興奮毒性
出典: フリー百科事典『ウィキペディア（Wikipedia）』 (2023/05/06 09:11 UTC 版)
興奮毒性（こうふんどくせい、英: excitotoxicity）とは、正常範囲では必要かつ安全なグルタミン酸などの神経伝達物質が病理学的な高濃度状態となり、受容体の過剰刺激によって神経細胞が損傷したり死滅したりする現象である。例えば、NMDA受容体やAMPA受容体などのグルタミン酸受容体が興奮性神経伝達物質であるグルタミン酸の過剰量存在下に置かれると、神経細胞には大きな損傷が生じる可能性がある。過剰なグルタミン酸は、細胞内に高濃度のカルシウムイオン（Ca2+）を流入させる。細胞内に流入したCa2+は、ホスホリパーゼ、エンドヌクレアーゼ、プロテアーゼ（カルパインなど）を含む多数の酵素を活性化する。これらの酵素は、細胞骨格の構成要素、細胞膜、DNAなどの細胞構造を損傷する[1][2]。生命のような進化した複雑適応系では特定の機構が単純かつ直接的なものであることは稀であり、例えば、毒性量以下のNMDAへの曝露は毒性量のグルタミン酸に対する神経細胞の生存を誘導するなど、複雑な応答が観察される[3][4]。
- ^ a b “Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease”. BMC Neurosci 10: 64. (2009). doi:10.1186/1471-2202-10-64. PMC 2716351. PMID 19545440.
- ^ “Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death”. Molecular Pharmacology 36 (1): 106–112. (Jul 1989). PMID 2568579.
- ^ Zheng, Sika; Eacker, Stephen M.; Hong, Suk Jin; Gronostajski, Richard M.; Dawson, Ted M.; Dawson, Valina L. (July 2010). “NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice”. The Journal of Clinical Investigation 120 (7): 2446–2456. doi:10.1172/JCI33144. ISSN 1558-8238. PMC 2898580. PMID 20516644.
- ^ Chuang, D. M.; Gao, X. M.; Paul, S. M. (August 1992). “N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cells”. Molecular Pharmacology 42 (2): 210–216. ISSN 0026-895X. PMID 1355259.
- ^ Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity or Glutamatergic Storm. Chapter 1 in CNS Neuroprotection. Marcoux FW and Choi DW, editors. Springer, New York. 2002. Pages 3-36
- ^ Hughes JR (February 2009). “Alcohol withdrawal seizures”. Epilepsy Behav 15 (2): 92–7. doi:10.1016/j.yebeh.2009.02.037. PMID 19249388.
- ^ Camacho, A; Massieu, L (2006). “Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death.”. Archives of Medical Research 37 (1): 11–8. doi:10.1016/j.arcmed.2005.05.014. PMID 16314180.
- ^ Fujikawa, DG (2005). “Prolonged seizures and cellular injury: understanding the connection.”. Epilepsy & Behavior 7 Suppl 3: S3–11. doi:10.1016/j.yebeh.2005.08.003. PMID 16278099.
- ^ Watkins, Jeffrey C; Jane, David E (2 February 2009). “The glutamate story”. British Journal of Pharmacology 147 (S1): S100–S108. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
- ^ Lucas, DR; Newhouse, JP (1957). “The toxic effect of sodium L-glutamate on the inner layers of the retina.”. Archives of Ophthalmology 58 (2): 193–201. doi:10.1001/archopht.1957.00940010205006. PMID 13443577.
- ^ Olney, JW (1969). “Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate.”. Science 164 (3880): 719–21. Bibcode: 1969Sci...164..719O. doi:10.1126/science.164.3880.719. hdl:10217/207298. PMID 5778021.
- ^ Hardingham, G. E.; Fukunaga, Y.; Bading, H. (May 2002). “Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways”. Nature Neuroscience 5 (5): 405–414. doi:10.1038/nn835. ISSN 1097-6256. PMID 11953750.
- ^ Yan, Jing; Bengtson, C. Peter; Buchthal, Bettina; Hagenston, Anna M.; Bading, Hilmar (9 October 2020). “Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants”. Science 370 (6513). doi:10.1126/science.aay3302. ISSN 1095-9203. PMID 33033186.
- ^ Head trauma : basic, preclinical, and clinical directions. Leonard P. Miller, Ronald L. Hayes, Jennifer K. Newcomb. New York: Wiley-Liss. (2001). pp. 87-113. ISBN 0-471-36015-5. OCLC 45618924
- ^ Clements, JD; Lester, RA; Tong, G; Jahr, CE; Westbrook, GL (1992). “The time course of glutamate in the synaptic cleft”. Science 258 (5087): 1498–501. Bibcode: 1992Sci...258.1498C. doi:10.1126/science.1359647. PMID 1359647.
