Neuroprotective potential of 1-methyl-1,2,3,4,-tetrahydroisochinoline in brain ischemia: role of NMDA receptor antagonism

• Autorzy: Duszczyk M. , Kuszczyk M. , Makarewicz D. , Salinska E. , Antkiewicz-Michaluk L. , Lazarewicz J.W.
• Języki publikacji: EN

Abstrakty

EN

Various endogenous teterahydroisochinoline derivatives present in the mammalian brain have been considered as neurotoxic substances. However 1-methyl-1,2,3,4-tetrahydroisochinoline (1MeTIQ) is known for its mild neuroprotective potential of the unclear mechanism. On the one hand 1MeTIQ exhibits anti-dopaminergic activity and reduces the neurotoxic effects of MPTP and rotenone, decreasing also the behavioral effects of MK-801 in rats in vivo. On the other hand the results of our previous study demonstrated that 1MeTIQ in vitro prevents glutamate-induced excitotoxicity in cultured neurons suggesting that this effect may be ascribed to its inhibitory effect on NMDA receptors. It is well known that the antagonists of NMDA receptors provide neuroprotection in brain ischemia, however the anti ischemic properties of 1MeTIQ were not tested previously. The aim of our present study was to verify in vitro putative antagonistic effects of 1MeTIQ on the NMDA receptors and to evaluate its neuroprotective potential in the animal models of brain ischemia. The receptor binding experiments using membranous fractions isolated from the rat brain cortex confirmed that 1MeTIQ in high micro molar concentrations inhibits in a concentration-dependent manner the specific binding of [3H] MK-801, while the binding of [3H]glutamate remains unaffected. The hypothesis that 1MeTIQ may be attributed to NMDA receptor antagonists acting as channel blockers was also supported by the results of experiments utilizing primary cultures of rat cerebellar granule cells submitted to acute NMDA and glutamate excitotoxicity. Under these conditions 1MeTIQ applied at high micro molar concentrations provided a pronounced neuroprotection and significantly inhibited generation of the calcium signal. The in vivo ischemic experiments demonstrated that application of 1MeTIQ in the dose of 50 mg/kg 30 min before the insult in the model of global forebrain ischemia in Mongolian gerbils or its repeated application in the same dose after hypoxia-ischemia in the rat model of perinatal asphyxia provided significant neuroprotection. In the gerbils treated with 1MeTIQ we observed the morphological and behavioral symptoms of neuroprotection and the postischemic hypothermia characteristic for medication of brain ischemia with the NMDA receptor antagonists. Collectively these data offer new arguments confirming the hypothesis that 1MeTIQ acts as a weak uncompetitive antagonist of NMDA receptors, providing the neuroprotection under various excitotoxic and ischemic conditions both in vitro and in vivo.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: 1
• Opis fizyczny: p.153-154

Twórcy

autor

Duszczyk M.

• Mossakowski Medical Research Centre, Department of Neurochemistry, Polish Academy of Sciences, Warsaw, Poland

autor

Kuszczyk M.

• Mossakowski Medical Research Centre, Department of Neurochemistry, Polish Academy of Sciences, Warsaw, Poland

autor

Makarewicz D.

• Mossakowski Medical Research Centre, Department of Neurochemistry, Polish Academy of Sciences, Warsaw, Poland

autor

Salinska E.

• Mossakowski Medical Research Centre, Department of Neurochemistry, Polish Academy of Sciences, Warsaw, Poland

autor

Antkiewicz-Michaluk L.

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

autor

Lazarewicz J.W.

• Mossakowski Medical Research Centre, Department of Neurochemistry, Polish Academy of Sciences, Warsaw, Poland