الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Autism Spectrum Disorder (ASD) is a mosaic of neurodevelopmental conditions, which show common deficits in two behavioral domains: (i) social interaction and communication difficulties, (ii) narrow interests, and repetitive and stereotyped behaviors. The prevalence of ASD has increased considerably in the last two decades, reaching around 1–2% of the general population due to greater recognition and knowledge of the disease.
Till now, the causes and risk factors of ASD are not well known with many operational risk factors; prenatal, peri- natal, and environmental. Early detection of ASD is crucial for prompt and early intervention to achieve significant improvement in behavioral performance and the intellectual abilities of children with ASD.
This study aimed to examine the potential of the selective GPER agonist G1 therapy on the behavioral, molecular, biochemical, and histopathological alterations induced in a VPA-rat model of autism according to the sex differences. To fulfill the aim, VPA (500 mg/kg) was intraperitoneally administered to 25 female Wistar rats (on gestational day 12.5) to induce the VPA-rat model of autism while physiological saline was administered to 5 control pregnant females at the same time. Both male and female
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progeny were included in the study. The pups from control dams (n=10M & 10F) were assigned into normal control (NC) groups, intraperitoneally administered with vehicle (DMSO). The pups from VPA-treated dams (n = 30M & 30F) were allocated into three subgroups (10 M or 10 F rats in each group) as follows: VPA (autistic) group intraperitoneally administered with vehicle (DMSO); VPA+G1-LD group intraperitoneally administered with G1 dissolved in DMSO (10 μg/kg bwt); and VPA+G1-HD group intraperitoneally administered with G1 dissolved in DMSO (20 μg/kg bwt). All the intraperitoneal administrations were given to rats once a day for 21 consecutive days.
After the end of the treatment period, rats performed behavioral assessments that assessed anxiety, locomotor, exploratory activities as well as repetitive and social interaction behaviors. The weights of rats were recorded weekly throughout the experimental period. Just at the completion of the experiment, the rats were weighed, euthenized with a single dose of urethane (1.25 g/kg, IP), sacrificed by cervical dislocation, and blood was promptly obtained through heart puncture. sera were separated and stored for biochemical analysis (hormonal and cytokine assays). Then, one part of the hippocampi was excised, stored immediately in RNA later, and frozen at - 80 ◦C until used for GPER, Aromatase and RORA gene expression analyses using quantitative real-time
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PCR (qRT-PCR). The other parts of hippocampi were excised and fixed in 10% buffered formalin solution immediately for preparation of paraffin blocks; or the hippocampi were excised, weighed, and frozen at -80◦C until used for assessment of GPER and Aromatase proteins contents, oxidative stress markers (MDA & PCO), and neurotransmitters analyses (Serotonin and GABA).
Prenatal exposure of male and female rats to VPA induced an animal model of autism that imitates human autistic features, including behavioral deficits, reduction in body weight gain and relative brain weight, neurotransmission impairment, provoking inflammatory and oxidative stress markers, and neurodegeneration.
The present male autistic model was associated with elevation in serum free T level and suppression of GPER and aromatase gene expression levels and contents in the hippocampus. Also, RORα expression was downregulated in the hippocampus. Regarding the female autistic rats, there is a reduction in its serum E2 level associated with elevation in serum free T level. This alteration in the female hormonal levels could be attributed to the downregulation of aromatase and RORα mRNA expression in the hippocampus, similar to autistic males. Moreover, the autistic females have not shown significant changes in GPER and aromatase contents in the hippocampus.
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The administration of the GPER agonist G1 to the male and female autistic rats attenuated the deterioration induced by VPA.
The administration of G1 to the autistic rats decreased their locomotor activity in OFT and exploratory activity as recorded in OFT and YM-T, increased the spontaneous alternation rates in autistic rats. Additionally, G1 administration alleviated social anxiety symptoms in autistic rats in the SIT and counteracted the adverse effects of VPA. And increased social investigations, as well as a social motivation coefficient, resulting in less avoidance behavior and social anxiety.
The treatment of male and female autistic rats with G1 caused the upregulation of their hippocampal RORα, which might have contributed to the pronounced reduction in free T levels via up-regulation of hippocampal aromatase expression in autistic males and females and protein content in autistic males.
G1 administration to male autistic rats significantly up-regulated hippocampal GPER mRNA expression and protein content.
G1 attenuated the increase in hippocampal GABA levels in VPA-rats compared to NC ones. The doses of the GPER selective agonist G1 showed an ameliorative effect on neurotransmitter
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balance, causing a significant elevation of hippocampal serotonin levels in autistic rats compared with untreated ones.
The administration of the GPER-selective agonist G1 to autistic rats resulted in reductions in hippocampal MDA and PCO levels, attenuation of the VPA-induced elevation in serum IL-1β.
Additionally, G1 administration diminished the dark necrotic and degenerating neurons in all hippocampal regions in the current autistic rats. Hence, improving neurogenesis and brain weight.
In conclusion, G1 treatment and GPER activation provide a promising therapeutic approach to counteract the autistic-like symptoms.