N-methyl-(r) salsolinol and the enzymes catalyzing its synthesis and metabolism in parkinson's disease

Abstract

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is an endogenous catechol isoquinoline detected in the human brain. It is produced by the nonenzymatic Pictet-Spengler reaction as the racemic mixture. However, a novel enzyme, (R)salsolinol synthase, was isolated from the human brain, which catalyzes the enantio-specific synthesis of (R)salsolinol from dopamine and acetaldehyde or keto acids. R-Salsolinol is N-methylated by (R)salsolinol N-methyltransferase (N-MT) into 2(N)-methyl-(R)salsolinol [NM-(R)Sal], which is oxidized by an oxidase sensitive to semicarbazide. NM-(R)Sal induces cell death in the dopaminergic cells of the rat substantia nigra after the systemic administration. The behavioral and pathological changes in rats were quite similar to those in other animal models of Parkinson's disease, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine. In cellular experiments, NM-(R)Sal binds to type A monoamine oxidase and induces apoptosis through activation of mitochondrial death signaling. Furthermore, NM-(R)Sal levels increase in the cerebrospinal fluid from parkinsonian patients, and the activity of its synthesizing neural (R)Sal N-MT is significantly higher in the lymphocytes prepared from parkinsonian patients than in control. The enantioselective neurotoxicity of NM-(R)Sal suggests that the enzymes related to the synthesis of this toxin might be associated with the etiology for PD. This chapter reviews the role of N-methylated isoquinolines and enzymes catalyzing N-methylation of small molecules in the pathogenesis of Parkinson's disease.