Autistic Rats Research Articles

Oxytocin lipidation expanding therapeutics for long-term reversal of autistic behaviors in rats.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms.Oxytocin, an endogenous polypeptide known as the "social hormone", has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood-brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among theseanalogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.

Salidroside Ameliorates Neuroinflammation in Autistic Rats by Inhibiting NLRP3/Caspase-1/GSDMD Signal Pathway

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that place a huge economic and emotional burden on society. Salidroside (Sal) has been reported to have therapeutic effects in a variety of neurological disorders such as Alzheimer's disease （AD） and Parkinson's disease (PD), however no studies have been conducted to show whether salidroside is effective in ASD. Pyroptosis is involved in the pathology of a variety of neurological disorders, but has not been reported in ASD. ObjectivesThe aim of this study was to investigate whether pyroptosis is involved in the pathological mechanisms of ASD, and whether salidroside has an impact on the pathological process of ASD by regulating pyroptosis. MethodsWe obtained a rat model of offspring ASD by prenatal intraperitoneal administration of valproic acid (VPA, 500mg/kg) to pregnant rats, and we treated seven-day-old offspring ASD with salidroside (Sal, 30mg/kg once daily) by gavage for 28 days as the salidroside treatment group. We examined the hippocampal state of ASD rats and the effect of salidroside on the hippocampus of VPA-induced ASD rats. In addition, in BV2 cells treated with LPS/Nig, we explored the mechanisms by which salidroside regulates neuroinflammation and pyroptosis in vitro. ResultsIn vivo, we observed VPA-induced hippocampal neuronal damage and activation of the NLRP3/Caspase-1/GSDMD signalling pathway in ASD rats, while salidroside alleviated neuronal damage in ASD rats. In vitro, we found that salidroside inhibited LPS/Nig-induced neuroinflammation and activation of the NLRP3/Caspase-1/GSDMD signalling pathway. These results suggest that the therapeutic effect of salidroside on hippocampal damage in ASD rats may be related to NLRP3/Caspase-1/GSDMD-mediated pyroptosis. ConclusionsOur work showed that salidroside ameliorates hippocampal neurological damage in ASD rats by targeting NLRP3/Caspase-1/GSDMD-mediated pyroptosis, providing a potential therapy drug for ASD.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Sex-dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain-gut axis in a VPA-induced autistic-like model of rats.

In this study, we aimed to investigate the inflammatory factors, oxidative stress, and histopathological consequences of the brain-gut axis in male and female rats prenatally exposed to VPA. Pregnant Wistar rats were randomly divided into two groups. The animals received saline, and valproic acid (VPA) (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). All offspring were weaned on postnatal day 21, and the experiments were done in male and female rats on day 60. The brain and intestine tissues were extracted to assess histopathology, inflammation, and oxidative stress. An increase of interleukin-1β (IL-1β) and interleukin-6 (IL-6) and a decrease of interleukin-10 (IL-10) were observed in the two sexes and two tissues of the autistic rats. In the VPA-exposed animals, malondialdehyde (MDA) and protein carbonyl (PC) increased in the brain of both sexes and the intestines of only the males. The total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased in both tissues of male and female autistic groups. Histopathological evaluation showed that the %apoptosis of the cortex in the autistic male and female groups was more than in controls whereas this parameter in the CA1 and CA3 was significant only in the male rats. In the intestine, histopathologic changes were seen only in the male autistic animals. The inflammatory and antioxidant factors were in line in the brain-gut axis in male and female rats prenatally exposed to VPA. Histopathological consequences were more significant in the VPA-exposed male animals.

Neuroprotective Potential of Tanshinone-IIA in Mitigating Propionic Acidinduced Experimental Autism-like Behavioral and Neurochemical Alterations: Insights into c-JNK and p38MAPK Pathways

Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK. In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma. Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan- IIA's molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections. Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.

