Efeito protetor do ácido valproico sobre a neuroxicidade induzida por cisplatina: uma abordagem comportamental, neuroquímica e histológica

Abstract

Cisplatin is an antineoplastic drug, which has a large chemical procedure that does not treat types of cancer, however, several adverse effects, among them: the neurotoxic also known as "workin" that manifests itself with impairment of work functioning, operational work, attention and processing speed or that interfere with patients' daily performance and quality of life. Currently, no treatment for this adverse effect has been approved. Valproic acid is an antiepileptic drug, also used as a mood stabilizer and recent studies have focused on its neuroprotective properties. The aim of the present work was to study the neuroprotective effects of valproic acid on cisplatin-induced neurotoxicity in rats, contextualizing a behavioral, neurochemical and histological approach. Thinking about the systemic system and the cost-benefit of the patient in treatment with platinum, we analyzed the effects of the administration of proic acid, in the evaluation doses, on hematological, hepatic and renal markers, as well as we evaluated the study of the curvature of weight evolution. and survival and mortality curves. Considering that cognitive behavioral changes, associated with cholinergic changes, oxidative damage, apoptosis and mitochondrial damage are possibly related to this adverse effect, we performed the open behavioral tests, in Y and NOR (novel object recognition), following the tests: Determination of enzyme acetylcholinesterase (AChE), studies of oxidant and antioxidant parameters (TBARS, nitrite and GSH) in prefrontal cortex and hippocampus, markers of apoptosis caspase 3 and BCL2 by immunofluorescence in hippocampus and the study of possible mitochondrial damage “swelling” mitochondria and the study of brain mitochondrial oxygen consumption. The experimental protocol was carried out for 4 weeks. A dose of 5mg/kg of cisplatin or saline was administered weekly and, daily, for five consecutive days (with an interval of two days between one cycle and another) valproic acid was administered at a dose of 25mg/kg, or 50mg/kg, or salina, in male rats (300-350 grams). It demonstrates that within the mechanisms of action, treatment with proic acid, the enzyme deacetylase (HD), was not altered, at doses they inhibit, and hepatic and important toxic drugs were not altered. Regarding hematological parameters, change only in the number of platelets. AVP has a beneficial effect benefiting less weight loss, life expectancy and increased mortality on animals treated with cislatin. It reversed, even if altered, as cognitive functions, as demonstrated not tested in Y and NOR, associated with the reduction of the AChE enzyme. As damage to the preal cortex and hippocampus is also associated, reversibly, with an intense series expression and increased expression of BCL2, tested in some regions of the oxidized hippocampus, in some cisplatin alterations in the brain by mitochondrial “inswelling” and the study of mitochondrial oxygen consumption in the brain. Findings that are clinical expertise due to evidence that treatment is comprised of cognitive impairment and structural abnormalities in the brain.