L-NAME reverses quinolinic acid-induced toxicity in rat corticostriatal slices: Involvement of src family kinases.
J Neurosci Res
; 85(12): 2770-7, 2007 Sep.
Article
in En
| MEDLINE
| ID: mdl-17265464
ABSTRACT
Quinolinic acid (QA) is an endogenous excitotoxin acting on N-methyl-d-aspartate receptors (NMDARs) that leads to the pathologic and neurochemical features similar to those observed in Huntington's disease (HD). The mechanism of QA toxicity also involves free radicals formation and oxidative stress. NMDARs are particularly vulnerable to the action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that can act as modulators of the activity of protein tyrosine kinases (PTKs) and phosphotyrosine phosphatases (PTPs). Because QA is able to activate neuronal nitric oxide synthase (nNOS) as well as to stimulate the NMDARs, we evaluated the effect of Nomega-Nitro-l-arginine-methyl ester (l-NAME), a selective nNOS inhibitor, on QA-induced neurotoxicity in rat corticostriatal slices. In electrophysiologic experiments we observed that slice perfusion with QA induced a strong reduction of field potential (FP) amplitude, followed by a partial recovery at the end of the QA washout. In the presence of l-NAME the recovery of FP amplitude was significantly increased with respect to QA alone. In synaptosomes, prepared from corticostriatal slices after the electrophysiologic recordings, we observed that l-NAME pre-incubation reversed the QA-mediated inhibitory effects on protein tyrosine phosphorylation pattern, c-src, lyn, and fyn kinase activities and tyrosine phosphorylation of NMDAR subunit NR2B, whereas the PTP activity was not recovered in the presence of l-NAME. These findings suggest that NO plays a key role in the molecular mechanisms of QA-mediated excitotoxicity in experimental model of HD.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinolinic Acid
/
Src-Family Kinases
/
NG-Nitroarginine Methyl Ester
/
Corpus Striatum
/
Enzyme Inhibitors
/
Neurotoxins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Neurosci Res
Year:
2007
Document type:
Article
Affiliation country:
Italy