SIGMA-RECEPTOR-MEDIATED NEUROPROTECTION AGAINST GLUTAMATE TOXICITY INPRIMARY RAT NEURONAL CULTURES

The role of the putative a receptor in mediating neuroprotection again st glutamate-induced neuronal injury was examined in mature cultured r at cortical neurons. With the exception of the selective sigma(1) liga nd (+)-3-PPP, all of the sigma ligands tested were neuroprotective, pr eventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC(50) value s) was as follows: (+)-SKF 10,047 (0.81 mu M)>(+)-cyclazocine (2.3 mu M)>dextromethorphan (3.1 mu M) = haloperidol (3.7 mu M)>(+)-pentazocin e (8.5 mu M)>DTG (42.7 mu M) = carbetapentane (46.3 mu M). When correc ted for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma( 1) site affinity. However, there does not appear to be a significant c orrelation between neuroprotective potency and the sigma(2) site. Crit ically, none of the a ligands were neurotoxic when tested alone at con centrations at least 5-30 times their respective neuroprotective EC(50 ) values. Results from preliminary experiments with the selective sigm a(1) ligand (+)-pentazocine indicated that sigma-mediated neuroprotect ion may involve the buffering of glutamate-induced calcium flux. Colle ctively, the results of these in vitro experiments demonstrate that si gma ligands are neuroprotective and therefore deserve further explorat ion as potential therapeutic agents in in vivo models of CNS injury an d neurodegenerative disorders.