Neuroprotective effects of high affinity Σ1 receptor selective compounds

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• The antipsychotic drug haloperidol exhibits neuroprotective properties.
• Neuroprotection is associated with antagonism at D2-like dopamine and sigma receptors.

Purpose of the Study:

• To investigate the link between neuroprotection and receptor antagonism.
• To evaluate novel compounds with varying affinities for sigma and D2-like dopamine receptors.

Main Methods:

• In vitro cytotoxicity assay using HT-22 hippocampal cells exposed to glutamate.
• Evaluation of novel compounds including SV series indoles and benzyl phenylacetamides.
• In vivo assessment using a transient middle cerebral artery occlusion (t-MCAO) stroke model.

Main Results:

• Haloperidol demonstrated potent neuroprotection in vitro; (+)-pentazocine did not.
• Cytoprotection correlated with affinity for sigma 1 receptors.
• LS-127 and LS-137 (benzyl phenylacetamides) reduced infarct volume by ~50% in the t-MCAO model.

Conclusions:

• Sigma 1 receptor selective compounds possess neuroprotective capabilities in cytotoxic conditions.
• Benzyl phenylacetamides targeting sigma 1 receptors are promising therapeutic candidates for stroke and head trauma recovery.