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Intranasal Insulin Administration Ameliorates Streptozotocin (ICV)-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Memory Impairment in Rats

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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 Aβ1–42 expression) 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.

Neuroprotective effects of intranasal insulin administration on streptozotocin (ICV)-induced memory impairment in rats

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Abbreviations

IRS-1:

Insulin receptor substrate 1

pIRS-1:

Phospho-insulin receptor substrate 1

PKB:

Protein kinase B

GSK-3:

Glycogen synthase kinase 3

IDE:

Insulin-degrading enzyme

GFAP:

Glial fibrillary acidic protein

Iba-1:

Ionized calcium-binding adapter molecule 1

COX-2:

Cyclooxygenase

NFκB:

Nuclear factor kappa B

TNF-α:

Tumor necrosis factor alpha

IL-10:

Interleukin-10

APP:

Amyloid precursor protein

BACE-1:

Beta-site APP cleaving enzyme 1

Aβ:

Amyloid-β

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Acknowledgments

Financial support from DBT (BT/PR4012/MED/ 30/672/201 Dated 28/03/2012) and SRF to N. Rajasekar from CSIR, New Delhi, India, are gratefully acknowledged.

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Authors and Affiliations

  1. Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    N. Rajasekar, Chandishwar Nath, Kashif Hanif & Rakesh Shukla

  2. Academy of Scientific and Innovative Research (AcSIR), Chennai, India

    N. Rajasekar, Chandishwar Nath, Kashif Hanif & Rakesh Shukla

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  1. N. Rajasekar
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Rajasekar, N., Nath, C., Hanif, K. et al. Intranasal Insulin Administration Ameliorates Streptozotocin (ICV)-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Memory Impairment in Rats. Mol Neurobiol 54, 6507–6522 (2017). https://doi.org/10.1007/s12035-016-0169-8

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