Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α

ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.

Octreotida no tratamento de fístulas entéricas de ratos

Presently, approved medicines do not exist to treat enterocutaneous fistulas. Somatostatin and its synthetic analogue octreotide are the more widely used with this purpose. However, the evidence supporting its use is still insufficient. Objective: The therapeutic effects of octreotide was investigated in an experimental model of enterocutaneous fistula. Methods: In twenty male Wistar rats weighing 210±17g a jejunocutaneous fistula was surgically done. After that, the animals had been randomly divided into three groups. In the group A (n=10) octreotide was administered once a day (4 m g/kg/body wt/s.c) while in the group B (n=10) the rats were injected with saline solution in similar amount to the used to dilute octreotide. The group C (n=10) had no fistula. The rodents had been inspected regarding the daily volume of the fistula output, the necessary time for its spontaneous healing, clinical and biochemical evaluation, RBC count, and nutritional state. Results: There was a fourfold faster spontaneous fistula healing in the rats treated with octreotide and they had not had significant clinical, biochemical, hematologic, or body weight reduction during the experiment. On the other hand, in the group B there was a sixty percent of body weight loss, with forty percent of the rats showing cachexia. Other important findings in this group was marked anemia, hypoglobulinemia, and profound hypoalbuminemia. Conclusion: The octreotide is better then placebo and they allow to say that, according to the strict conditions of the experiment, the drug was effective in the healing of uncomplicated enterocutaneous fistulas in rats.

Somatostatina e seu análogo sintético octreotida são as drogas mais amplamente utilizadas para tratar fístulas enterocutâneas. Todavia, as evidências suportando seu uso ainda são insuficientes. Objetivo: Investigar os efeitos terapêuticos de octreotida em um modelo experimental de fístula enterocutânea. Métodos: Em trinta ratos machos Wistar com peso 210± 17g foi confeccionada cirurgicamente uma fístula jejunocutânea. Os animais foram aleatoriamente divididos em três grupos de dez. No grupo A, administrou-se uma dose única diária de octreotida (4 mig/kg/peso corporal/SC) enquanto no grupo B injetou-se por via SC solução salina a 0,9% em quantidade idêntica à utilizada para veicular octreotida. O grupo C serviu de controle. Os roedores foram inspecionados a respeito do volume diário do débito das fístulas, tempo necessário para sua cicatrização espontânea, avaliação clínico-bioquímica, hematológica e nutricional. Resultados: Os ratos tratados com octreotida não tiveram significantes alterações clínico-bioquímicas ou ponderais quando comparados ao controle (sem fístula) e cicatrizaram as fístulas espontaneamente em um tempo significativamente menor (3,8 ± 1,6 dias) que os do grupo B (15,3 ± 4,5 dias) (p 0,05). No grupo B verificou-se queda ponderal média de 60% ao final da pesquisa, com 40% dos animais exibindo caquexia, anemia, hipoglobulinemia e hipoalbuminemia. Conclusão: A octreotida foi superior ao placebo e permitem afirmar que, segundo as estritas condições do experimento, o fármaco foi eficaz na cicatrização de fístulas enterocutâneas não complicadas de ratos.