S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function.
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.
Gelosa
Paolo
P
Department of Pharmacological Sciences, University of Milan, Italy.
Banfi
Cristina
C
Brioschi
Maura
M
Nobili
Elena
E
Gianella
Anita
A
Guerrini
Uliano
U
Pignieri
Alice
A
Tremoli
Elena
E
Sironi
Luigi
L
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000008:administration & dosage; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D014292:Trimetazidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000209:Acute-Phase Proteins; D000959:Antihypertensive Agents; C541481:S 35171; D012982:Sodium, Dietary; D014292:Trimetazidine