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Possible role of nitric oxide in the development of L‐2‐chloropropionic acid‐induced cerebellar granule cell necrosis
Author(s) -
Widdowson P.S.,
Gyte A.,
Simpson M.G.,
Farnworth M.,
Dunn D.,
Moore R.B.,
Wyatt I.,
Lock E.A.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15351.x
Subject(s) - cerebellum , nitric oxide , neurotoxicity , nmda receptor , glutamate receptor , programmed cell death , granule cell , pharmacology , nitroarginine , chemistry , nitric oxide synthase , receptor , toxicity , medicine , endocrinology , biochemistry , biology , apoptosis , central nervous system , dentate gyrus
1 L‐2‐Chloropropionic acid (L‐CPA) produces selective neuronal cell necrosis in rat cerebellum when administered orally at 750 mg kg −1 that is mediated in part through activation of N‐methyl‐D‐aspartate (NMDA) receptors. Cerebellar granule cell death occurs between 30 and 36 h following L‐CPA administration exhibiting a number of features in common with excitatory amino acid‐induced cell death. We have used this in vivo model to examine the neurochemical processes following L‐CPA‐induced activation of NMDA receptors leading to neuronal cell death in the rat cerebellum. 2 The effects of a number of compounds which potently block nitric oxide synthase in vitro were examined on L‐CPA‐induced neurotoxicity 48 h following L‐CPA dosing, to discover whether the neuronal cell death is mediated in part by excessive nitric oxide generation. Four inhibitors were studied, N G ‐nitro‐L‐arginine (L‐NOARG), N G ‐nitro‐L‐arginine methyl ester (L‐NAME), N G ‐iminoethyl‐L‐ornithine (L‐NIO) and 3‐bromo‐7‐nitroindazole (BrNI). 3 L‐NAME (50 mg kg −1 , i.p. twice daily) and BrIN (50 mg kg −1 , i.p. twice daily) administration prevented the L‐CPA‐induced loss of granule cells which can reach up to 80–90% of the total cell number in rats treated with L‐CPA alone. L‐NOARG (50 mg kg −1 , i.p. twice daily) and L‐NIO administered at either 25 or 100 mg kg −1 , twice daily did not produce any significant protection against L‐CPA‐induced neurotoxicity. 4 Both L‐NAME and BrIN also prevented the L‐CPA‐induced increase in cerebellar water content and sodium concentrations. L‐NIO when administered at the highest doses prevented the increase in cerebellar sodium concentration but not water content. L‐NIO and L‐NOARG were ineffective in preventing the L‐CPA‐induced increases in cerebellar water and sodium concentrations. 5 L‐CPA‐induced reductions in cerebellar aspartate and glutamate concentrations and increases in glutamine and GABA concentrations were prevented by L‐NAME and BrIN, but not by L‐NIO or L‐NOARG. Also reductions in L‐[ 3 H]‐glutamate binding to glutamate ionotrophic and metabotrophic receptors in the granule cell layer of rat cerebellum was prevented by L‐NAME and BrIN, but not L‐NIO or L‐NOARG. 6 In conclusion, the neuroprotection offered by L‐NAME and BrIN suggests that L‐CPA‐induced cerebellar granule cell necrosis is possibly mediated by or associated with excessive generation of nitric oxide. The inability of nitric oxide synthase inhibitors, L‐NOARG and L‐NIO to afford protection may result from their limited penetration into the brain (L‐NIO) or rapid dissociation from the enzyme.