S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function.

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.

• Authors: Paolo Gelosa, Cristina Banfi, Maura Brioschi, Elena Nobili, Anita Gianella, Uliano Guerrini, Alice Pignieri, Elena Tremoli, Luigi Sironi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 604 Issue 1-3 Pg. 117-24 (Feb 14 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19135993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acute-Phase Proteins
• Antihypertensive Agents
• S 35171
• Sodium, Dietary
• Trimetazidine

Topics

• Acute-Phase Proteins (biosynthesis, urine)
• Animals
• Antihypertensive Agents (administration & dosage, pharmacology, therapeutic use)
• Blood Pressure (drug effects)
• Blotting, Western
• Electrophoresis, Gel, Two-Dimensional
• Hypertension (complications, drug therapy, pathology)
• Liver (drug effects, metabolism)
• Magnetic Resonance Imaging
• Male
• Mitochondria (drug effects, enzymology, metabolism, physiology)
• Proteinuria (prevention & control)
• Rats
• Rats, Inbred SHR
• Sodium, Dietary (administration & dosage)
• Stroke (etiology, pathology, prevention & control)
• Trimetazidine (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)