Nanocápsulas carregadas de luteína revertem comportamento semelhante a transtorno do espectro autista e protegem contra danos neurofisiológicos e hepatotóxicos induzido por ácido valpróico em ratas fêmeas

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder usually diagnosed in childhood and with symptoms that include communication and social interaction deficits, restricted and repetitive behavior. Currently, there is no complete understanding of the molecular pathogenesis of ASD, therefore, an experimental model of ASD has been proposed through the prenatal administration of valproic acid (VPA) in rats. The toxic potential of VPA is characterized by triggering behavioral deficits similar to ASD, impaired anxiety and social memory levels, neurochemical abnormalities, morphological disturbances and liver toxicity. Bioactive compounds such as lutein, an important carotenoid, have antioxidant and neuroprotective potential, as it crosses the blood-brain barrier, demonstrating beneficial effects on the neurological, metabolic and hepatic systems. Lutein-loaded nanocapsules provide better bioavailability of this carotenoid in the body, enhancing its neuroprotective and hepatoprotective effects. In this sense, the aim of this thesis was to investigate whether lutein-loaded nanocapsules reverse ASD-like behaviors and protect against neurophysiological, behavioral and hepatic damage induced by VPA administration in female rats. Thirty adult Wistar rats (90 - 120 days old) were used as parents. Pregnant rats (F0 generation) on the 12.5th day were separated and received intraperitoneal injection of VPA (600 mg/kg) or saline solution (0.9% NaCl, 1 mL/kg). On the 21st day, female pups (F1 generation) were subdivided into two groups and received nanocapsules loaded with lutein (5 mg/kg) or saline solution (1 mL/kg), orally for 14 days. At the end of treatment (15th day), the animals underwent behavioral tests of social deficits, social memory, locomotion and anxiety. After behavioral tests, blood, hippocampus and liver were collected for biochemical analysis. We analyzed the effect of lutein-loaded nanocapsules on attenuating behavioral, neurophysiological and hepatotoxic deficits in in vivo and ex vivo analyses. Thus, this thesis involved two main studies separated into two articles. In the first study, we evaluated social deficits and social memory through the three-chamber test and locomotor activity and anxiety through the open field test. In both tests, lutein-loaded nanocapsules were able to reverse the social, memory, locomotion and anxiety deficits induced by prenatal administration of VPA. Furthermore, we analyzed by electrophoresis the indicators of oxidative stress and biomarkers of apoptosis in the hippocampus. Results demonstrated that lutein-loaded nanocapsules restored oxidative damage (ROS; 9 TBARS; SOD and Nrf2) and levels of apoptotic biomarkers (Hsp-70; p38-MAPK; Bax and Bcl-2), which are associated with the effects beneficial to the neurological system. We also highlight the protective action of lutein-loaded nanocapsules in modulating ASD-like behaviors and neurochemical damage induced by VPA in female rats. These results suggest that nanocapsules loaded with lutein have therapeutic potential for treating oxidative damage linked to behavioral deficits similar to ASD. In the second study, we analyzed the metabolic effect of lutein-loaded nanocapsules on changes in energy metabolism derived from modulations of liver function in the offspring of rats exposed to VPA. The results of oxidative stress and apoptotic markers corroborate the results of the first article, indicating that nanocapsules loaded with lutein were able to protect against damage induced by VPA administration, both in neurological tissue and in hepatic tissue. In the other analyses, it was also possible to perceive the positive regulation of cell viability, lipid metabolism and metabolic markers in the liver and plasma provided by the treatment with nanocapsules loaded with lutein. Our results showed that lutein-loaded nanocapsules can be a natural alternative treatment to protect against ASD-like behavioral damage, social memory and anxiety deficits, oxidative stress, apoptosis biomarkers, neuronal and liver dysfunctions caused by administration of VPA in the prenatal period in female rats.