Inhibitory effects of endogenous dopaminergic neurotoxin, norsalsolinol ondopamine secretion in PC12 rat pheochromocytoma cells

Naturally occurring neurotoxins, 6,7-dihydroxy-1,2,3,3-tetrahydroisoquinoli nes (DHTIQs), thought to be the causative agents of Parkinsonism. DHTIQs in cluding norsalsolinol have been found in the mammalian central nervous syst em. Norsalsolinol can be formed by a non-enzymatic Pictet-Spengler condensa tion reaction between dopamine and formaldehyde, and has been detected in t he urine of Parkinsonian patients. However, the effects of DHTIQs on the se cretion of dopamine, as well as other neurotransmitters, are not well under stood. This study investigated the effects of norsalsolinol on dopamine sec retion from nerve growth factor-differentiated PC12 cells. Norsalsolinol (1 -100 muM) pretreatment suppressed both ATP (100 muM)- and K+ (50 mM)-induce d dopamine secretion from PC12 cells in a concentration-dependent fashion, but did not affect basal dopamine secretion. In beta -escin-permeabilized P C12 cells, norsalsolinol pretreatment suppressed Ca2+ (pCa = 4-8)-induced d opamine secretion, but did not inhibit the secretagogue-induced change in i ntracellular Ca2+ concentration. These results suggest that norsalsolinol c auses the inhibition of secretagogue-induced dopamine secretion from PC12 c ells without altering intracellular Ca2+ concentration. Inhibition of dopam ine secretion by norsalsolinol may also be involved in postural abnormality in Parkinson's disease. (C) 2001 Elsevier Science Ltd. All rights reserved .