الفهرس 
DEDICATIONOnly 14 pages are availabe for public view
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Abstract
Autism spectrum disorders are developmental disability characterized by persistent impairments in social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. These impairments can cause lack engagement or participation in daily activities and communication.
Valproic acid is a broad spectrum, antiepileptic drug, and also a potent teratogen. A single administration of VPA in utero leads to developmental delays and lifelong deficits in motor performance, social behavior, and anxiety-like behavior in rat offspring, including developmental, anatomical and functional similarities with human autistic patients.
Given the significant correlation between androgen levels and ASDs symptoms/traits. It was hypothesized that administration of anti-androgen medications to individuals diagnosed with ASDs, would produce notable clinical improvements. Brain-derived neurotrophic factor has emerged as a key neurotrophin regulating synaptic plasticity, neuronal differentiation and survival. Recently, BDNF depletion is reported in neurodegenerative as well as in psychiatric disorders, associated with severity of neurological dysfunction. Role of BDNF as a biomarker in ASDs is gaining significance since BDNF protein expression is regulated by gonadal steroids. Mammalian target of rapamycin is a protein kinase involved in translation control and long-lasting synaptic plasticity that are the basis for the higher order brain function, including long-term memory. The hyperactivation of the mTOR system participates in the pathogenesis of several genetic conditions associated with ASDs and the expression of autistic phenotypes.
In the current study, pregnant rats were divided into 2 sets; control and VPA-treated rats. On GD12.5, pregnant female rats received a single
Summary & conclusion
intraperitoneal injection of 600 mg/kg sodium valproate; alternatively, the same volume of physiological saline was administered at the same time and this latter group of rats was considered as control. The offspring of set 1 (which received physiological saline) were divided into 2 groups; ten pups each, and the offspring of set 2 (which received VPA) were divided into 5 groups; ten pups each. Finally, seven groups were organized as follows: group 1, the Control, in which pups from set 1 didn’t receive any treatment; group 2, Sesame oil- treated group in which pups from set 1 were given sesame oil vehicle only from PND 1 until PND10; group 3, VPA-induced ASDs model in which pups from set 2 (pups of VPA- treated mothers) didn’t receive any further treatment; group 4, VPA/Sesame oil group in which pups from set 2 (pups of VPA-treated mothers) were given sesame oil from PND1 until PND10; group 5, VPA/Testosterone group in which pups from set 2 (pups of VPA-treated mothers) received 1 mg/day testosterone propionate subcutaneously every 2 days from PND1 until PND10; group 6, VPA/ Flutamide group in which pups from set 2 (pups of VPA-treated mothers) received flutamide 1 mg/kg subcutaneously every two days from PND1 until PND10; group 7, VPA/ Finasteride group in which pups from set 2 (pups of VPA-treated mothers) received one injection of finasteride 50 mg/kg subcutaneously at day 2 of birth.
The current study aimed to investigate the therapeutic effects of anti-androgens in VPA- induced ASDs in rats. To test our hypothesis, pups were tested for developmental milestones and behavioral changes. BDNF assay using ELISA, histopathological and m-TOR expression using immunohistochemical analysis of the cerebral cortex, cerebellum and hippocampus were also investigated.
Preterm-VPA exposure resulted in ASDs-like behaviors in rats, such as repetitive behavior and social interaction impairment. VPA exposure
also up-regulated the expression of BDNF in both the cerebral cortex and the cerebellum. Furthermore, this VPA model of ASDs increased mTOR immunopositivity in the cerebral cortex, cerebellum and hippocampus.
Antiandrogens ameliorated the VPA-induced ASDs-like behavior, improved developmental delay, suppressed the repetitive behavior, and increased sociability in rats. The studied antiandrogens caused a significant decrease in the levels of BDNF in cerebral cortex and cerebellum. The cerebral cortex, cerebellum and hippocampus restored their normal healthy neurons and the immunopositivity of mTOR was similarly decreased.