6-OHDA-Induced Parkinson’s Disease via activation of TRPV1. Neurochem. Res., 2017, 42(12), 3431-3438. doi: 10.1007/s11064-017-2388-4 PMID: 28861768Liu, J.; Liu, H.; Zhao, Z.; Wang, J.; Guo, D.; Liu, Y. Regulation of Actg1 and Gsta2 is possible mechanism by which capsaicin alleviates apoptosis in cell model of 6-OHDA-induced Parkinson’s disease. Biosci. Rep., 2020, 40(6), BSR20191796. doi: 10.1042/BSR20191796 PMID: 32537633Bok, E.; Chung, Y.C.; Kim, K.S.; Baik, H.H.; Shin, W.H.; Jin, B.K. Modulation of M1/M2 polarization by capsaicin contributes to the survival of dopaminergic neurons in the lipopolysaccharide-lesioned substantia nigra in vivo. Exp. Mol. Med., 2018, 50(7), 1-14. doi: 10.1038/s12276-018-0111-4 PMID: 29968707Ouyang, M.; Zhang, Q.; Shu, J.; Wang, Z.; Fan, J.; Yu, K.; Lei, L.; Li, Y.; Wang, Q. Capsaicin ameliorates the loosening of mitochondria-associated endoplasmic reticulum membranes and improves cognitive function in rats with chronic cerebral hypoperfusion. Front. Cell. Neurosci., 2022, 16, 822702. doi: 10.3389/fncel.2022.822702 PMID: 35370565Goyal, A.; Solanki, A.; Verma, A. Preclinical evidence-based review on therapeutic potential of eugenol for the treatment of brain disorders. Curr. Mol. Med., 2023, 23(5), 390-400. doi: 10.2174/1566524022666220525145521 PMID: 35619280Galano, A.; Martínez, A. Capsaicin, a tasty free radical scavenger: mechanism of action and kinetics. J. Phys. Chem. B, 2012, 116(3), 1200-1208. doi: 10.1021/jp211172f PMID: 22188587Lu, M.; Chen, C.; Lan, Y.; Xiao, J.; Li, R.; Huang, J.; Huang, Q.; Cao, Y.; Ho, C.T. Capsaicin—the major bioactive ingredient of chili peppers: bio-efficacy and delivery systems. Food Funct., 2020, 11(4), 2848-2860. doi: 10.1039/D0FO00351D PMID: 32246759Amna, T.; Hwang, I.; Shang, K.; Amina, M.; Al-Musayeib, N.M.; Al-Deyab, S.S. Influence of capsaicin on inflammatory cytokines induced by lipopolysaccharide in myoblast cells under in vitro environment. Pharmacogn. Mag., 2017, 13(49)(Suppl. 1), 26. doi: 10.4103/0973-1296.203984 PMID: 28479722Tang, J.; Luo, K.; Li, Y.; Chen, Q.; Tang, D.; Wang, D.; Xiao, J. Capsaicin attenuates LPS-induced inflammatory cytokine production by upregulation of LXRα. Int. Immunopharmacol., 2015, 28(1), 264-269. doi: 10.1016/j.intimp.2015.06.007 PMID: 26093270Abdel-Salam, O.M.E.; Sleem, A.A.; Sayed, M.A.E.B.M.; Youness, E.R.; Shaffie, N. Capsaicin exerts anti-convulsant and neuroprotective effects in pentylenetetrazole-induced seizures. Neurochem. Res., 2020, 45(5), 1045-1061. doi: 10.1007/s11064-020-02979-3 PMID: 32036609Khatibi, N.H.; Jadhav, V.; Charles, S.; Chiu, J.; Buchholz, J.; Tang, J.; Zhang, J.H. Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats. Acta Neurochir. Suppl., 2011, 111(111), 225-230. doi: 10.1007/978-3-7091-0693-8_38 PMID: 21725760Inyang, D.; Saumtally, T.; Nnadi, C.N.; Devi, S.; So, P.W. A systematic review of the effects of capsaicin on Alzheimer’s Disease. Int. J. Mol. Sci., 2023, 24(12), 10176. doi: 10.3390/ijms241210176 PMID: 37373321He, F.Q.; Qiu, B.Y.; Zhang, X.H.; Li, T.K.; Xie, Q.; Cui, D.J.; Huang, X.L.; Gan, H.T. Tetrandrine attenuates spatial memory impairment and hippocampal neuroinflammation via inhibiting