Plant-mediated green synthesis of gold nanoparticles using an aqueous extract of Passiflora ligularis, optimization, characterizations, and their neuroprotective effect on propionic acid-induced autism in Wistar rats

The current study was conducted to examine an innovative method for synthesizing gold nanoparticles (AuNPs) from an aqueous sweet granadilla (Passiflora ligularis Juss) P. ligularis. Furthermore, the synthesized AuNPs were used to explore their potential neuroprotective impact against propionic acid (PPA)-induced autism. A sweet granadilla extract was used to achieve the synthesis of AuNPs. The structural and dimensional dispersion of AuNPs were confirmed by different techniques, including UV–Vis spectrophotometer (UV–Vis), X-ray Diffraction (XRD) Pattern, Energy Dispersive X-ray (EDX), Zeta potential, and High-Resolution Transmission Electron Microscopy (HRTEM) analysis. The AuNPs mediated by P. ligularis adopt a spherical shape morphology and the particle size was distributed in the range of 8.43–13 nm without aggregation. Moreover, in vivo, the anti-autistic effects of AuNPs administration were higher than those of P. ligularis extract per second. In addition, the reduced anxiety and neurobehavioral deficits of AuNPs were observed in autistic rats which halted the brain oxidative stress, reduced inflammatory cytokines, ameliorated neurotransmitters, and neurochemical release, and suppressed apoptotic genes (p < 0.05). The alleviated antiapoptotic gene expression and histopathological analysis confirmed that the treatment of AuNPs showed significant neural pathways that aid in reducing tissue damage and necrosis. The results emphasize that the biomedical activity was increased by using the green source synthesis P. ligularis -AuNPs. Additionally, the formulation of AuNPs demonstrates strong neuroprotective effects against PPA-induced autism that were arbitrated by a range of different mechanisms, such as anti-inflammatory, antioxidant, neuromodulator, and antiapoptotic effects.

The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism

IntroductionThis study was performed to evaluate the effects of low and moderate treadmill exercise for one month on social interaction, anxiety-like behaviors, and spatial learning and memory in male and female autistic rats. MethodsPregnant rats received valproic acid (VPA) (600 mg/kg/i.p) once on gestational day 12.5 to induce autism-like symptoms in the offspring. After delivery, the offspring were divided into six main groups, each with male and female subgroups: Control (CTL, prenatal normal saline), autism (prenatal VPA), low-intensity training (LIT,normal saline + low treadmill exercise), moderate -intensity training (MIT, normal saline + moderate treadmill exercise), VPA + LIT, and VPA + MIT. On the 60th day, the offspring were tested by the elevated plus maze (EPM), open field test (OFT), social interaction test (SIT), and Morris water maze (MWM). ResultsThe results showed that both LIT and MIT could partly alleviate anxiety-like behaviors induced by prenatal VPA exposure in two sexes. Social impairment was observed in the autistic rats and was improved by LIT in both sexes and MIT in females. No significant change was seen in the spatial learning and memory of autistic rats by exercise. ConclusionThe findings suggest that treadmill exercise can be helpful for improving some autism-like behaviors. Further studies are needed to investigate the involved mechanisms.

Therapeutic Potency of Camellia sinensis Extract on Neurochemical and Oxidative Changes Correlates to Autistic Disorder in Rat Pups Model

Background: Prenatal exposure to valproate is capable of inducing experimental autism in rat pups. This study aimed to investigate the role of Camellia sinensis green tea extract (GTE) in ameliorating the neurochemical changes induced by autism. Methods: Pregnant rats were treated with a single intraperitoneal dose of sodium valproate (600 mg/kg) on the 12.5th gestational day. The treatment with GTE (300 mg/kg) orally in autistic rat pups at postnatal day 15 for 20 days. Result: Induction of autism resulted in a significant decrease in the cerebellum and cortical 5-HT, DA, NE, GABA, glycine and taurine and a decrease in brain cholesterol and antioxidants enzymes (GSH, SOD and CAT) at P less than 0.05. However, it showed a significant increase in MAO, AChE, glutamate, aspartate, serine and lipid peroxidation in addition to elevation in inflammatory biomarkers in brain tissue. Treatment with GTE extract showed significant decrease in AChE and MAO in addition to reduction in the excitatory amino acid GABA in brain tissue which in accordance resulted in marked elevation in cerebellar and cortical monoamine contents. Furthermore, administration of GTE improved the antioxidant defence system in cerebellum and cerebral cortex by activating the level of GSH, SOD and CAT. These results are accompanied by marked reduction in oxidative stress biomarker (NO and MDA) and lowering in the level of TNF-α and IL-6. In conclusion, it could be stated that GTE exerts an ameliorative effect on autistic rat pups possibly due to antioxidant and anti-inflammatory effects and could be effective in the management of autism.

Sex-related beneficial effects of exercise on cardiac function and rhythm in autistic rats.

