Polyamines modulate the neurotoxic effects of NMDA in vivo.
The ability of polyamines to alter NMDA-induced neurotoxicity in neonatal rats was examined to determine whether polyamines modulate NMDA receptor activity in vivo. Unilateral injections of NMDA and/or polyamines were made into the striatum of 7-day-old rats. After 5 days, the brains were removed and 20 microns thick coronal sections were cut and stained 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 52% of the area of the uninjected hemisphere. The polyamine agonist spermine (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%. Administration of spermine alone produced dose-dependent tissue damage that ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antagonist 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 alone produced limited damage at doses above 100 nmol. The weak partial agonist diethylenetriamine had no effect by itself or on NMDA-induced toxicity at the doses tested. These results indicate that polyamines can modulate the activity of NMDA receptors in vivo and suggest that polyamines or related compounds may have important therapeutic potential as neuroprotective agents.
Munir
M
M
Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104.
Subramaniam
S
S
McGonigle
P
P
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D003959:Diamines / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000494:pharmacology*
C065351:1,10-diaminodecane; D003959:Diamines; D009498:Neurotoxins; D011073:Polyamines; C005391:diethylenetriamine; D013096:Spermine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate