Efeito antiinflamatório e antioxidante do honokiol na prole de ratos wistar induzida ao autismo expostos ao ácido valpróico no período pré-natal

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a high global prevalence, manifested through behavioral characteristics, as well as restricted and repetitive patterns of behavior and atypical sensory responses. Honokiol, a polyphenolic bioactive substance considered one of the main components extracted from the plant Magnolia officinalis, possesses several therapeutic properties involving antioxidant, anti-inflammatory, antimicrobial, anticancer, antithrombotic, antidepressant, and neuroprotective actions. This study investigates its effects on behavior, oxidative stress, proteins, AChE, monoamines, and intestinal disaccharidases in an animal model of ASD. Initially, in silico analyses were performed to predict pharmacokinetics, toxicity, identification of pharmacological targets, and the strength of interaction and conservation of protein structure between rats and humans. In the in vivo study, eight-week-old nulliparous male and female Wistar rats were used as breeding stock (CEUA/UFC: 89011223-0). The female breeding stock were randomly divided into four groups according to the treatment they received: control, VPA (valproic acid 600 mg/single dose), honokiol (honokiol 10 mg/kg/day), VPA+honokiol (valproic acid + honokiol, at the same doses as above). The pups (females and males) were used for behavioral, neurochemical, and digestive evaluation. Behavioral activity was assessed using open field tests, social interaction tests, elevated plus maze, and Y-maze tests. In the locomotor evaluation, considering spontaneous movement parameters, females in the VPA+HK group showed an approximately 45.4% reduction in the number of matings compared to the VPA group. Regarding anxious behavior, it was observed that females in the VPA group presented less anxiety and greater impulsivity; however, treatment with honokiol reduced this impulsivity by 57.6% in the VPA+HK group when compared to the VPA group. In the oxidative profile, honokiol promoted significant antioxidant effects: it reduced MDA levels in the prefrontal cortex by 40.7% and in the hippocampus by 42% compared to the VPA group. Furthermore, it increased GSH levels in the hippocampus by 94%, although it reduced this concentration in the prefrontal cortex by 80% compared to the control group. A decrease in total proteins was also observed in the prefrontal cortex of males by 20.5%, and in females there was a 16.4% reduction in the hippocampus in the VPA+HK group compared to the VPA group. In the monoaminergic system, honokiol reduced serotonin levels by 58% in males and 44.6% in females (VPA versus VPA+HK). In the cholinergic system, a 38% reduction in acetylcholinesterase (AChE) levels was observed in the hippocampus of females treated with honokiol. Finally, in the intestine, honokiol increased sucrase enzyme activity by 1.68 times in males compared to the VPA group. Taken together, these results demonstrate that honokiol exerted a significant neuroprotective action in the VPAinduced ASD model, by increasing glutathione levels, reducing MDA and total proteins, improving risk perception, and modulating serotonergic and cholinergic pathways, favoring greater serotonin availability and lower AChE activity.