Possible involvement of tetrahydrobiopterin in the disturbance of redox homeostasis in sepsis - Induced brain dysfunction.

Background and Aim: Tetrahydrobiopterin (BH ₄ ) is an essential co-factor that regulates nitric oxide (NO) and reactive oxygen species (ROS) production by nitric oxide synthases (NOS). In this study, we evaluated the effects of sepsis on BH ₄ level and redox status in the brain by using the rat model of sepsis-induced by cecal ligation and puncture (CLP) and examined whether BH ₄ and/or acetyl-L-carnitine (ALC) could prevent the neuronal apoptosis and neurological changes induced by sepsis.
Material and Method: Male albino rats were randomly and blindly divided into 8 groups: sham, sham + BH ₄ , sham + ALC, sham +BH ₄ + ALC, CLP, CLP + BH ₄ , CLP + ALC, and CLP+BH ₄ + ALC. We measured neurological indicators, brain levels of BH ₄ , guanosine triphosphate cyclohydrolase (GTPCH), sepiapterin reductase (SR) and dihydropteridine reductase (DHPR) genes expression (Essential enzymes in BH ₄ biosynthesis and recycling pathways). We investigated also brain redox status and both endothelial and inducible NOS expressions.
Results: Brain of septic rats demonstrated a reduced BH ₄ bioavailability, downregulation of BH ₄ synthetic enzymes, increased production of hydrogen peroxide and impaired antioxidant enzymes activities. Treatments with BH ₄ and/or ALC increased BH ₄ level, upregulated BH ₄ synthetic enzymes expressions, and attenuated oxidative-induced neuronal apoptosis.
Conclusion: Our results suggest that BH ₄ and/or ALC might protect the brain against oxidative stress induced neuronal apoptosis by restoring bioavailability of BH ₄ and upregulating of BH ₄ synthetic enzymes in the brain during sepsis.
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