cytochrome-c-t and 6-methyl-2-(phenylethynyl)pyridine

Activation of metabotropic glutamate receptor 5 (mGluR5) has been shown to reduce caspase-dependent apoptosis in primary neuronal cultures induced by staurosporine and etoposide. beta-Amyloid (Abeta)-induced neurotoxicity in culture appears to be in part caspase mediated. In the present studies the effects of treatment with an mGluR5 agonist or antagonist on Abeta-induced neuronal apoptosis were examined in rat cortical neuronal cultures. Pretreatment with the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) markedly reduced the number of apoptotic cells after exposure to Abeta (25-35), as well as associated LDH release. Blockade of mGluR5 by the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP) attenuated these effects of CHPG. A similar neuroprotective effect of mGluR5 activation by CHPG was observed in cultures treated with full-length Abeta peptide (1-42). CHPG attenuated Abeta (25-35)-induced cytochrome c release and decreased levels of active caspase-3 protein. CHPG also reduced translocation of apoptosis-inducing factor (AIF) induced by Abeta (25-35). Thus, mGluR5 activation limits the release of mitochondrial proteins associated with induction of both caspase-dependent and -independent apoptosis.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Apoptosis Inducing Factor; Caspase 3; Caspases; Cells, Cultured; Cerebral Cortex; Cytochromes c; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Flavoproteins; Glycine; Membrane Proteins; Mitochondria; Neurons; Neuroprotective Agents; Peptide Fragments; Phenylacetates; Protein Transport; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Up-Regulation