CNS Injury Models Research Articles

Dextromethorphan analogs are neuroprotective in vitro and block glutamate-induced excitotoxic calcium signals in neurons

Consistent with the neuroprotective effects of the non-opioid antitussive dextromethorphan (DM) described in several models of CNS injury, micromolar concentrations of three novel analogs of DM markedly attenuated the injury produced by glutamate in cultured rat cortical neurons. Furthermore, the neuroprotective actions of the DM analogs correlated with their effects to block glutamate-induced excitotoxic calcium signals and were unrelated to metabolism to the phencyclidine (PCP)-like drug dextrorphan (DX). These observations establish a new class of compounds related to DM which, by virtue of their efficacy to protect neurons against a severe glutamate insult, may possess therapeutic potential as treatment modalities for a number of neurodegenerative diseases.

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 σ 1 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 EC 50 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 σ 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the σ 2 site. Critically, none of the σ ligands were neurotoxic when tested alone at concentrations at least 5–30 times their respective neuroprotective EC 50 values. Results from preliminary experiments with the selective σ 1 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.