1,2,3,4,-Tetrahydroisochinolines (TIQ) are endogenous substances present in brain in low concentrations. Several TIQ derivatives are neurotoxic producing a Parkinson’s syndrome. In turn 1-methyl-1- ,2,3,4,-tetrahydroisochinoline (1MeTIQ) was found to reduce neuronal death in various models of neurotoxicity. Our previous results revealed that 1MeTIQ reduces excitotoxicity in the primary culture of rat cerebellar granule cells, inhibits glutamate evoked 45Ca accumulation in neurons and suppresses [3H]MK-801 binding to rat cortical membranes. Thus we hypothesized that this compound may be attributed to NMDA receptor antagonists. To verify this supposition, in the present study we compared the neuroprotective potential of 1MeTIQ with the established uncompetitive NMDA receptor antagonists MK-801 and memantine. The primary cultures of rat cerebellar granule neurons were briefly exposed to glutamate, and the substances tested were either co-applied with the excitotoxin or we tested their ability to induce tolerance to glutamate by pre- or post-conditioning. Consequently, 100, 250 or 500 µM 1MeTIQ, 0.5 µM MK-801 or 5 µM memantine were applied for 30 min either together with glutamate, 24 or 48 h before (pre-conditioning), or 0.5 h, 1 h and 3 h after (post-conditioning) exposure to 100 µM or 250 µM glutamate. Our results demonstrated that MK-801, memantine and 1MeTIQ induce an almost complete neuroprotection when co-applied with glutamate. Similar effects of 1MeTIQ and of the established NMDA receptor antagonists were observed in the pre-treatment experiments, even with 48 h lag between application of tested substances and the excitotoxic challenge. In the post-treatment experiments, MK-801 and memantine as well as 500 µM 1MeTIQ applied up to 3 h after brief exposition to glutamate significantly decreased the excitotoxic lesion, while 1MeTIQ in lower concentrations was ineffective. Thus, we demonstrated that 1MeTIQ acts as a weak NMDA receptor antagonist. The new finding of this study is that 1MeTIQ like MK-801 or memantine is neuroprotective when administered before and after exposure to glutamate. We suggest that 1MeTIQ induces long-lasting tolerance of cultured neurons to the excitotoxic insults, and consequently that the mechanism of neuroprotective effects of 1MeTIQ observed under various experimental conditions may be partially attributed to tolerance developing after pre- or post-treatment of neurons with this substance. The studies were supported by Polish MNiSW grant no. N N401 066438
JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.