PMID- 26660109 OWN - NLM STAT- MEDLINE DCOM- 20171229 LR - 20220408 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 53 IP - 10 DP - 2016 Dec TI - Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes. PG - 6730-6744 AB - 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 muM) 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 muM) 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 alpha/beta in astrocytes. Further, memantine attenuated STZ-induced amyloid precursor protein (APP), beta-site APP-cleaving enzyme-1 and amyloid-beta(1-42) expression 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-alpha 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. FAU - Rajasekar, N AU - Rajasekar N AD - Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. AD - Academy of Scientific and Innovative Research (AcSIR), Chennai, India. FAU - Nath, Chandishwar AU - Nath C AD - Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. AD - Academy of Scientific and Innovative Research (AcSIR), Chennai, India. FAU - Hanif, Kashif AU - Hanif K AD - Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. AD - Academy of Scientific and Innovative Research (AcSIR), Chennai, India. FAU - Shukla, Rakesh AU - Shukla R AD - Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. rakeshshuklacdri@gmail.com. AD - Academy of Scientific and Innovative Research (AcSIR), Chennai, India. rakeshshuklacdri@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151211 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Amyloid) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Biomarkers) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, rat) RN - 0 (NF-kappa B) RN - 0 (Nerve Growth Factors) RN - 0 (Nitrites) RN - 0 (RNA, Messenger) RN - 5W494URQ81 (Streptozocin) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 2.7.11.26 (glycogen synthase kinase 3 alpha) RN - EC 3.4.24.56 (Insulysin) RN - W8O17SJF3T (Memantine) SB - IM MH - Amyloid/*metabolism MH - Amyloid beta-Protein Precursor/metabolism MH - Animals MH - Astrocytes/drug effects/*metabolism/*pathology MH - Biomarkers/metabolism MH - Cell Line, Tumor MH - Cyclooxygenase 2/metabolism MH - Down-Regulation/drug effects MH - Fluorescent Antibody Technique MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Inflammation/metabolism/*pathology MH - Insulin Receptor Substrate Proteins/metabolism MH - Insulysin/metabolism MH - Memantine/*pharmacology MH - NF-kappa B/metabolism MH - Nerve Growth Factors/genetics/*metabolism MH - Nervous System/*pathology MH - Nitric Oxide Synthase Type II/metabolism MH - Nitrites/metabolism MH - Oxidative Stress/drug effects MH - Phosphorylation/drug effects MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Receptor, Insulin/*metabolism MH - Signal Transduction/drug effects MH - Streptozocin OTO - NOTNLM OT - Amyloidogenic protein expression OT - Astrocytes OT - Insulin receptor signaling OT - Memantine OT - Neurotrophic factor OT - Streptozotocin EDAT- 2015/12/15 06:00 MHDA- 2017/12/30 06:00 CRDT- 2015/12/15 06:00 PHST- 2015/10/08 00:00 [received] PHST- 2015/11/29 00:00 [accepted] PHST- 2015/12/15 06:00 [pubmed] PHST- 2017/12/30 06:00 [medline] PHST- 2015/12/15 06:00 [entrez] AID - 10.1007/s12035-015-9576-5 [pii] AID - 10.1007/s12035-015-9576-5 [doi] PST - ppublish SO - Mol Neurobiol. 2016 Dec;53(10):6730-6744. doi: 10.1007/s12035-015-9576-5. Epub 2015 Dec 11.