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Journal of neuroscience research 2025 June ; 103 (6)
Adenylyl Cyclase Activator: Forskolin Mediates CREB ser133 Phosphorylation in the Hippocampus, Alleviates Autism-Like Deficits in a Valproic Acid Model of Wistar Rats
Ashish Jain (1), Neha Dhir (1), Praisy K Prabha (1), Anupam Raja (1), Amit Raj Sharma (2), Tamanna Kaundal (1), Shiv Charan (1), Alka Bhatia (3), Dibyajyoti Banerjee (3), Biman Saikia (4), Deepy Zohmangaihi (5), Manoj K Goyal (6), Bikash Medhi (1), Ajay Prakash (1)
1. Experimental Pharmacology Laboratory (EPL), Neurobehavioral Research Laboratory (NBRL), Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 2. Experimental Pharmacology Laboratory (EPL), Neurobehavioral Research Laboratory (NBRL), Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India., Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 3. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 4. Department of Immunopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 5. Department of Biochemistry, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. 6. Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social deficits, restricted interest, and repetitive behaviors. The prevalence is higher in males (4:1). FDA-approved drugs, Aripiprazole, and risperidone, only target comorbid conditions and have significant side effects. Dysregulation in cAMP-responsive element-binding protein (CREB) signaling is reported in autistic individuals. Forskolin is traditionally used in Ayurvedic medicine with lesser side effects. It is a potent adenylyl cyclase (AC) activator, increases intracellular cyclic adenosine monophosphate (cAMP) levels, thereby activating the protein kinase A (PKA)/CREB pathway with clinically proven benefits as an anticancer, anti-asthmatic, and in metabolic disorder, and crosses the blood-brain-barrier (BBB) junction. The present study aimed to investigate the impact of Forskolin and sought to explore the role of estrogen beta (ERβ/ESR2) receptors in a valproic acid (VPA) model of ASD. Pregnant Wistar rats received VPA or an equal volume of saline on gestational day (GD) 12.5. From postnatal day (PND) 23, male and female rats were divided separately into control, VPA, risperidone, and Forskolin (10-30 mg/kg) groups. Systemic administration of Forskolin ameliorated anxiety, social deficit, repetitive behavior, spatial recognition memory, motor coordination, gastrointestinal (GIT) motility, brain edema, and BBB permeability in a dose-dependent manner. Moreover, chronic Forskolin treatment significantly alleviated VPA-induced neuronal damage in the prefrontal cortex (PFC), hippocampus (HC), and cerebellum, and increased the intracellular CREB ser133 protein phosphorylation. Forskolin upregulated the mRNA expression of CREB signaling, which was altered by prenatal VPA administration. Our findings indicate that Forskolin provides neuroprotection through CREB signaling, suggesting its therapeutic potential for ASD.
DHARA ID: D064265 Pubmed ID: 40457879
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