Farnesyl-L-cysteine analogs block SAM-induced Parkinson's disease-like symptoms in rats

Injection of the endogenous methyl donor, S-adenosyl methionine (SAM), into rat brain induces Parkinson's disease (PD)-like symptoms possibly by stimu lating deleterious protein methylation. Gel-filtration chromatography of ra t brain extracts treated with [H-3-methyl]-SAM revealed the presence of rad ioactive peaks with apparent molecular weights of about 5 kDa. Treatment wi th guanidine HCl altered the elution volumes of the labeled peaks. Lyophili zed peak fractions released volatile H-3-methanol on incubation with NaOH, indicating the presence of carboxyl methyl esters. Because prenylated prote ins are avid methyl accepters at the terminal carboxylic acid groups, 1 mu mol S-farnesylcysteine (FC) analogs blocked the SAM-induced tremors in the experimental rats. FC analogs did nut only reverse the associated rigidity, abnormal posture, and hypokinesia, but stimulated hyperactivity in the ani mals. This amphetamine-like effect was monitored for 20 min in an animal ac tivity monitor and movement times between 400 +/- 100 and 560 +/- 125 s cov ering distances between 78 +/- 29 to 125 +/- 35 m were recorded for rats tr eated with FC analogs with or without SAM. Control animals moved only for 6 0 +/- 13 s covering about 6 +/- 1 m, indicating a 7-9-fold and 13-21-fold i ncrease in duration of movement and distance covered, respectively. N-Acety l-S-farnesylcysteine (AFC) potentiated amphetamine-induced ipsiversive rota tion of 6-hydroxydopamine-lesioned rats from 390 +/- 130 to 830 +/- 110, wi th AFC alone having no significant effect on net rotation compared to contr ols. These data indicate that intracerebroventricular injection of SAM may induce PD symptoms by interfering with the methylation/demethylation homeos tasis of prenylated proteins that function in the dopaminergic and other si gnaling pathways, and that the FC analogs may counteract the SAM effects by acting synergistically on events subsequent to neurotransmitter release. ( C) 2000 Elsevier Science Inc.