Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits.

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.

Naringenin Ameliorates Chronic Sleep Deprivation-Induced Pain via Sirtuin1 Inhibition.

Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreased levels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia.

Effect of modulating the allosteric sites of N-methyl-D-aspartate receptors in ischemia-reperfusion induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is one of the major health problems in developed as well as developing countries. The literature regarding the role of N-methyl-D-aspartate receptors (NMDAR) and the impact of the modulation of its allosteric sites on renal function is inadequate. The present study investigated the effect of modulating allosteric sites of NMDAR in ischemia-reperfusion-induced AKI. MATERIALS AND METHODS: We subjected rats to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. We measured blood urea nitrogen, serum creatinine, uric acid, and lactate dehydrogenase to assess kidney injury. We assayed the thiobarbituric acid-reactive substances, reduced glutathione level, and myeloperoxidase and catalase activity to assess oxidative stress in renal tissue, and used hematoxylin-eosin staining to observe histopathologic changes. RESULTS: Ischemia-reperfusion induced AKI, as demonstrated by an increase in serum parameters, oxidative stress and histopathologic changes in renal tissue. The NMDA agonist glutamic acid and polyamine binding site agonist spermidine significantly aggravated oxidative stress and ischemia-reperfusion-induced AKI. Various NMDA receptor antagonists, including glycine binding site inhibitor kynurenic acid, polyamine binding site inhibitor ketamine, and channel blocking agent magnesium sulfate, attenuated ischemia-reperfusion-induced AKI and significantly reduced oxidative stress, which suggests a role for NMDA receptors and the importance of regulating its allosteric sites in AKI. CONCLUSIONS: Acute kidney injury is associated with the activation of NMDA receptors, as well as significant oxidative stress. The antagonism of various allosteric sites of NMDA receptors affords significant benefit against ischemia-reperfusion-induced AKI.