Restoring Brain Function in Autism: GSK3β Inhibition by 6-Bromoindirubin-3'-oxime Reverses Valproic Acid-induced...

Area of Science:

• Neuroscience
• Pharmacology
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) presents challenges in social interaction, characterized by restricted interests and repetitive behaviors.
• Current FDA-approved treatments for ASD, like aripiprazole and risperidone, primarily manage comorbid symptoms and carry significant side effects.
• Valproic acid (VPA) exposure during gestation is a known risk factor for developing ASD-like behaviors in offspring.

Purpose of the Study:

• To investigate the therapeutic potential of 6-bromoindirubin-3 omino-oxime (6BIO), a GSK3β inhibitor, in a VPA-induced rat model of ASD.
• To evaluate the effects of postnatal 6BIO administration on behavioral, cognitive, and neurobiological deficits associated with VPA exposure.

Main Methods:

• VPA was administered to pregnant Wistar rats on gestational day 12.5 to induce an ASD model.
• Offspring received daily postnatal treatment with risperidone or 6BIO (15 or 30 μg/kg) until postnatal day 82.
• Behavioral tests, neurochemical analyses (Western blotting, immunohistochemistry), and gene/protein expression studies were performed.

Main Results:

• Postnatal 6BIO treatment dose-dependently improved anxiety-like behavior, social deficits, repetitive behaviors, and cognitive functions in VPA-exposed rats.
• 6BIO administration reduced VPA-induced neuronal damage in the prefrontal cortex, hippocampus, and cerebellum.
• 6BIO suppressed upregulated GSK3β phosphorylation and modulated key genes (Wnt, CHD8, SHANK3) and proteins (β-catenin, NLGN3) involved in ASD pathophysiology.

Conclusions:

• 6-bromoindirubin-3 omino-oxime (6BIO) demonstrates significant neuroprotective effects in a VPA-induced rat model of ASD.
• The therapeutic benefits of 6BIO appear to be mediated through the inhibition of GSK3β.
• 6BIO shows promise as a potential therapeutic agent for ASD, warranting further clinical investigation.