Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits. (16th April 2021)

• Record Type: Journal Article
• Authors: Bansal, Seema; Agrawal, Madhunika; Mahendiratta, Saniya; Kumar, Subodh; Arora, Shiyana; Joshi, Rupa; Prajapat, Manisha; Sarma, Phulen; Prakash, Ajay; Chopra, Kanwaljit; Medhi, Bikash
• Is Part Of: Fundamental & clinical pharmacology. Volume 35:Number 6(2021)
• Page Start: 1018
• Page End: 1031
• Publication Date: 2021-04-16
• Subjects: insulin signaling pathway -- mTOR inhibitor -- neurobehavioral deficits; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/fcp.12677
• Languages: English
• ISSNs: 0767-3981

Abstract

Abstract: Background: It is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival. Objectives: Elucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF‐1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits. Methods: Rats were administered with streptozotocin (3 mg/kg) intracerebroventricular, followed by administration of everolimus (1 mg/kg ) orally for 21 days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group. Results: Streptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor‐1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF‐α), apoptotic (NF‐κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin. Conclusion: Findings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.