This study was performed to evaluate the effects of prenatal exposure to pregabalin (PGB) on behavioral changes of rat offspring in an animal model of valproic acid (VPA)-induced autism-like symptoms. Pregnant rats received VPA (600 mg/kg/i.p.) once at 12.5 gestational days for autism-like symptom induction in offspring. After the delivery single male and single female offspring from each mother were randomly selected for behavioral test (anxiety, pain response, pleasure, and motor function) at 60th day adulthood (n = 7). Offspring received prenatal PGB (15 & 30 mg/kg/i.p.) during gestational days 9.5 to 15.5 either alone or in combination with VPA (PGB15, PGB30, PGB15 + VPA, and PGB30 + VPA). Control offspring received normal saline during the same period. The result showed that prenatal VPA exposure was associated with autism-like behaviors in rat offspring. PGB treatment during the gestational period revealed significant reduction in sucrose preference test and anxiety in elevated plus maze and open field test in offspring. Also, PGB treatments exhibited a dose-dependent increase in pain threshold in prenatally VPA exposed rats in tail-flick and hot plate test. Also, there was a sex-related significant impairment in motor function in beam balance and open field test, and male rats were affected more than females. However, no significant sex differences in sucrose preference and pain sensitivity were observed in prenatal PGB-treated rat offspring. In conclusion, prenatal exposure to VPA increased the risk of autism-like behaviors in the offspring rats, and PGB treatment during the gestational period was associated with some beneficial effects, including anxiety reduction and motor impairment in autism-like symptoms in rat offspring. K E Y W O R D S anhedonia, anxiety, autism, pain, pregabalin, valproic acid | 501 SHAMSI MEYMANDI Et Al. 1 | INTRODUCTION Autism spectrum disorder (ASD) is a complicated, behaviorally defined disorder, including communication and social interaction deficits and restricted, repetitive and stereotyped behaviors (Bolte et al., 2019). Prevalence estimates and diagnosis rates of ASD have risen substantially in the last two decades reaching 1.5% in developed countries (Lyall et al., 2017). According to the World Health Organization (WHO) report in 2018, 1 in 160 children had ASD. In most of cases, ASD is associated with epilepsy, since different studies showed that 22% to 38% of children with autism also suffer from comorbid epilepsy (

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Autism spectrum disorders are complex behavioral disorders that can be caused by exposure to valproic acid (VPA) during pregnancy. A therapeutic role for exercise training has been reported in many neurological diseases and problems, including autism. We aimed to evaluate various intensities of endurance exercise training and investigate its effects on oxidative and antioxidant factors in the liver of young males in a rat model of autism. Female rats were divided into a treatment (autism) and a control group. The autism group received VPA intraperitoneally on day 12.5 of pregnancy and the control pregnant females received saline. On the 30th day post‑birth, a social interaction test was performed on the offspring to confirm autistic‑like behavior. Offspring were divided into three subgroups: no exercise, mild exercise training, and moderate exercise training. Then the oxidative index of malondialdehyde (MDA) and the antioxidant indices of superoxide dismutase (SOD), total antioxidant capacity (TAC), and catalase in liver tissue were examined. The results of this study showed that both indices of sociability and social novelty decreased in the autism group. MDA levels in the liver of the autistic group increased, and moderate exercise training was shown to reduce the levels. Catalase and SOD activity as well as TAC levels decreased in the autism group, and moderate‑intensity exercise training was shown to increase the values. Parameters of hepatic oxidative stress were altered in VPA‑induced autism, and moderate‑intensity endurance exercise training was demonstrated to have beneficial effects on hepatic oxidative stress factors by modul ating the antioxidant/oxidant ratio.

BackgroundCardiovascular diseases are prevalent in autistic patients. As exercise is useful in the treatment of medical conditions, this study aimed to identify the effect of low‐intensity endurance exercise (LIEE) and moderate‐intensity endurance exercise (MIEE) on cardiovascular events in autistic rats.MethodsValproic acid (VPA) was administrated once on gestational day 12.5 to pregnant rats to produce autism‐like symptoms in offspring. Thirty‐day‐old offspring were divided into 12 groups: Male‐CTL, Male‐VPA, Male‐CTL + LIEE, Male‐CTL + MIEE, Male‐VPA + LIEE, Male‐VPA + MIEE, Female‐CTL, Female‐VPA, Female‐CTL + LIEE, Female‐CTL + MIEE, Female‐VPA + LIEE, and Female‐VPA + MIEE. LIEE and MIEE were performed 5 days a week for 30 days. Twenty‐four hours after the last exercise session, electrocardiogram and hemodynamic and cardiac function indices were recorded.ResultsThe results indicated that +dp/dt max and contractility index (CI) decreased in the Female‐VPA group compared to the Female‐CTL group. LIEE increased these parameters in the Female‐VPA + LIEE group. However, MIEE normalized CI in the Male‐VPA + MIEE compared to the Male‐VPA group. Tau increased in the Female‐VPA group compared to the Female‐CTL group and it decreased in the Female‐VPA + MIEE group compared to the Female‐VPA group. LIEE and MIEE recovered the reduction of heart rate and the increase in P, R, and T amplitudes in Male‐VPA group. LIEE and MIEE increased heart rate variability in the Male‐VPA and Female‐VPA groups.ConclusionsThe findings showed that LIEE and MIEE alleviated cardiac dysfunction and disturbances in heart rhythm in the autistic offspring. Exercise may be recommended as a routine program for autistic patients to prevent and treat the harmful cardiovascular consequences of autism.