σ receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures

The role of the putative σ receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective σ₁ ligand (+)-3-PPP, all of the σ ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC₅₀ values) was as follows: (+)-SKF 10,047 (0.81 μM) > (+)- cyclazocine (2.3 μM) > dextromethorphan (3.1 μM) = haloperidol (3.7 μM) > (+)-pentazocine (8.5 μM) > DTG (42.7 μM) = carbetapentane (46.3 μM). When corrected for relative σ versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and σ₁ site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the σ₂ site. Critically, none of the σ ligands were neurotoxic when tested alone at concentrations at least 5–30 times their respective neuroprotective EC₅₀ values. Results from preliminary experiments with the selective σ₁ ligand (+)-pentazocine indicated that σ-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that σ ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.