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2011 | 71 | 1 |

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The group III metabotropic glutamate receptor agonists attenuate neuronal cell death in primary cortical cultures exposed to oxygen-glucose deprivation

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Oxygen-glucose deprivation (OGD) induces excitotoxic cell death mediated primarily by excessive release of glutamate. A growing body of evidence suggests that metabotropic glutamate (mGlu) receptors can modulate glutamatergic transmission, so these receptors are regarded as potential targets for neuroprotective drugs. Group III mGluRs (mGlu4, mGlu6, mGlu7 and mGlu8) agonists are known to reduce glutamatergic neurotransmission by inhibiting glutamate release. Therefore in the present study we tried to find out whether the agonist of group III mGluR (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1) and the first selective allosteric mGlu7 receptor agonist, N,N’-bis (diphenylmethyl)-1,2- ethanediamine (AMN082) have neuroprotective potential in primary neuronal cortical cultures exposed to oxygen-glucose deprivation, as an in vitro ischemic injury paradigm. In order to evoke toxic effects cortical cultures were exposed to OGD for 1 - 5 h. ACPT-1, at concentrations of 1, 10, 100 and 200 µM, or AMN082, at concentrations of 0.01, 0.1, 0.5 and 1 µM, were applied in two ways: twice, just before the start of OGD and immediately after OGD or once, immediately after OGD. Neurotoxicity was measured by lactate dehydrogenase (LDH) efflux from the damaged cells into the culture media 24 h after the end of OGD. It was found that a double application of ACPT-1 or AMN082 significantly attenuated the LDH release by 20-30% and 30-43%, respectively. A particularly important finding is that AMN082, given once after the end of OGD also significantly decreased ischemic-induced LDH release by 30%. These data were confirmed by immunohistochemical staining for the presence of characteristic neuronal protein MAP-2. In conclusion, the above results indicate that group III mGlu receptor agonists may have neuroprotective potential and may play a potential therapeutic role in neurodegenerative disorders. The study was supported by Grant No N N401 091037 from the MSHE, Poland.

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  • Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
  • Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
  • Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland


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