PMID:19135993

Citation	Gelosa, P, Banfi, C, Brioschi, M, Nobili, E, Gianella, A, Guerrini, U, Pignieri, A, Tremoli, E and Sironi, L (2009) S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function. Eur. J. Pharmacol. 604:117-24
Abstract	S 35171 is one of a family of compounds that have been designed to protect mitochondrial function. We tested the hypothesis that S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats (SHRSPs), an animal model developing spontaneous brain damage preceded by proteinuria and systemic inflammation revealed by the urinary accumulation of acute-phase proteins (APPs) originating in the liver. Male SHRSPs fed a permissive diet received vehicle or S 35171 (10 mg/kg/day) started simultaneously with a high-sodium diet (group A) or after the establishment of proteinuria (group B). The drug delayed urinary APPs accumulation and the appearance of magnetic resonance imaging (MRI)-monitored brain lesions (after 62+/-3 days in group A, and 51+/-2 days in controls, P<0.01). The delay was more pronounced in group B as 30% of the animals survived the entire 90-day experimental period without brain abnormality. Proteomic analysis showed no significant alteration in the expression pattern of brain mitochondrial proteins, but the liver mitochondrial levels of carbamoylphosphate synthase I (CPS-I), an enzyme involved in urea metabolism) and the antioxidant peroxiredoxin-3 spot were affected by hypertension and S 35171. Stress reduces CPS-I and induces the peroxiredoxin-3 spot, whereas S 35171 brought about normal CPS-I expression and a 12-fold higher level of the peroxiredoxin-3 spot. As both enzymes are involved in maintaining mitochondrial functions, their increased expression after S 35171 treatment may be responsible for delaying the pathological condition that leads to the development of brain damage in SHRSPs.
Links	PubMed Online version:10.1016/j.ejphar.2008.12.027
Keywords	Acute-Phase Proteins/biosynthesis; Acute-Phase Proteins/urine; Animals; Antihypertensive Agents/administration & dosage; Antihypertensive Agents/pharmacology; Antihypertensive Agents/therapeutic use; Blood Pressure/drug effects; Blotting, Western; Electrophoresis, Gel, Two-Dimensional; Hypertension/complications; Hypertension/drug therapy; Hypertension/pathology; Liver/drug effects; Liver/metabolism; Magnetic Resonance Imaging; Male; Mitochondria/drug effects; Mitochondria/enzymology; Mitochondria/metabolism; Mitochondria/physiology; Proteinuria/prevention & control; Rats; Rats, Inbred SHR; Sodium, Dietary/administration & dosage; Stroke/etiology; Stroke/pathology; Stroke/prevention & control; Trimetazidine/administration & dosage; Trimetazidine/analogs & derivatives; Trimetazidine/pharmacology; Trimetazidine/therapeutic use
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