Cardiovascular 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. Valproic 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. The 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. The 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.

Effect of sex differences and time of oxytocin administration on treatment of rat model of autism spectrum disorder: Focused on necroptosis markers.

Autism is a neurodevelopmental disorder. A variety of molecular and cellular abnormalities leads to behavioral deficits in autism. Nevertheless, its etiology and treatment strategy are not completely understood. Oxytocin has recently shown improvements in social functioning. This study aimed to evaluate the necroptosis pathway for the neuroprotective effects of oxytocin in the valproic acid-induced autism spectrum disorder model. The autism spectrum disorder was induced by valproic acid on gestational day 12.5 (600 mg/kg, intraperitoneally). Offspring received intranasal oxytocin (1μg/μL) on the 21st and 40th days after birth. The offspring behaviors were scrutinized by self-grooming, marble-burying, three-chamber, and Morris water maze tests. Western blot was performed on the hippocampus and amygdala tissues to investigate the expression of RIP3 and MLKL markers. The valproic acid group demonstrated more anxiety, repetitive behaviors, and expression of RIP3 and MLKL markers, and less social interaction and spatial memory compared with the control group. Oxytocin considerably improved social interactions, preference for social novelty, and memory. The elevated expression of RIP3 and MLKL markers in valproic acid-induced autistic rats were alleviated after treatment with oxytocin. We also highlighted the importance of age and gender in autism spectrum disorder interventions. Our findings suggested that oxytocin administration was as an effective treatment in two areas of repetitive/stereotyped behaviors, social interactions/cognitive function. Notably, early administration of oxytocin resulted in better therapeutic responses in autism-like behaviors. The molecular tests introduce oxytocin as a potential candidate for reducing the expression of necroptosis mediators in the brain. This reinforced our hypothesis that the necroptosis pathway takes part in autism spectrum disorder.

Spironolactone Alters the Levels of Neuronal Function Markers in Autistic Rats

Spironolactone Alters the Levels of Neuronal Function Markers in Autistic Rats

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway.&#x0D; Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting.&#x0D; Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p &lt; 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats.&#x0D; Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

Valproate-induced murine autism spectrum disorder is associated with dysfunction of amygdala parvalbumin interneurons and downregulation of AMPK/SIRT1/PGC1α signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by difficulty in social behavior and restricted behaviors. Also, in ASD, several accompanying disorders such as anxiety are observed. Considering the important role of amygdala in the pathophysiology of ASD, the present study focused on the neuronal changes and it possible signaling pathway in amygdala. After prenatal exposure to valproate (VPA; 600mg/kg, i.p, on embryonic day 12.5), amount of ROS, MMP, caspase-3 activity, AMPK, SIRT1 and PGC1α proteins, and parvalbumin interneurons in the amygdala were assessed following evaluation of ASD and anxiety-like behaviors. Amygdala analysis revealed ROS accumulation and decreased MMP in autistic rats. In addition, caspase-3 activation elevated and immunoreactivity for parvalbumin interneurons decreased. These were accompanied by anxiety and autistic-like behaviors in open field test, elevated zero maze and U-Shaped 2 Choice Field maze. Also, our data showed that in the valproate group, protein levels of AMPK, SIRT1 and PGC1α reduced. Collectively, our results indicate that prenatal exposure to valproate leads to anxiety and autistic-like behaviors, partly through its targeting amygdala parvalbumin interneurons dysfunction and this might be affected by disturbed AMPK/SIRT1/PGC1α signaling pathway.

Calcium voltage-gated channel subunit alpha 1C and glial fibrillary acidic protein signaling pathways as a selective biomarker in predicting the efficacy of liposomal loaded co-enzyme Q in the autistic rat model.

