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Effect of nicotinamide (NAM) on neuronal apoptosis and vasopressin secretion during experimental sepsis

Grant number: 14/08017-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2015
Effective date (End): December 31, 2016
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Maria José Alves da Rocha
Grantee:Najeeb Ullah
Home Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Despite considerable technological advances, systemic infections, including sepsis and its complications (septic shock and multiple organ dysfunctions) is still a major clinical challenge and major cause of death in Intensive Care Units all over the world. In Brazil, the mortality rate for sepsis is 57.3%(ILAS, 2010), or the other way round, 42.7% of the patients are able to survive. Moreover, these patients that leave the hospital may have cognitive alterations, resulting in future admissions, burdening even more the national public health system. Impairment of memory, attention, concentration and/or loss of general cognitive functions are some of the dysfunctions reported to be due to encephalopathy in such patients. Important progress in the comprehension of the pathophysiology of sepsis has been made through experiments, but many more studies are still needed to come to a more profound understanding of the encephalopathy- neuronal dysfunctions associated to this disease. Sepsis induces excessive production and release of inflammatory mediators such as cytokines, chemokines, nitric oxide (NO), leukotrienes, etc. These may directly or indirectly affect the brain causing besides cognitive, autonomic, and neuroendocrine dysfunction (Chong et al., 2002). One of the neuroendocrine alterations that puzzle the medical doctors and scientists is the vasopressin secretion impairment that occurs during the late phase of sepsis, despite the persistent hypotension that can cause septic shock and death.Recently a wide range of clinical and experimental studies have reported that in the addition to brain ischemic damage, septic shock is characterized by neuronal and glial apoptosis, which is more likely to be triggered by the pro-inflammatory mediator nitric oxide. Therefore the main objective of this work is to fully characterize sepsis-associated biochemical and histopathological changes in brains of rat after sepsis induced by peritonitis. These changes and its consequence in neuroendocrine alterations seen in sepsis may be prevented by treatment with the free radical scavenger nicotinamide (NAM). The proposal of this project is to understand the mechanism of sepsis-induced cell death, thatcould lead to the development of new therapeutic approaches for brain cell protection during sepsis. In this project, we will study if NAM has a protective role against sepsis induced cell death in the CNS in rat model by various approaches. Changes in expression levels of different mRNA and their protein involved in cell death pathways, and vasopressin synthesis will be analyzed in the brain of septic rats. Secondly, effects of NAM administration will be determined on these neuronal alterations and vasopressin secretion.