Rasagiline and its (S) enantiomer increase survival and prevent stroke in salt-loaded stroke-prone spontaneously hypertensive rats

The aim of this study was to determine whether chronic treatment with the s elective MAO-B inhibitor rasagiline, N-propargyl-1-(R)-aminoindan (R-PAI), can prevent or delay stroke or improve its outcome in salt-loaded stroke-pr one spontaneously hypertensive rats (SHRSP). The S-enantiomer of rasagiline , S-PAI a much weaker MAO inhibitor was included in the study in order to e xpose a possible contribution from MAO inhibition to any beneficial effect by R-PAL SHRSP were isolated, fed rat stroke prone diet and given 1% NaCl i nstead of water. Drugs were administered in the drinking fluid for 84 days. Rats were grouped as follows: (1) Untreated control; (2) R-PAI 1 mg/kg/day ; (3) R-PAI 3 mg/kg/day; (4) S-PAI 3 mg/kg/day; (5) S-PAI 6 mg/kg/day. Surv ival, stroke frequency and neurological severity score following stroke wer e determined. R-PAI at 3 mg/kg/day significantly increased cumulative survi val from 56.09 +/- 1.77 days in the untreated to 73.6 +/- 2.22 days in the R-PAI treated; S-PAI at 6 mg/kg/day to 78.61 +/- 2.05 (censored at 84 days) . In these groups stroke was delayed, its incidence was decreased and its o utcome was less severe than in the control group. Proteinurea observed in t he untreated rats and in both lower dose groups of R-PAI and S-PAI was abse nt in the higher dose groups of both drugs. Histological examination of the brains and kidneys showed that the effects on stroke and survival were ass ociated with decreased infarcts and hemorrhages in the brains and decreased tubular nephropathy and glomerulopathy. The time-dependent rise in systoli c blood pressure in the untreated rats was significantly attenuated only in the R-PAI group at 3 mg/kg/day but not in the S-PAI group. There were no s ignificant effects on heart rate. MAO-B activity in the brain was 95% block ed by both doses of R-PAI but only 62% by S-PAI at 6 mg/kg/day. In salt-loa ded SHRSP chronic therapy with either R-PAI or S-PAI prevented stroke and s evere vascular lesions in the kidney. When stroke did occur its neurologica l outcome was less severe. The drugs were equipotent when they were given a t a ratio of 1:2. The mechanism has yet to be elucidated. The differential effects of the drugs on blood pressure and MAO inhibition rule out either e ffect as the sole explanation.