title: Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes.
abstract: Our earlier studies showed that insulin receptor (IR) dysfunction along with neuroinflammation and amyloidogenesis played a major role in streptozotocin (STZ)-induced toxicity in astrocytes. N-methyl-D-aspartate (NMDA) receptor antagonist-memantine shows beneficial effects in Alzheimer's disease (AD) pathology. However, the protective molecular and cellular mechanism of memantine in astrocytes is not properly understood. Therefore, the present study was undertaken to investigate the effect of memantine on insulin receptors, neurotrophic factors, neuroinflammation, and amyloidogenesis in STZ-treated astrocytes. STZ (100 μM) treatment for 24 h in astrocytes resulted significant decrease in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and insulin-degrading enzyme (IDE) expression in astrocytes. Treatment with memantine (1-10 μM) improved STZ-induced neurotrophic factor decline (BDNF, GDNF) along with IR dysfunction as evidenced by a significant increase in IR protein expression, phosphorylation of IRS-1, Akt, and GSK-3 α/β in astrocytes. Further, memantine attenuated STZ-induced amyloid precursor protein (APP), β-site APP-cleaving enzyme-1 and amyloid-β1-42expression and restored IDE expression in astrocytes. In addition, memantine also displays protective effects against STZ-induced astrocyte activation showed by reduction of inflammatory markers, nuclear factor kappa-B translocation, glial fibrillary acidic protein, cyclooxygenase-2, tumor necrosis factor-α level, and oxidative-nitrostative stress. The results suggest that besides the NMDA receptor antagonisic activity, effect on astroglial IR and neurotrophic factor may also be an important factor in the beneficial effect of memantine in AD pathology. Graphical Abstract Novel neuroprotective mechanisms of memenatine in streptozotocin-induced toxicity in astrocytes.
authors.affiliation: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: N
authors.initials: N
authors.lastname: Rajasekar
authors.affiliation: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
authors.affiliation: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
authors.affiliation: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. rakeshshuklacdri@gmail.com.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India. rakeshshuklacdri@gmail.com.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007339:Insulysin / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D016328:NF-kappa B; D009414:Nerve Growth Factors; D009573:Nitrites; D012333:RNA, Messenger; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D007339:Insulysin; D008559:Memantine
keywords: Amyloidogenic protein expression; Astrocytes; Insulin receptor signaling; Memantine; Neurotrophic factor; Streptozotocin