NF-κB activation in a rat model of Alzheimer’s disease induced by amyloid-β(1–42). Brain Res., 2011, 1384, 89-96. doi: 10.1016/j.brainres.2011.01.103 PMID: 21300035Pákáski, M.; Hugyecz, M.; Sántha, P.; Jancsó, G.; Bjelik, A.; Domokos, Á.; Janka, Z.; Kálmán, J. Capsaicin promotes the amyloidogenic route of brain amyloid precursor protein processing. Neurochem. Int., 2009, 54(7), 426-430. doi: 10.1016/j.neuint.2009.01.012 PMID: 19428784An, Y.; Li, Y.; Hou, Y.; Huang, S.; Pei, G. Alzheimer’s Amyloid- β accelerates cell senescence and suppresses the SIRT1/NRF2 pathway in human microglial cells. Oxid. Med. Cell. Longev., 2022, 2022, 3086010.Bahn, G.; Park, J.S.; Yun, U.J.; Lee, Y.J.; Choi, Y.; Park, J.S.; Baek, S.H.; Choi, B.Y.; Cho, Y.S.; Kim, H.K.; Han, J.; Sul, J.H.; Baik, S.H.; Lim, J.; Wakabayashi, N.; Bae, S.H.; Han, J.W.; Arumugam, T.V.; Mattson, M.P.; Jo, D.G. NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models. Proc. Natl. Acad. Sci. USA, 2019, 116(25), 12516-12523. doi: 10.1073/pnas.1819541116 PMID: 31164420Noble, W.; Hanger, D.P.; Miller, C.C.J.; Lovestone, S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol., 2013, 4, 83. doi: 10.3389/fneur.2013.00083 PMID: 23847585Ren, P.; Chen, J.; Li, B.; Zhang, M.; Yang, B.; Guo, X.; Chen, Z.; Cheng, H.; Wang, P.; Wang, S.; Wang, N.; Zhang, G.; Wu, X.; Ma, D.; Guan, D.; Zhao, R. Nrf2 ablation promotes Alzheimer’s disease-like pathology in APP/PS1 transgenic mice: The role of neuroinflammation and oxidative stress. Oxid. Med. Cell. Longev., 2020, 2020, 1-13. doi: 10.1155/2020/3050971 PMID: 32454936Rojo, A.I.; Pajares, M.; Rada, P.; Nuñez, A.; Nevado-Holgado, A.J.; Killik, R.; Van Leuven, F.; Ribe, E.; Lovestone, S.; Yamamoto, M.; Cuadrado, A. NRF2 deficiency replicates transcriptomic changes in Alzheimer’s patients and worsens APP and TAU pathology. Redox Biol., 2017, 13, 444-451. doi: 10.1016/j.redox.2017.07.006 PMID: 28704727Zgorzynska, E.; Dziedzic, B.; Walczewska, A. An overview of the nrf2/are pathway and its role in neurodegenerative diseases. Int. J. Mol. Sci., 2021, 22(17), 9592. doi: 10.3390/ijms22179592 PMID: 34502501Janyou, A.; Wicha, P.; Jittiwat, J.; Suksamrarn, A.; Tocharus, C.; Tocharus, J. Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory. Sci. Rep., 2017, 7(1), 10556. doi: 10.1038/s41598-017-11181-5 PMID: 28874782Kanninen, K.; Malm, T.M.; Jyrkkänen, H.K.; Goldsteins, G.; Keksa-Goldsteine, V.; Tanila, H.; Yamamoto, M.; Ylä-Herttuala, S.; Levonen, A.L.; Koistinaho, J. Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol. Cell. Neurosci., 2008, 39(3), 302-313. doi: 10.1016/j.mcn.2008.07.010 PMID: 18706502Eftekharzadeh, B.; Maghsoudi, N.; Khodagholi, F. Stabilization of transcription factor Nrf2 by tBHQ prevents oxidative stress-induced amyloid β formation in NT2N neurons. Biochimie, 2010, 92(3), 245-253. doi: 10.1016/j.biochi.2009.12.001 PMID: 20026169Akhter, H.; Katre, A.; Li, L.; Liu, X.; Liu, R.M. Therapeutic potential and anti-amyloidosis mechanisms of tert-butylhydroquinone for Alzheimer’s disease. J. Alzheimers Dis., 2011, 26(4), 767-778. doi: 10.3233/JAD-2011-110512 PMID: 21860091Kanninen, K.; Heikkinen, R.; Malm, T.; Rolova, T.; Kuhmonen, S.; Leinonen, H.; Ylä-Herttuala, S.; Tanila, H.; Levonen, A.L.; Koistinaho, M.; Koistinaho, J. Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2009, 106(38), 16505-16510. doi: 10.1073/pnas.0908397106 PMID: 19805328Hayes, M.T. Parkinson’s Disease and parkinsonism. Am. J. Med., 2019, 132(7), 802-807. doi: 10.1016/j.amjmed.2019.03.001 PMID: 30890425Sung, VW. Nicholas, AP Nonmotor symptoms in Parkinson’s disease: Expanding the view of Parkinson’s disease beyond a pure motor, pure dopaminergic problem. Neurol. Clin., 2013, 31(3)(Suppl.), S1-S16. doi: 10.1016/j.ncl.2013.04.013Dauer, W.; Przedborski, S. Parkinson’s disease. Neuron, 2003, 39(6), 889-909. doi: 10.1016/S0896-6273(03)00568-3 PMID: 12971891Huang, B.; Liu, J.; Ju, C. Licochalcone A prevents the loss of dopaminergic neurons by inhibiting microglial activation in Lipopolysaccharide (LPS)-induced Parkinson’s Disease models. Int. J. Mol. Sci., 2017, 18(10), 2043.Wang, X.; Wang, C.; Wang, J.; Zhao, S.; Zhang, K.; Wang, J.; Zhang, W.; Wu, C.; Yang, J. Pseudoginsenoside-F11 (PF11) exerts anti-neuroinflammatory effects on LPS-activated microglial cells by inhibiting TLR4-mediated TAK1/IKK/NF-κB, MAPKs and Akt signaling pathways. Neuropharmacology, 2014, 79, 642-656. doi: 10.1016/j.neuropharm.2014.01.022 PMID: 24467851Kim, K.I.; Baek, J.Y.; Jeong, J.Y.; Nam, J.H.; Park, E.S.; Bok, E.; Shin, W.H.; Chung, Y.C.; Jin, B.K. Delayed treatment of capsaicin produces partial motor recovery by enhancing dopamine function in MPP + -lesioned rats via ciliary neurotrophic factor. Exp. Neurobiol., 2019, 28(2), 289-299. doi: 10.5607/en.2019.28.2.289 PMID: 31138996Liu, J.; Liu, H.; Zhao, Z.; Wang, J.; Guo, D.; Liu, Y. Regulation of Actg1 and Gsta2 is possible mechanism by which capsaicin alleviates apoptosis in cell model of 6-OHDA-induced Parkinson’s disease. Biosci. Rep., 2020, 40(6)Siddique, Y.H.; Naz, F.; Jyoti, S. Effect of capsaicin on the oxidative stress and dopamine content in the transgenic Drosophila model of Parkinson’s disease. Acta Biol. Hung., 2018, 69(2), 115-124. doi: 10.1556/018.69.2018.2.1 PMID: 29888671Brandes, M.S.; Gray, N.E. NRF2 as a therapeutic target in neurodegenerative diseases. ASN Neuro, 2020, 12. doi: 10.1177/1759091419899782 PMID: 31964153Blesa, J.; Trigo-Damas, I.; Quiroga-Varela, A.; Jackson-Lewis, V.R. Oxidative stress and Parkinson’s disease. Front. Neuroanat., 2015, 9, 91. doi: 10.3389/fnana.2015.00091 PMID: 26217195Colamartino, M.; Duranti, G.; Ceci, R.; Sabatini, S.; Testa, A.; Cozzi, R. A multi-biomarker analysis of the antioxidant efficacy of Parkinson’s disease therapy. Toxicol. In Vitro, 2018, 47, 1-7. doi: 10.1016/j.tiv.2017.10.020 PMID: 29080800Holmström, K.M.; Baird, L.; Zhang, Y.; Hargreaves, I.; Chalasani, A.; Land, J.M.; Stanyer, L.; Yamamoto, M.; Dinkova-Kostova, A.T.; Abramov, A.Y. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol. Open, 2013, 2(8), 761-770. doi: 10.1242/bio.20134853 PMID: 23951401Manoharan, S; Guillemin, GJ; Abiramasundari, RS; Essa, MM; Akbar, M; Akbar, MD The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease, Parkinson’s Disease, and Huntington’s disease: A mini review. Oxid. Med. Cell. Longev., 2016.Wei, Z.; Li, X.; Li, X.; Liu, Q.; Cheng, Y. Oxidative stress in Parkinson’s Disease: A systematic review and meta-analysis. Front. Mol. Neurosci., 2018, 11, 236. doi: 10.3389/fnmol.2018.00236 PMID: 30026688Chen, P.C.; Vargas, M.R.; Pani, A.K.; Smeyne, R.J.; Johnson, D.A.; Kan, Y.W.; Johnson, J.A. