MGLuR5 activation reduces beta-amyloid-induced cell death in primary neuronal cultures and attenuates translocation of cytochrome c and apoptosis-inducing factor.
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.
Movsesyan
Vilen A
VA
Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Stoica
Bogdan A
BA
Faden
Alan I
AI
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D010648:Phenylacetates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C107349:2-chloro-5-hydroxyphenylglycine; C494831:Aifm1 protein, rat; D016229:Amyloid beta-Peptides; D051033:Apoptosis Inducing Factor; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005420:Flavoproteins; C578937:Grm5 protein, rat; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010648:Phenylacetates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C121465:6-methyl-2-(phenylethynyl)pyridine; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005998:Glycine