12604665

pubmed:Citation

3

Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.

eng

IM

MEDLINE

0022-3565

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NLM

913-23

pubmed-meshheading:12604665-8-Hydroxy-2-(di-n-propylamino)tetralin, pubmed-meshheading:12604665-Animals, pubmed-meshheading:12604665-Apoptosis, pubmed-meshheading:12604665-Calcium, pubmed-meshheading:12604665-Caspase 3, pubmed-meshheading:12604665-Caspases, pubmed-meshheading:12604665-Cells, Cultured, pubmed-meshheading:12604665-Corpus Striatum, pubmed-meshheading:12604665-Enzyme Activation, pubmed-meshheading:12604665-Excitatory Amino Acid Agonists, pubmed-meshheading:12604665-N-Methylaspartate, pubmed-meshheading:12604665-Neuroprotective Agents, pubmed-meshheading:12604665-Periaqueductal Gray, pubmed-meshheading:12604665-Rats, pubmed-meshheading:12604665-Rats, Sprague-Dawley, pubmed-meshheading:12604665-Receptors, Serotonin, pubmed-meshheading:12604665-Receptors, Serotonin, 5-HT1, pubmed-meshheading:12604665-Serotonin Receptor Agonists

5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures.

Journal Article, Research Support, U.S. Gov't, P.H.S.