Thesis (Ph.D.) - Cairo University - Faculty of Medicine - Department of Physiology

The increased incidence of sepsis worldwide raised the attention of its early and frequent complication which is the brain dysfunction that is associated with high morbidity and mortality and can result in neurocognitive impairment. However the pathophysiology of sepsis associated brain dysfunction is complex and multifactorial, it is still poorly understood. The present study aimed to investigate tetrahydrobiopterin (BH4) alteration during sepsis and its effect on nitro-oxidative stress in the brain and related neurocognitive impairment and the possible modulatory role of carnitine in such impairment. To achieve this aim, albino rats were submitted to either laparotomy only or sepsis induction. The animals received either vehicle, BH, carnitine or BH4 and carnitine. Neurocognitive assessments were done using modified Bederson's neurological examination and novel object recognition task. 24 hours after sepsis induction, the animals were sacrificed. The peripheral and central IL-6 levels were measured. Also, oxidative stress parameters in the brain were measured (MDA level, H2O2 level, catalase and superoxide dismutase activities, eNOS and iNOS gene expression).In addition, the gene expression of the synthetic enzymes of BH4 (GTPCH1, SR and DHFR) and its level were assessed. Some brain regions were assessed histologically to evaluate the neuronal apoptosis and their aquaporin 4 levels. The results showed that sepsis induced an attenuation of the brain level of BH4 which was associated with an enhancement of the oxidative stress. BH4 and /or carnitine supplementation attenuated the increase in the peripheral IL-6 level and the increase in oxidative stress in the brain and ameliorated the neuronal apoptosis in hippocampus, frontal cortex and cerebellum with subsequent improvement of the neurocognitive outcome

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