THE MODULATORY ROLE OF NITRIC-OXIDE IN THE REGULATION OF PROENKEPHALIN AND PRODYNORPHIN GENE EXPRESSIONS INDUCED BY KAINIC ACID IN RAT HIPPOCAMPUS

The effect of L-arginine (L-ARG), a nitric oxide donor, or N-omega-nit ro-L-arginine (L-NAME), a nitric oxide synthase inhibitor, on the regu lation of kainic acid(KA)-induced proenkephalin (proENK) and prodynorp hin (proDYN) mRNA expressions in rat hippocampus was studied. The proE NK and proDYN mRNA levels were markedly increased 6 h after KA (10 mg/ kg, i.p.) administration. The elevations of both proENK and proDYN mRN A levels induced by KA was effectively inhibited by pre-administration of L-ARG (400 mg/kg, i.p.), but was not affected by pre-treatment wit h L-NAME (200 mg/kg, i.p.). The blockade of KA-induced proENK and proD YN mRNA levels by the pre-treatment with L-ARG was well correlated wit h proto-oncoprotein levels, such as c-Fos, Fra-2, FosB, JunD, JunB, an d c-Jun, as well as AP-1 and ENKCRE-2 DNA binding activities. The pre- administration with L-NAME further increased KA-induced c-jun and c-fo s mRNA levels in addition to their protein product levels, although th e pre-treatment with L-NAME did not affect KA-induced FosB, Fra-2, Jun B, and JunD protein levels at 6 h after treatment. In addition, the pr e-administration with L-NAME further increased the KA-induced AP-1 and ENKCRE-2 DNA binding activities. Our results suggest that L-ARG plays an important role in inhibiting KA-induced proENK or proDYN mRNA expr ession, and its inhibitory action may be mediated through reducing the proto-oncoprotein levels, such as c-Fos, Fra-2, FosB, c-Jun, JunD, an d JunB. In addition, L-NAME potentiated the c-Fos or c-Jun gene expres sion, as well as AP-1 or ENKCRE-2 DNA binding activity. However, these increases did not show the potentiative effect on KA-induced increase s of proENK and proDYN mRNA level. (C) 1998 Elsevier Science B.V.