Autism spectrum disorder (ASD) is an extreme neuropsychotic disturbance with both environmental and genetic origins. Sodium propionate (PPA) a metabolic bioproduct of gut microbiota is well-thought-out as a successful autism animal model. Nevertheless, Liposomal drug delivery system possess the advantagous of biocompatibility, targeting organs, ability to carry large drug payloads and skipping macrophages for this purpose the current study was carried out to investigate the hypothesis that Calcium Voltage-Gated channel subunit alpha 1C (CACNA1C) and glial fibrillary acidic protein (GFAP) signaling pathways crosstalk with the efficacy of Co-enzyme Q10 (Co-Q10) and liposomal loaded Co-enzyme Q10 (L Co-Q10) in PPA mediated autistic rat model. Autism was conducted by buffered PPA (500mg/Kg b.wt) daily for 5 consecutive days subsequently treatment via Co-Q10 in a dose of (10mg/kg b.wt) and L Co-Q10 (2mg/kg b.wt) for four weeks then the autistic model was followed for signs of autism at different time intervals of (one, two and four weeks). The control, PPA intoxicated, and treated groups were subjected to behavioral tests (Y-Maze and open field), antioxidant analysis, gene expression analysis, and histological examination at different time intervals of the study. The results revealed that Co-Q10 and L Co-Q10 significantly elevated antioxidative stress biomarkers, comprising superoxide dismutase (SOD), glutathione (GSH), and total antioxidant capacity (TAC). In addition, they significantly ameliorated the oxidative stress biomarker malondialdehyde (MDA). Meanwhile, they significantly downregulated GFAP and CACNA1C mRNA gene expressions, Co-Q10 and LCo-Q10 showed improvement in almost brain regions post PPA histopathological alterations, even better results were manifested via LCo-Q10 groups. These results showed the superiority of LCo-Q10 over Co-Q10 in competing autism. In conclusion: The administration of anti-inflammatory and antioxidant agents such as Co-Q10 and L Co-Q10 may represent a promising strategy to counteract pathological behaviors in ASD model via targeting organs, increasing retention time, and reducing side effects.

Inhibiting silence information regulator 2 and glutaminase in the amygdala can improve social behavior in autistic rats.

To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats. Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and SIRT2-knockout ( SIRT2 -/-) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed. Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all P<0.01). Compared with the wild-type rats, SIRT2 -/- rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all P<0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all P<0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all P<0.01). The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out SIRT2 gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.

Effects of arginine vasopressin on the transcriptome of prefrontal cortex in autistic rat model.

Our previous studies have also demonstrated that AVP can significantly improve social interaction disorders and stereotypical behaviours in rats with VPA-induced autism model. To further explore the mechanisms of action of AVP, we compared the PFC transcriptome changes before and after AVP treatment in VPA-induced autism rat model. The autism model was induced by intraperitoneally injected with VPA at embryonic day 12.5 and randomly assigned to two groups: the VPA-induced autism model group and the AVP treatment group. The AVP treatment group were treated with intranasal AVP at postnatal day 21 and for 3 weeks. The gene expression levels and function changes on the prefrontal cortex were measured by RNA-seq and bioinformatics analysis at PND42 and the mRNA expression levels of synaptic and myelin development related genes were validated by qPCR. Our results confirmed that AVP could significantly improve synaptic and axon dysplasia and promote oligodendrocyte development in the prefrontal cortex in VPA-induced autism models by regulating multiple signalling pathways.

Novel research on Neuroprotective effect of Bacopa monnieri L. against propionic acid induced investigation on autism in Sprague Dawley rat

Autism spectrum disorder (ASD) is characterized by complex behavioral and memory impairments resulting from abnormal brain development. The research objective is to identify the lack of understanding of the etiology of autism. The Ayurvedic system of medicine recognizes Bacopa monnieri for their potential nootropic activity to maximize brain and neuronal processes such as learning and memory. Brahmi, Bacopa monnieri has been demonstrated in Ayurvedic preparation as memory booster medicine. The neuroprotective properties of hydroalcoholic extract of Bacopa monnieri against propionic acid-induced neuroprotective effect in autistic rat models were investigated in the present study. The animal species used in the study are adult Sprague Dawley rats of both sexes were divided into four groups and administered the vehicle/extract for 28 days. Between the 22nd and 28th days of the trial, autism was caused by an intracerebroventricular infusion of propionic acid. Rats were treated to the fundamental methods such as different in vivo behavior and memory evaluation procedures during this infusion period, including the actophotometer test and the Morris water maze test. Animals were euthanized on the 29th day of the investigation to obtain brain material. Extracted brain tissues were used to calculate levels of neuroinflammatory markers (TNF-) and histological examination.

