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

Paolo Gelosa, Cristina Banfi, Maura Brioschi, Elena Nobili, Anita Gianella, Uliano Guerrini, Alice Pignieri, Elena Tremoli, Luigi Sironi

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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.

Original languageEnglish
Pages (from-to)117-124
Number of pages8
JournalEuropean Journal of Pharmacology
Volume604
Issue number1-3
DOIs
Publication statusPublished - Feb 14 2009

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Peroxiredoxin III
Stroke
Glycogen Synthase
Brain
Acute-Phase Proteins
Proteinuria
Diet
Liver
Mitochondrial Proteins
Enzymes
Proteomics
Urea
Animal Models
Antioxidants
Sodium
Magnetic Resonance Imaging
Hypertension
Inflammation
Pharmaceutical Preparations

Keywords

  • Cerebral ischemia
  • Mitochondria
  • Proteome
  • Stroke-prone rats

ASJC Scopus subject areas

  • Pharmacology

Cite this

S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function. / Gelosa, Paolo; Banfi, Cristina; Brioschi, Maura; Nobili, Elena; Gianella, Anita; Guerrini, Uliano; Pignieri, Alice; Tremoli, Elena; Sironi, Luigi.

In: European Journal of Pharmacology, Vol. 604, No. 1-3, 14.02.2009, p. 117-124.

Research output: Contribution to journalArticle

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