title: Intranasal Insulin Administration Ameliorates Streptozotocin (ICV)-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Memory Impairment in Rats.
abstract: Alzheimer's disease (AD) is associated with reduced insulin level and impairment of insulin receptor (IR) signaling in the brain, which correlates to amyloid pathology, neuroinflammation, and synaptic neurotoxicity. Clinical studies show that intranasal insulin improves memory in AD patients without peripheral hypoglycemia. However, neuroprotective molecular mechanism of the beneficial effect of intranasal insulin in AD pathology is unexplored. Therefore, we investigated the role of intranasal insulin on intracerebroventricular (ICV) streptozotocin (STZ)-induced memory impairment in rats as evaluated in the Morris water maze test. STZ (ICV) treated rats had shown memory impairment along with a significant decrease in IR signaling molecules (IR, pIRS-1, pAkt, and pGSK-3α/β expression) and IDE expression in both hippocampus and cerebral cortex. Intranasal insulin delivery prevented these changes. Moreover, intranasal insulin was found to inhibit significantly glial cell activation (GFAP and Iba-1 expression), neuroinflammation (COX-2 expression, NFκB translocation, TNF-α, and IL-10 level) and amyloidogenic protein expression (BACE-1 and Aβ1-42expression) in STZ (ICV)-injected rats. STZ (ICV)-induced caspase activation and postsynaptic neurotoxicity were also prevented by treatment with intranasal insulin. Our findings reveal that insulin has the neuroprotective effect and clearly signifies the potential use of intranasal insulin delivery for the treatment of AD. Graphical Abstract Neuroprotective effects of intranasal insulin administration on streptozotocin (ICV)-induced memory impairment in rats.
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: D000281:Administration, Intranasal; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage* / Q000627:therapeutic use; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects*; D013311:Streptozocin
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D016328:NF-kappa B; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013311:Streptozocin; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat
keywords: Amyloidogenic protein expression; Glial activation; Insulin receptor dysfunction; Intranasal insulin; post synaptic neurotoxicity