Acetyl-L-carnitine and/or liposomal co-enzyme Q10 prevent propionic acid-induced neurotoxicity by modulating oxidative tissue injury, inflammation, and ALDH1A1-RA-RARα signaling in rats

Propionic acid (PPA) is a short-chain fatty acid produced endogenously by gut microbiota and found in foodstuffs and pharmaceutical products as an additive. Exposure to PPA has been associated with the development of autism spectrum disorder (ASD). The purpose of this study was to investigate the protective effect of acetyl‐L‐carnitine (ALCAR) and liposomal Co-enzyme Q10 (CoQ10) against cerebral and cerebellar oxidative injury, inflammation, and cell death, and alterations in ALDH1A1-RA-RARα signaling in an autism-like rat model induced by PPA. The rats were treated with PPA and concurrently received ALCAR and/or CoQ10 for 5 days. The animals were sacrificed, and the cerebral cortex and cerebellum were collected for analysis. PPA caused histopathological alterations along with increased malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 in the cerebrum and cerebellum of rats. Reduced glutathione (GSH) and antioxidant enzymes were declined in the brain of rats that received PPA. Concurrent treatment with ALCAR and/or CoQ10 prevented tissue injury, decreased MDA, NF-κB p65, and pro-inflammatory cytokines, and enhanced cellular antioxidants in PPA-administered rats. ALCAR and/or CoQ10 upregulated Bcl-2 and decreased Bax and caspase-3 in the brain of rats. In addition, ALCAR and/or CoQ10 upregulated cerebral and cerebellar ALDH1A1 and RARα in PPA-treated rats. The combination of ALCAR and CoQ10 showed more potent effects when compared with the individual treatments. In conclusion, ALCAR and/or CoQ10 prevented tissue injury, ameliorated oxidative stress, inflammatory response, and apoptosis, and upregulated ALDH1A1-RA-RARα signaling in the brain of autistic rats.

Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and cognitive behaviors. Histamine H3 receptor (H3R) antagonists are considered as therapeutic factors for treating cognitive impairments. The aim of the present study was to evaluate the effects of the H3R antagonist, ciproxifan (CPX), on cognition impairment especially, spatial learning memory, and synaptic plasticity in the CA1 region of the hippocampus in autistic rats. Pregnant rats were injected with either valproic acid (VPA) (600 mg/kg, i.p.) or saline on an embryonic day 12.5 (E12.5). The effects of the H3R antagonist, ciproxifan (CPX) (1, 3 mg/kg, i.p.), were investigated on learning and memory in VPA-exposed rat pups and saline-exposed rat pups using Morris water maze (MWM) and social interaction tasks. The H2R antagonist, famotidine (FAM) (10, 20, 40 mg/kg, i.p.), was used to determine whether brain histaminergic neurotransmission exerted its procognitive effects through the H2R. In addition, synaptic reinforcement was evaluated by in vivo field potential recording. The results showed that VPA-exposed rat pups had significantly lower sociability and social memory performance compared to the saline rats. VPA-exposed rat pups exhibited learning and memory impairments in the MWM task. In addition, VPA caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results demonstrated that CPX 3 mg/kg improved VPA-induced cognitive impairments and FAM 20 mg/kg attenuated cognitive behaviors as well as electrophysiological properties. CPX 3 mg/kg improved VPA-induced impairments of LTP as well as learning and memory deficits through H2R.

Treadmill Exercise Improves Stereotypical Behaviors in Autistic Rats: Treadmill Exercise Improves ASD.

Background: Autism spectrum disorder (ASD) is identified by developmental deficits that lead to repetitive/stereotypic patterns of behavior and impaired social interactions. Studies have been indicated that exercise can decrease stereotypic behaviors in animal models of ASD. This research was designed to discover the effects of different models of forced exercise on stereotypical behaviors in a rat model of ASD induced by thimerosal (THIM). Materials and Methods: Fifty-six male Wistar rats were divided into eight groups. The rats were received saline (1 ml/kg) or THIM (300 μg Hg/kg) by four intramuscular injections on 7, 9, 11, and 15 postnatal days. The rats were also treated by several protocols of treadmill exercise, including non-sedentary, sedentary, protocol 1, protocol 2, and a combination of protocols 1 and 2. Results: Our study showed that THIM decreased the grooming time compared to the control group. Moreover, protocol 2 exercise significantly decreased grooming time in stranger zone 2 compared to the THIM group. Conclusions: Our results showed that stereotypical behaviors exaggerated by THIM and moderate exercise could improve ASD-associated behaviors in the THIM-treated rats. Hence, moderate exercise may be a useful protocol for the treatment of ASD.