- ^ Yang Derek D. (October 1997). “Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene”. Nature 389 (6653): 865–870. Bibcode: 1997Natur.389..865Y. doi:10.1038/39899. PMID 9349820.
- ^ Ankarcrona Maria (October 1995). “Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function”. Neuron 15 (4): 961–973. doi:10.1016/0896-6273(95)90186-8. PMID 7576644.
- ^ Hulsebosch (Apr 2009). “Mechanisms of chronic central neuropathic pain after spinal cord injury”. Brain Res Rev 60 (1): 202–13. doi:10.1016/j.brainresrev.2008.12.010. PMC 2796975. PMID 19154757.
- ^ Nakamura (Aug 2010). “S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration”. Mitochondrion 10 (5): 573–8. doi:10.1016/j.mito.2010.04.007. PMC 2918703. PMID 20447471.
- ^ a b Dutta (Jan 2011). “Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis”. Prog Neurobiol 93 (1): 1–12. doi:10.1016/j.pneurobio.2010.09.005. PMC 3030928. PMID 20946934.
- ^ Stavrovskaya, IG; Kristal, BS (2005). “The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?”. Free Radical Biology & Medicine 38 (6): 687–97. doi:10.1016/j.freeradbiomed.2004.11.032. PMID 15721979.
- ^ Allen, J; Romay-Tallon, R; Brymer, K; Caruncho, H; Kalynchuk, L (2018). “Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression”. Frontiers in Neuroscience 12: 386. doi:10.3389/fnins.2018.00386. PMC 5997778. PMID 29928190.
- ^ Li (2001). “Na+-K+-ATPase inhibition and depolarization induce glutamate release via reverse Na+-dependent transport in spinal cord white matter”. Neuroscience 107 (4): 675–683. doi:10.1016/s0306-4522(01)00385-2. PMID 11720790.
- ^ Basic neurochemistry : molecular, cellular, and medical aspects. George J. Siegel (6th ed ed.). Philadelphia: Lippincott Williams & Wilkins. (1999). ISBN 0-397-51820-X. OCLC 39013748
- ^ a b Hardingham, GE; Fukunaga, Y; Bading, H (2002). “Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways”. Nature Neuroscience 5 (5): 405–14. doi:10.1038/nn835. PMID 11953750.
- ^ Hardingham, Giles E.; Bading, Hilmar (2010). “Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders”. Nature Reviews Neuroscience 11 (10): 682–696. doi:10.1038/nrn2911. PMC 2948541. PMID 20842175.
- ^ Brand, LE (2009). “Human exposure to cyanobacteria and BMAA”. Amyotrophic Lateral Sclerosis 20: 85–95. doi:10.3109/17482960903273585. PMID 19929739.
- ^ Vyas, KJ; Weiss, JH (2009). “BMAA--an unusual cyanobacterial neurotoxin”. Amyotrophic Lateral Sclerosis 10: 50–55. doi:10.3109/17482960903268742. PMID 19929732.
- ^ a b Chiu, AS (2012). “Excitotoxic potential of the cyanotoxin β-methyl-amino-l-alanine (BMAA) in primary human neurons”. Toxicon 60 (6): 1159–1165. doi:10.1016/j.toxicon.2012.07.169. PMID 22885173.
- ^ Papapetropolous, S (2007). “Is there a role for naturally occurring cyanobacterial toxins in neurodegeneration? The beta-N-methylamino-L-alanine (BMAA) paradigm.”. Neurochemistry International 50 (7): 998–1003. doi:10.1016/j.neuint.2006.12.011. PMID 17296249.
- ^ Nord, Team (2007). Analysis, occurrence and toxicity of BMAA. Denmark: Nordic. pp. 46–47. ISBN 9789289315418
- ^ Dunlop, R.A., Cox, P.A., Banack, S.A., Rodgers, J.K. (2013). “The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation”. PLOS ONE 8 (9): e75376. Bibcode: 2013PLoSO...875376D. doi:10.1371/journal.pone.0075376. PMC 3783393. PMID 24086518.
- ^ Holtcamp, W. (2012). “The emerging science of BMAA: do cyanobacteria contribute to neurodegenerative disease?”. Environmental Health Perspectives 120 (3): a110–a116. doi:10.1289/ehp.120-a110. PMC 3295368. PMID 22382274.
- ^ Cox, PA, Davis, DA, Mash, DC, Metcalf, JS, Banack, SA. (2015). “Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain”. Proceedings of the Royal Society B 283 (1823): 20152397. doi:10.1098/rspb.2015.2397. PMC 4795023. PMID 26791617.
[続きの解説]
- 興奮毒性のページへのリンク
