Ps. Widdowson et al., POSSIBLE ROLE OF NITRIC-OXIDE IN THE DEVELOPMENT OF L-2-CHLOROPROPIONIC ACID-INDUCED CEREBELLAR GRANULE CELL NECROSIS, British Journal of Pharmacology, 117(8), 1996, pp. 1761-1767
1 L-2-Chloropropionic acid (L-CPA) produces selective neuronal cell ne
crosis in rat cerebellum when administered orally at 750 mg kg(-1) tha
t 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 comm
on with excitatory amino acid-induced cell death. We have used this in
vivo model to examine the neurochemical processes following L-CPA-ind
uced activation of NMDA receptors leading to neuronal cell death in th
e rat cerebellum. 2 The effects of a number of compounds which potentl
y block nitric oxide synthase in vitro were examined on L-CPA-induced
neurotoxicity 48 h following L-CPA dosing, to discover whether the neu
ronal cell death is mediated in part by excessive nitric oxide generat
ion. 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 eith
er 25 or 100 mg kg(-1), twice daily did not produce any significant pr
otection against L-CPA-induced neurotoxicity. 4 Both L-NAME and BrIN a
lso prevented the L-CPA-induced increase in cerebellar water content a
nd sodium concentrations. L-NIO when administered at the highest doses
prevented the increase in cerebellar sodium concentration but not wat
er 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 concentra
tions and increases in glutamine and GABA concentrations were prevente
d by L-NAME and BrIN, but not by L-NIO or L-NOARG. Also reductions in
L-[H-3]-glutamate binding to glutamate ionotrophic and metabotrophic r
eceptors 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 neurop
rotection offered by L-NAME and BrIN suggests that L-CPA-induced cereb
ellar granule cell necrosis is possibly mediated by or associated with
excessive generation of nitric oxide. The inability of nitric oxide s
ynthase inhibitors, L-NOARG and L-NIO to afford protection may result
from their limited penetration into the brain (L-NIO) or rapid dissoci
ation from the enzyme.