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. Proc. Natl. Acad. Sci. USA, 2009, 106(8), 2933-2938. doi: 10.1073/pnas.0813361106 PMID: 19196989Rojo, A.I.; Innamorato, N.G.; Martín-Moreno, A.M.; De Ceballos, M.L.; Yamamoto, M.; Cuadrado, A. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia, 2010, 58(5), 588-598. doi: 10.1002/glia.20947 PMID: 19908287Williamson, T.P.; Johnson, D.A.; Johnson, J.A. Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology, 2012, 33(3), 272-279. doi: 10.1016/j.neuro.2012.01.015 PMID: 22342405Johnson, J.A.; Johnson, D.A.; Kraft, A.D.; Calkins, M.J.; Jakel, R.J.; Vargas, M.R.; Chen, P.C. The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. Ann. N. Y. Acad. Sci., 2008, 1147(1), 61-69. doi: 10.1196/annals.1427.036 PMID: 19076431Jimenez-Sanchez, M.; Licitra, F.; Underwood, B.R.; Rubinsztein, D.C. Huntington’s disease: Mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb. Perspect. Med., 2017, 7(7), a024240. doi: 10.1101/cshperspect.a024240 PMID: 27940602McColgan, P.; Tabrizi, S.J. Huntington’s disease: A clinical review. Eur. J. Neurol., 2018, 25(1), 24-34. doi: 10.1111/ene.13413 PMID: 28817209Hardingham, G.E. Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem. Soc. Trans., 2009, 37(6), 1147-1160. doi: 10.1042/BST0371147 PMID: 19909238Lastres-Becker, I.; De Miguel, R.; De Petrocellis, L.; Makriyannis, A.; Di Marzo, V.; Fernández-Ruiz, J. Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington’s disease. J. Neurochem., 2003, 84(5), 1097-1109. doi: 10.1046/j.1471-4159.2003.01595.x PMID: 12603833Shih, A.Y.; Imbeault, S.; Barakauskas, V.; Erb, H.; Jiang, L.; Li, P.; Murphy, T.H. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem., 2005, 280(24), 22925-22936. doi: 10.1074/jbc.M414635200 PMID: 15840590Jin, Y.N.; Johnson, G.V.W. The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease. J. Bioenerg. Biomembr., 2010, 42(3), 199-205. doi: 10.1007/s10863-010-9286-7 PMID: 20556492Gu, M.; Gash, M.T.; Mann, V.M.; Javoy-Agid, F.; Cooper, J.M.; Schapira, A.H.V. Mitochondrial defect in Huntington’s disease caudate nucleus. Ann. Neurol., 1996, 39(3), 385-389. doi: 10.1002/ana.410390317 PMID: 8602759Tabrizi, S.J.; Workman, J.; Hart, P.E.; Mangiarini, L.; Mahal, A.; Bates, G.; Cooper, J.M.; Schapira, A.H.V. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann. Neurol., 2000, 47(1), 80-86. doi: 10.1002/1531-8249(200001)47:13.0.CO;2-K PMID: 10632104Steffan, J.S.; Bodai, L.; Pallos, J.; Poelman, M.; McCampbell, A.; Apostol, B.L.; Kazantsev, A.; Schmidt, E.; Zhu, Y.Z.; Greenwald, M.; Kurokawa, R.; Housman, D.E.; Jackson, G.R.; Marsh, J.L.; Thompson, L.M. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature, 2001, 413(6857), 739-743. doi: 10.1038/35099568 PMID: 11607033Ganner, A.; Pfeiffer, Z.C.; Wingendorf, L.; Kreis, S.; Klein, M.; Walz, G.; Neumann-Haefelin, E. The acetyltransferase p300 regulates NRF2 stability and localization. Biochem. Biophys. Res. Commun., 2020, 524(4), 895-902. doi: 10.1016/j.bbrc.2020.02.006 PMID: 32057361Jin, Y.N.; Yu, Y.V.; Gundemir, S.; Jo, C.; Cui, M.; Tieu, K.; Johnson, G.V.W. Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One, 2013, 8(3), e57932. doi: 10.1371/journal.pone.0057932 PMID: 23469253Stack, C.; Ho, D.; Wille, E.; Calingasan, N.Y.; Williams, C.; Liby, K.; Sporn, M.; Dumont, M.; Beal, M.F. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic. Biol. Med., 2010, 49(2), 147-158. doi: 10.1016/j.freeradbiomed.2010.03.017 PMID: 20338236Tsvetkov, A.S.; Arrasate, M.; Barmada, S.; Ando, D.M.; Sharma, P.; Shaby, B.A.; Finkbeiner, S. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat. Chem. Biol., 2013, 9(9), 586-592. doi: 10.1038/nchembio.1308 PMID: 23873212Saito, Y.; Yako, T.; Otsu, W.; Nakamura, S.; Inoue, Y.; Muramatsu, A.; Nakagami, Y.; Shimazawa, M.; Hara, H. A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner. Free Radic. Biol. Med., 2020, 152, 235-247. doi: 10.1016/j.freeradbiomed.2020.03.012 PMID: 32217192Ninomiya, Y.; Tanuma, S.; Tsukimoto, M. Differences in the effects of four TRPV1 channel antagonists on lipopolysaccharide-induced cytokine production and COX-2 expression in murine macrophages. Biochem. Biophys. Res. Commun., 2017, 484(3), 668-674. doi: 10.1016/j.bbrc.2017.01.173 PMID: 28153725Franklin, R.J.M. ffrench-Constant, C. Regenerating CNS myelin-from mechanisms to experimental medicines. Nat. Rev. Neurosci., 2017, 18(12), 753-769. doi: 10.1038/nrn.2017.136 PMID: 29142295Legroux, L.; Arbour, N. Multiple sclerosis and T lymphocytes: An entangled story. J. Neuroimmune Pharmacol., 2015, 10(4), 528-546. doi: 10.1007/s11481-015-9614-0 PMID: 25946987Al-Kafaji, G; Bakheit, HF; AlAli, F Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis. PLoS ONE, 2022, 17(2 February)Campbell, G.R.; Mahad, D.J. Mitochondrial changes associated with demyelination: Consequences for axonal integrity. Mitochondrion, 2012, 12(2), 173-179. doi: 10.1016/j.mito.2011.03.007 PMID: 21406249Brooks, J.W.; Pryce, G.; Bisogno, T.; Jaggar, S.I.; Hankey, D.J.R.; Brown, P.; Bridges, D.; Ledent, C.; Bifulco, M.; Rice, A.S.C.; Di Marzo, V.; Baker, D. Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB1/CB2 receptors. Eur. J. Pharmacol., 2002, 439(1-3), 83-92. doi: 10.1016/S0014-2999(02)01369-9 PMID: 11937096’t Hart, B.A.; Gran, B.; Weissert, R. EAE: imperfect but useful models of multiple sclerosis. Trends Mol. Med., 2011, 17(3), 119-125. doi: 10.1016/j.molmed.2010.11.006 PMID: 21251877Rangachari, M.; Kuchroo, V.K. Using EAE to better understand principles of immune function and autoimmune pathology. J. Autoimmun., 2013, 45, 31-39. doi: 10.1016/j.jaut.2013.06.008 PMID: 23849779Sharma, Y.; Garabadu, D. RETRACTED ARTICLE: Intracerebroventricular streptozotocin administration impairs mitochondrial calcium homeostasis and bioenergetics in memory-sensitive rat brain regions. Exp. Brain Res., 2020, 238(10), 2293-2306. doi: 10.1007/s00221-020-05896-7 PMID: 32728854Noh, H.; Jeon, J.; Seo, H. Systemic injection of LPS induces region-specific neuroinflammation and mitochondrial dysfunction in normal mouse brain. Neurochem. Int., 2014, 69(1), 