Banca de DEFESA: ISABELLY DE OLIVEIRA PINHEIRO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : ISABELLY DE OLIVEIRA PINHEIRO
DATE: 31/07/2024
TIME: 14:00
LOCAL: Sala de Videoconferência - Faculdade de Medicina - UFCA
TITLE:

Evaluation of the effects of diazoxide on brain damage secondary to lipopolysaccharide-induced sepsis in mice

KEY WORDS:

Diazoxide. Sepsis. Brain damage. Lipopolysaccharide. Oxidative stress.

PAGES: 100
BIG AREA: Ciências da Saúde
AREA: Medicina
SUMMARY:

Sepsis is defined as organ dysfunction caused by a deregulated host response to infection and is associated with high mortality. The administration of lipopolysaccharide (LPS) is considered an attractive animal model of gram-negative sepsis. During sepsis, there is an inflammatory process that results in dramatic changes in cellular metabolism and increases in oxidative stress that promote cytotoxic effects. Studies have shown the drug diazoxide (DZX) to be an effective modulator of the intracellular pathways involved in the response to oxidative stress, reporting protective action against myocardial ischemia, neuroprotective action in spinal cord injuries and cerebral ischemia. Diazoxide is an ATP-sensitive potassium channel inhibitor, classically prescribed as a hyperglycemic agent in cases of hypoglycemia, as well as for its antihypertensive effect in rapidly reducing blood pressure. The aim of this study was to evaluate the effects of diazoxide on brain damage secondary to sepsis induced by lipopolysaccharides in mice. The experimental protocol was approved by the Ethics Committee for the Use of Animals of the Federal University of Cariri (CEUA-UFCA, protocol no. 002/2024). Adult male Swiss mice (20 to 25 g) from the Animal Experimentation Bioterium of the Faculdade de Medicina do Cariri - BIOEXA/FAMED were used. The formalin test was carried out to assess the anti-inflammatory and antinociceptive potential of DZX at a dose of 5 mg/Kg (ip). To assess the central action of DZX in the sepsis model, the rats were divided into three groups (n=6): (1) Control; (2) LPS3 - treated with LPS (3.0 mg/kg, ip), and; (3) DZX5 + LPS3 - pre-treated with diazoxide (5 mg/Kg, ip) and with LPS (3.0 mg/kg, ip). Capillary blood glucose was collected from a drop of blood from the mouse's tail before and after treatment. Twenty-four hours after the LPS injection, the animals were subjected to behavioral tests (open field and forced swimming). The animals were then anaesthetized with ketamine hydrochloride (90 mg/kg, ip) and xylazine (10 mg/kg, i.p.) and their brains removed for the quantification of total proteins, thiol, superoxide dismutase (SOD) and catalase (n=5). One animal from each group was sent for morphological study using TTC (2,3,5- triphenyltetrazolium chloride) staining. The data was presented as mean ± standard error of the mean and ANOVA One-way analysis of variance was used, followed by the Student-Newman Keuls test as a post-hoc, considering significant differences for p<0.5. The results showed that in the formalin test, DZX exhibited a potent antinociceptive effect in the inflammatory phase of the test, indicating its anti-inflammatory potential. The tests evaluating the central action of DZX showed that the animals treated with LPS had a decrease in locomotor activity (31%) and exploratory activity (62%) and an increase in the number of groomings (2 times) evaluated by the open field test. In the forced swim test, LPS caused an increase in immobility time (2 times), which may suggest a central depressant action. DZX was able to prevent behavioral changes in the number of crossings and number of rearing, but not in grooming behavior. In the forced swim test, DZX was unable to prevent the depressant action caused by LPS. Treatment with LPS drastically decreased blood glucose (51%) and pre-treatment with DZX was unable to prevent hypoglycemia. Treatment with LPS significantly reduced catalase activity and cytosolic sulfhydryl protein levels in mouse brains; pretreatment with DZX was unable to prevent these alterations. We conclude that diazoxide did not show any response to hypoglycemia or oxidative damage at the dose studied, but it is a promising anti-inflammatory agent and was able to prevent behavioral changes in brain damage secondary to LPS-induced sepsis.

COMMITTEE MEMBERS:
Externo à Instituição - CICERO FRANCISCO BEZERRA FELIPE
Interno - FRANCISCO NASCIMENTO PEREIRA JUNIOR
Interno - IRI SANDRO PAMPOLHA LIMA
Presidente - MARIA ELIZABETH PEREIRA NOBRE