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In vitro and in vivo protective effect of orphenadrine on glutamate neurotoxicity

Abstract:

The anticholinergic drug orphenadrine is used in the treatment of Parkinson's disease. In this study we evaluate the neuroprotective effects of orphenadrine on excitotoxicity in vivo and in vitro. Orphenadrine prevented the mitochondrial and the cytoplasmic membrane potential decrease evoked by NMDA (100 μM) in rat dissociated cerebellar granule cells showing an IC50 value of 11.6±4.7 μM (mean±SEM, n=5) and 13.5±2.3 μM (n=3), respectively. Orphenadrine was able to protect cerebellar granule cell cultures from glutamate-induced neurotoxicity. Kainic acid (KA, 10 mg/kg)-induced excitotoxicity was evaluated in vivo using the microglial marker peripheral-type benzodiazepine receptor (PBR) and heat shock protein 72 (HSP72) expression in the hippocampus. The B(max) of PBR for control tissues was 589.1±40.0 fmol/mg protein (n=4), increasing to 1692.5±51.6 fmol/mg protein (n=5) after the KA treatment. Pretreatment with orphenadrine (10 mg/kg) blocked the KA-induced increase in PBR density. As expected, KA-administration induced the expression of HSP72 that was blocked in the orphenadrine+KA-treated rats. We demonstrate that orphenadrine, interacting at the NMDA receptor, is able to prevent the neurotoxicity mediated by activation at glutamate ionotropic receptors. Copyright (C) 1999 Elsevier Science Ltd.