The mechanism of 1,2,3,4-tetrahydroisoquinolines neuroprotection: the importance of free radicals scavenging properties and inhibition of glutamate-induced excitotoxicity.
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), unlike several other tetrahydroisoquinolines, displays neuroprotective properties. To elucidate this action we compared the effects of 1MeTIQ with 1,2,3,4-tetrahydroisoquinoline (TIQ), a compound sharing many activities with 1MeTIQ (among them reducing free radicals formed during dopamine catabolism), but offering no clear neuroprotection. We found that the compounds similarly inhibit free-radical generation in an abiotic system, as well as indices of neurotoxicity (caspase-3 activity and lactate dehydrogenase release) induced by glutamate in mouse embryonic primary cell cultures (a preparation resistant to NMDA toxicity). However, in granular cell cultures obtained from 7-day-old rats, 1MeTIQ prevented the glutamate-induced cell death and 45Ca2+ influx, whereas TIQ did not. This suggested a specific action of 1MeTIQ on NMDA receptors, which was confirmed by the inhibition of [3H]MK-801 binding by 1MeTIQ. Finally, we demonstrated in an in vivo microdialysis experiment that 1MeTIQ prevents kainate-induced release of excitatory amino acids from the rat frontal cortex. Our results indicate that 1MeTIQ, in contrast to TIQ, offers a unique and complex mechanism of neuroprotection in which antagonism to the glutamatergic system may play a very important role. The results suggest the potential of 1MeTIQ as a therapeutic agent in various neurodegenarative illnesses of the central nervous system.
Antkiewicz-Michaluk
Lucyna
L
Department of Biochemistry, Polish Academy of Sciences, Cracow, Poland. antkiew@if-pan.krakow.pl
Lazarewicz
Jerzy W
JW
Patsenka
Antoni
A
Kajta
Malgorzata
M
Zieminska
Elzbieta
E
Salinska
Elzbieta
E
Wasik
Agnieszka
A
Golembiowska
Krystyna
K
Vetulani
Jerzy
J
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002127:Calcium Isotopes / Q000493:pharmacokinetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D016166:Free Radical Scavengers / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D005998:Glycine / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D017551:Microdialysis / Q000379:methods; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D013997:Time Factors
D002127:Calcium Isotopes; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D018698:Glutamic Acid; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; C014843:1,2,3,4-tetrahydroisoquinoline; D016291:Dizocilpine Maleate; D007770:L-Lactate Dehydrogenase; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005998:Glycine; D004298:Dopamine