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 selective MAO-B inhibitor rasagiline, N-propargyl-1-(R)-aminoindan (R-PAI), can prevent or delay stroke or improve its outcome in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). The S-enantiomer of rasagiline, S-PAI a much weaker MAO inhibitor was included in the study in order to expose a possible contribution from MAO inhibition to any beneficial effect by R-PAI. SHRSP were isolated, fed rat stroke prone diet and given 1% NaCl instead 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. Survival, stroke frequency and neurological severity score following stroke were determined. R-PAI at 3 mg/kg/day significantly increased cumulative survival 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 outcome was less severe than in the control group. Proteinurea observed in the untreated rats and in both lower dose groups of R-PAI and S-PAI was absent in the higher dose groups of both drugs. Histological examination of the brains and kidneys showed that the effects on stroke and survival were associated with decreased infarcts and hemorrhages in the brains and decreased tubular nephropathy and glomerulopathy. The time-dependent rise in systolic 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 significant effects on heart rate. MAO-B activity in the brain was 95% blocked by both doses of R-PAI but only 62% by S-PAI at 6 mg/kg/day. In salt-loaded SHRSP chronic therapy with either R-PAI or S-PAI prevented stroke and severe vascular lesions in the kidney. When stroke did occur its neurological outcome was less severe. The drugs were equipotent when they were given at 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 effect as the sole explanation.
Eliash
S
S
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Israel. seliash@ccsg.tau.ac.il
Speiser
Z
Z
Cohen
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D007189:Indans / Q000097:blood*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D013237:Stereoisomerism; D020521:Stroke / Q000097:blood / Q000517:prevention & control*; D015996:Survival Rate; D016896:Treatment Outcome
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D012965:Sodium Chloride