POLYAMINES MODULATE THE NEUROTOXIC EFFECTS OF NMDA IN-VIVO

The ability of polyamines to alter NMDA-induced neurotoxicity in neona tal rats was examined to determine whether polyamines modulate NMDA re ceptor activity in vivo. Unilateral injections of NMDA and/or polyamin es were made into the striatum of 7-day-old rats. After 5 days, the br ains were removed and 20 Am thick coronal sections were cut and staine d with Cresyl violet. A computer-based image analysis system was used to densitometrically measure the cross-sectional area of intact tissue in the control and injected hemispheres. Administration of NMDA (5-40 nmol) produced a dose-dependent tissue damage that ranged from 7 to 5 2% of the area of the uninjected hemisphere. The polyamine agonist spe rmine (10-500 nmol) dose-dependently exacerbated the toxicity of a 15 nmol dose of NMDA, increasing the size of the lesion by up to 50%. Adm inistration of spermine alone produced dose-dependent tissue damage th at ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antago nist MK-801. The polyamine inverse agonist 1,10-diaminodecane (DA-10, 50-400 nmol) inhibited the damage produced by NMDA in a dose-dependent manner, with a maximal inhibition of 50%. Administration of DA-10 alo ne produced limited damage at doses above 100 nmol. The weak partial a gonist diethylenetriamine had no effect by itself or on NMDA-induced t oxicity at the doses tested. These results indicate that polyamines ca n modulate the activity of NMDA receptors in vivo and suggest that pol yamines or related compounds may have important therapeutic potential as neuroprotective agents.