(R) salsolinol N‐methyltransferase activity increases in parkinsonian lymphocytes

Abstract

Recently, an endogenous catechol isoquinoline, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol], was proved to be a neurotoxin specific for dopamine neurons by in vivo and in vitro experiments. This N-methyl(R)salsolinol was found to increase significantly in the cerebrospinal fluid of untreated parkinsonian patients, suggesting its possible involvement in the pathogenesis of Parkinson's disease. To clarify the mechanism of the increase, the activity of enzymes related to the metabolism of the neurotoxin was examined in lymphocytes prepared from parkinsonian patients and controls. In patients with Parkinson's disease, the activity of a neutral N-methyltransferase, measured by using (R)salsolinol as a substrate, was found to increase significantly (100.2 +/- 81.8 pmol/min/mg of protein) in comparison with that in controls (18.9 +/- 15.0 pmol/min/mg of protein). The distribution of the activity was bimodal in the parkinsonian patients, whereas it was singular in controls. The activity of other related enzymes, an alkaline N-methyltransferase and N-methyl(R)salsolinol oxidase, in parkinsonian lymphocytes was the same as in controls. Increase of the neutral N-methyltransferase may be an endogenous factor in the pathogenesis of Parkinson's disease.

Autotoxicity, methylation and a road to the prevention of Parkinson’s disease

“…1(c) and (d)). [15][16][17][18][19][20][21][22][23][24][25] Some are reported to be increased in PD and/or their N-methylating enzyme increased. They all inhibit complex 1, the chief biochemical event in both MPTP poisoning and in PD.…”

Neuroprotective function of R-(−)-1-(benzofuran-2-yl)-2-propylaminopentane, [R-(−)-BPAP], against apoptosis induced by N-methyl(R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells

“…R-( À )-BPAP was found to increase the biosynthesis and secretion of neurotrophins; such as GDNF, nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF), in mouse asctrocytes, suggesting its neuroprotective potency (Ohta et al, 2002;Shimazu et al, 2003). This paper describes that ( À )-BPAP and related benzofuran derivatives suppressed apoptosis induced by a dopaminergic neurotoxin, N-methyl(R)salsolinol [R(1),N-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, NM(R)Sal] (Maruyama et al, 1996(Maruyama et al, , 2001bNaoi et al, 1998) in human dopaminergic neuroblastoma SH-SY5Y cells. The structure-activity relationship and the mechanism underlying the anti-apoptotic function were studied.…”

Quantitative chiral analysis of salsolinol in different brain regions of rats genetically predisposed to alcoholism

“…It is assumed that there is a relationship between ethanol intake and the levels of salsolinol in different brain regions [4][5][6]. While salsolinol can produce reinforcing effects in the mesolimbic dopamine system, its mechanisms of action are largely unknown [7][8][9][10]. Salsolinol is postulated to result from the condensation of acetaldehyde, the main metabolite of ethanol, with dopamine in the brain of mammals [3,11,12].…”