Autistic‐Like Behaviors, Oxidative Stress Status, and Histopathological Changes in Cerebellum of Valproic Acid Rat Model of Autism Are Improved by the Combined Extract of Purple Rice and Silkworm Pupae

Abstract

Due to the crucial role of oxidative stress on the pathophysiology of autism and the concept of synergistic effect, the benefit of the combined extract of purple rice and silkworm pupae (AP1) for autism disorder was the focus. Therefore, we aimed to determine the effect of AP1 on autistic-like behaviors, oxidative stress status, and histopathological change of cerebellum in valproic acid (VPA) rat model of autism. VPA was injected on postnatal day (PND) 14 and the animals were orally given AP1 at doses of 50, 100, and 200 mg·kg−1 BW between PND 14 and PND 40. The autism-like behaviors were analyzed via hot-plate, rotarod, elevated plus-maze, learning, memory, and social behavior tests. Oxidative stress and the histological change in the cerebellum were assessed at the end of study. AP1 treated rats improved behaviors in all tests except that in hot-plate test. The improvement of oxidative stress and Purkinje cell loss was also observed in the cerebellum of VPA-treated rats. Our data suggest that AP1 partially reduced autism-like behaviors by improving oxidative stress and Purkinje cell loss. Further research is required to identify the active ingredients in AP1 and gender difference effect.

Beneficial effects of pioglitazone, a selective peroxisome proliferator‐activated receptor‐γ agonist in prenatal valproic acid‐induced behavioral and biochemical autistic like features in Wistar rats

“…The biochemical profile showed elevation in TBARS, IL‐6, TNF‐α with reduction in GSH and IL‐10 in cerebellum, brainstem and prefrontal cortex of VPA‐treated rats. These findings are consistent with previous studies showing symptoms of autism in patients and rodents (Schneider and Przewłocki, 2005; Markram et al, 2009; Morakotsriwan et al, 2016; Ha et al, 2017; Al‐Amin et al, 2015; Hegazy et al, 2015; Eissa et al, 2018; Li et al, 2018). Treatment with PPAR‐γ agonist, pioglitazone improved the behavior deficits and impaired biochemical phenotypes in VPA‐treated rats.…”

“…The impaired social behavior, anxiety, locomotor and repetitive behavior like hyperactivity in rats (Markram et al, 2008; Schneider and Przewłocki, 2005) has similarity with autistic subjects (Roullet et al, 2013; American Psychiatric Association, 2013). Preclinical studies have also exhibited cerebellar damage, loss of cerebellar purkinje cells in number and size, damage to cranial nerve motor nuclei, reduced brainstem neurons, reactive gliosis, neuronal disorganization, structural connectivity alteration in prefrontal cortex, elevation of brain Interleukin‐6 (IL‐6) as well as tumor necrosis factor‐α (TNF‐α) similar to autistic human data (Morakotsriwan et al, 2016; Codagnone et al, 2015; Rodier et al, 1996; Al‐Amin et al, 2015; Xu et al, 2015). The low amount of reduced glutathione (GSH) has found in cerebellum and temporal cortex of autistic patients as compared to normal subjects (Rose et al, 2012).…”

Molecular Pathology and Pharmacological Treatment of Autism Spectrum Disorder-Like Phenotypes Using Rodent Models

“…Reactive oxygen species (ROS), apoptotic markers, the expression level of NFκB and the levels of pro-inflammatory cytokines are all increased in VPA-treated rodents, whereas the antioxidant glutathione and various anti-inflammatory cytokines are reduced (Tung and Winn, 2011 ). Moreover, increased BBB permeability and perioxidation, which are indicators of pro-inflammatory responses, have also been found in VPA-exposed animals (Banji et al, 2011 ; Pragnya et al, 2014 ; Al-Amin et al, 2015 ; Gao et al, 2016 ; Kumar and Sharma, 2016b ; Morakotsriwan et al, 2016 ; Zhang et al, 2017b ). Several substances have been tested as methods of reducing this inflammatory response and thus the related ASD-like phenotypes.…”

“…Fingolimod and N-acetylcysteine, off-label drugs used to treat multiple sclerosis and acetaminophen overdose, respectively, have been reported to have anti-inflammation and anti-apoptotic effects in the VPA-treated rodent brains (Wu et al, 2017a ; Zhang et al, 2017b ). Nutrition and food extracts from green tea, Korean red ginseng, purple rice, and silkworm pupae have also been shown to reduce ASD-like phenotypes in VPA-treated rodent models, possibly via an anti-inflammatory mechanism (Banji et al, 2011 ; Kim et al, 2013 ; Gonzales et al, 2016 ; Morakotsriwan et al, 2016 ; Du et al, 2017 ). From the above findings, it is clear that further studies are needed to elucidate the various neuro-immune mechanisms underlying VPA-induced pathophysiology.…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…Developing appropriate pharmacological treatments is further complicated by the high prevalence of comorbid conditions in ASD, including affective disorders (such as anxiety, or depression) or neurological disorders (such as epilepsy), often requiring additional prescriptions [7,8]. A number of complementary and alternative medicines, including Korean red ginseng [9,10] and purple rice with silkworm pupae [11], have been shown in small pilot trials to improve symptoms of ASD, including stereotypies, social behaviour, and anxiety (Table 1). However, they do not yet have the evidence base required for more widespread adoption [12].…”