35-40. doi: 10.1016/j.neuint.2014.02.008 PMID: 24607701Tsuji, F.; Murai, M.; Oki, K.; Seki, I.; Ueda, K.; Inoue, H.; Nagelkerken, L.; Sasano, M.; Aono, H. Transient receptor potential vanilloid 1 agonists as candidates for anti-inflammatory and immunomodulatory agents. Eur. J. Pharmacol., 2010, 627(1-3), 332-339. doi: 10.1016/j.ejphar.2009.10.044 PMID: 19878665Wang, J.; Zou, Q.; Suo, Y.; Tan, X.; Yuan, T.; Liu, Z.; Liu, X. Lycopene ameliorates systemic inflammation-induced synaptic dysfunction via improving insulin resistance and mitochondrial dysfunction in the liver–brain axis. Food Funct., 2019, 10(4), 2125-2137. doi: 10.1039/C8FO02460J PMID: 30924473Rehman, S.U.; Ali, T.; Alam, S.I.; Ullah, R.; Zeb, A.; Lee, K.W.; Rutten, B.P.F.; Kim, M.O. Ferulic acid rescues LPS-induced neurotoxicity via modulation of the TLR4 receptor in the mouse hippocampus. Mol. Neurobiol., 2019, 56(4), 2774-2790. doi: 10.1007/s12035-018-1280-9 PMID: 30058023Khan, A.; Ali, T.; Rehman, S.U. Neuroprotective effect of quercetin against the detrimental effects of LPS in the adult mouse brain. Front. Pharmacol., 2018, 9, 1383. doi: 10.3389/fphar.2018.01383Chen, W.J.; Du, J.K.; Hu, X.; Yu, Q.; Li, D.X.; Wang, C.N.; Zhu, X.Y.; Liu, Y.J. Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior. Physiol. Behav., 2017, 182, 54-61. doi: 10.1016/j.physbeh.2017.09.024 PMID: 28964807Singh, N.K.; Garabadu, D. Quercetin Exhibits α7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-induced mitochondrial toxicity and cognitive impairments in experimental rodents. Neurotox. Res., 2021, 39(6), 1859-1879. doi: 10.1007/s12640-021-00410-5 PMID: 34554409Rowland, L.P.; Shneider, N.A. Amyotrophic lateral sclerosis. N. Engl. J. Med., 344(22), 1688-1700.Ravits, J.M.; La Spada, A.R. ALS motor phenotype heterogeneity, focality, and spread: Deconstructing motor neuron degeneration. Neurology, 2009, 73(10), 805-811. doi: 10.1212/WNL.0b013e3181b6bbbd PMID: 19738176Neumann, M.; Sampathu, D.M.; Kwong, L.K.; Truax, A.C.; Micsenyi, M.C.; Chou, T.T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.M.; McCluskey, L.F.; Miller, B.L.; Masliah, E.; Mackenzie, I.R.; Feldman, H.; Feiden, W.; Kretzschmar, H.A.; Trojanowski, J.Q.; Lee, V.M.Y. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 2006, 314(5796), 130-133. doi: 10.1126/science.1134108 PMID: 17023659Higashi, T.; Murata, N.; Fujimoto, M.; Miyake, S.; Egusa, M.; Higuchi, H.; Maeda, S.; Miyawaki, T. Capsaicin may improve swallowing impairment in patients with amyotrophic lateral sclerosis: A randomized controlled trial. Acta Med. Okayama, 2022, 76(2), 179-186. PMID: 35503446Obrador, E.; Salvador, R.; López-Blanch, R.; Jihad-Jebbar, A.; Vallés, S.L.; Estrela, J.M. Oxidative stress, neuroinflammation and mitochondria in the pathophysiology of amyotrophic lateral sclerosis. Antioxidants, 2020, 9(9), 901. doi: 10.3390/antiox9090901 PMID: 32971909McCombe, P.A.; Henderson, R.D. The Role of immune and inflammatory mechanisms in ALS. Curr. Mol. Med., 2011, 11(3), 246-254. doi: 10.2174/156652411795243450 PMID: 21375489Mhatre, M.; Floyd, R.A.; Hensley, K. Oxidative stress and neuroinflammation in Alzheimer’s disease and amyotrophic lateral