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

Abstract

Background and aim: Tetrahydrobiopterin (BH₄) 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 BH₄ level and redox status in the brain by using the rat model of sepsis-induced by cecal ligation and puncture (CLP) and examined whether BH₄ 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 + BH₄, sham + ALC, sham +BH₄+ ALC, CLP, CLP + BH₄, CLP + ALC, and CLP+BH₄+ ALC. We measured neurological indicators, brain levels of BH₄, guanosine triphosphate cyclohydrolase (GTPCH), sepiapterin reductase (SR) and dihydropteridine reductase (DHPR) genes expression (Essential enzymes in BH₄ 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 BH₄ bioavailability, downregulation of BH₄ synthetic enzymes, increased production of hydrogen peroxide and impaired antioxidant enzymes activities. Treatments with BH₄ and/or ALC increased BH₄ level, upregulated BH₄ synthetic enzymes expressions, and attenuated oxidative-induced neuronal apoptosis.

Conclusion: Our results suggest that BH₄ and/or ALC might protect the brain against oxidative stress induced neuronal apoptosis by restoring bioavailability of BH₄ and upregulating of BH₄ synthetic enzymes in the brain during sepsis.

Keywords: Apoptosis; Brain; Encephalopathy; Oxidative stress; Sepsis; Tetrahydrobiopterin.