sclerosis: Common links and potential therapeutic targets. J. Alzheimers Dis., 2004, 6(2), 147-157. doi: 10.3233/JAD-2004-6206 PMID: 15096698Minj, E.; Yadav, R.K.; Mehan, S. Targeting abnormal Nrf2/HO-1 signaling in amyotrophic lateral sclerosis: Current insights on drug targets and influences on neurological disorders. Curr. Mol. Med., 2021, 21(8), 630-644. doi: 10.2174/18755666MTEz5MTUw0 PMID: 33430731Ghezzi, P.; Bernardini, R.; Giuffrida, R.; Bellomo, M.; Manzoni, C.; Comoletti, D.; Di Santo, E.; Benigni, F.; Mennini, T. Tumor necrosis factor is increased in the spinal cord of an animal model of motor neuron degeneration. Eur. Cytokine Netw., 1998, 9(2), 139-144. PMID: 9681389Kobayashi, E.H.; Suzuki, T.; Funayama, R.; Nagashima, T.; Hayashi, M.; Sekine, H.; Tanaka, N.; Moriguchi, T.; Motohashi, H.; Nakayama, K.; Yamamoto, M. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun., 2016, 7(1), 11624. doi: 10.1038/ncomms11624 PMID: 27211851Shibata, N.; Nagai, R.; Uchida, K.; Horiuchi, S.; Yamada, S.; Hirano, A.; Kawaguchi, M.; Yamamoto, T.; Sasaki, S.; Kobayashi, M. Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res., 2001, 917(1), 97-104. doi: 10.1016/S0006-8993(01)02926-2 PMID: 11602233Sarlette, A.; Krampfl, K.; Grothe, C.; Neuhoff, N.; Dengler, R.; Petri, S. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol., 2008, 67(11), 1055-1062. doi: 10.1097/NEN.0b013e31818b4906 PMID: 18957896Wang, Y.; Tang, C.; Tang, Y.; Yin, H.; Liu, X. Capsaicin has an anti-obesity effect through alterations in gut microbiota populations and short-chain fatty acid concentrations. Food Nutr. Res., 2020, 64(0) doi: 10.29219/fnr.v64.3525 PMID: 32180694Chen, L.; Huang, Z.; Du, Y.; Fu, M.; Han, H.; Wang, Y.; Dong, Z. Capsaicin attenuates Amyloid-β-induced synapse loss and cognitive impairments in mice. J. Alzheimers Dis., 2017, 59(2), 683-694. doi: 10.3233/JAD-170337 PMID: 28671132Lu, J.; Zhou, W.; Dou, F.; Wang, C.; Yu, Z. TRPV1 sustains microglial metabolic reprogramming in Alzheimer’s disease. EMBO Rep., 2021, 22(6), e52013. doi: 10.15252/embr.202052013 PMID: 33998138Jiang, X.; Jia, L.W.; Li, X.H.; Cheng, X.S.; Xie, J.Z.; Ma, Z.W.; Xu, W.J.; Liu, Y.; Yao, Y.; Du, L.L.; Zhou, X.W. Capsaicin ameliorates stress-induced Alzheimer’s disease-like pathological and cognitive impairments in rats. J. Alzheimers Dis., 2013, 35(1), 91-105. doi: 10.3233/JAD-121837 PMID: 23340038Xu, W.; Liu, J.; Ma, D.; Yuan, G.; Lu, Y.; Yang, Y. Capsaicin reduces Alzheimer-associated tau changes in the hippocampus of type 2 diabetes rats. PLoS One, 2017, 12(2), e0172477. doi: 10.1371/journal.pone.0172477 PMID: 28225806Park, E.S.; Kim, S.R.; Jin, B.K. Transient receptor potential vanilloid subtype 1 contributes to mesencephalic dopaminergic neuronal survival by inhibiting microglia-originated oxidative stress. Brain Res. Bull., 2012, 89(3-4), 92-96. doi: 10.1016/j.brainresbull.2012.07.001 PMID: 22796104Cabranes, A.; Venderova, K.; de Lago, E.; Fezza, F.; Sánchez, A.; Mestre, L.; Valenti, M.; García-Merino, A.; Ramos, J.A.; Di Marzo, V.; Fernández-Ruiz, J. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol. Dis., 2005, 20(2), 207-217. doi: 10.1016/j.nbd.2005.03.002 PMID: 16242629