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Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats.
Life Sci. 2017 Mar 15; 173:1-10.LS

Abstract

AIMS

Insulin/insulin receptor signaling is involved in cognitive functions. Clinical studies have shown that intranasal insulin administration improves memory functions. However, the molecular mechanisms associated with improvement in memory functions are largely unexplored. Therefore, we investigated the protective effect of intranasal insulin in intracerebroventricular (ICV) streptozotocin (STZ) induced memory impairment in rats.

MAIN METHODS

Rats were injected with STZ (3mg/kg, ICV) bilaterally twice, on days 1 and 3 and intranasal insulin (2IU/rat/day) was given for 14days. Memory was assessed by Morris water maze test. Cerebral blood flow (CBF) was measured by laser-Doppler flowmetry. The biochemical and molecular studies were done in cortex and hippocampus of rat brain.

KEY FINDINGS

STZ (ICV) administration caused memory impairment along with the reduction of CBF, ATP level, and Nrf-2 expression. Treatment with intranasal insulin significantly improved memory functions as well as restored CBF, ATP content and Nrf-2 expression in STZ injected rats. STZ administration stimulated oxidative-nitrosative stress as evidenced by a significant increase in ROS, malondialdehyde, NO level and inducible nitric oxide synthase expression and the decrease in glutathione level; which was normalized by intranasal insulin delivery. STZ-induced cholinergic dysfunction (AChE activity and α7-nAChR expression), and mitochondrial hypofunction was largely prevented by treatment with intranasal insulin. Intranasal insulin delivery successfully restored BDNF level and pCREB expression in STZ injected rats.

SIGNIFICANCE

The study shows the beneficial effects of intranasal insulin against STZ-induced memory impairment, which attributed to improved CBF, cholinergic function, brain energy metabolism, BDNF, Nrf-2 expression and antioxidative action.

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Authors+Show Affiliations

Rajasekar N
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
Nath C
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
Hanif K
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
Shukla R
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Chennai, India. Electronic address: rakeshshuklacdri@gmail.com.

MeSH

Administration, IntranasalAnimalsBlood Flow VelocityBrain-Derived Neurotrophic FactorCerebral CortexCerebrovascular CirculationGene Expression RegulationHippocampusInsulinMaleMaze LearningMemory DisordersNF-E2-Related Factor 2RatsRats, Sprague-DawleyStreptozocinalpha7 Nicotinic Acetylcholine Receptor

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27693383

Citation

Rajasekar, N, et al. "Intranasal Insulin Improves Cerebral Blood Flow, Nrf-2 Expression and BDNF in STZ (ICV)-induced Memory Impaired Rats." Life Sciences, vol. 173, 2017, pp. 1-10.
Rajasekar N, Nath C, Hanif K, et al. Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats. Life Sci. 2017;173:1-10.
Rajasekar, N., Nath, C., Hanif, K., & Shukla, R. (2017). Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats. Life Sciences, 173, 1-10. https://doi.org/10.1016/j.lfs.2016.09.020
Rajasekar N, et al. Intranasal Insulin Improves Cerebral Blood Flow, Nrf-2 Expression and BDNF in STZ (ICV)-induced Memory Impaired Rats. Life Sci. 2017 Mar 15;173:1-10. PubMed PMID: 27693383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats. AU - Rajasekar,N, AU - Nath,Chandishwar, AU - Hanif,Kashif, AU - Shukla,Rakesh, Y1 - 2016/09/28/ PY - 2016/07/04/received PY - 2016/08/19/revised PY - 2016/09/26/accepted PY - 2016/10/4/pubmed PY - 2017/3/16/medline PY - 2016/10/4/entrez KW - Acetylcholinesterase KW - CREB activation KW - Cerebral blood flow KW - Insulin KW - Oxidative stress SP - 1 EP - 10 JF - Life sciences JO - Life Sci VL - 173 N2 - AIMS: Insulin/insulin receptor signaling is involved in cognitive functions. Clinical studies have shown that intranasal insulin administration improves memory functions. However, the molecular mechanisms associated with improvement in memory functions are largely unexplored. Therefore, we investigated the protective effect of intranasal insulin in intracerebroventricular (ICV) streptozotocin (STZ) induced memory impairment in rats. MAIN METHODS: Rats were injected with STZ (3mg/kg, ICV) bilaterally twice, on days 1 and 3 and intranasal insulin (2IU/rat/day) was given for 14days. Memory was assessed by Morris water maze test. Cerebral blood flow (CBF) was measured by laser-Doppler flowmetry. The biochemical and molecular studies were done in cortex and hippocampus of rat brain. KEY FINDINGS: STZ (ICV) administration caused memory impairment along with the reduction of CBF, ATP level, and Nrf-2 expression. Treatment with intranasal insulin significantly improved memory functions as well as restored CBF, ATP content and Nrf-2 expression in STZ injected rats. STZ administration stimulated oxidative-nitrosative stress as evidenced by a significant increase in ROS, malondialdehyde, NO level and inducible nitric oxide synthase expression and the decrease in glutathione level; which was normalized by intranasal insulin delivery. STZ-induced cholinergic dysfunction (AChE activity and α7-nAChR expression), and mitochondrial hypofunction was largely prevented by treatment with intranasal insulin. Intranasal insulin delivery successfully restored BDNF level and pCREB expression in STZ injected rats. SIGNIFICANCE: The study shows the beneficial effects of intranasal insulin against STZ-induced memory impairment, which attributed to improved CBF, cholinergic function, brain energy metabolism, BDNF, Nrf-2 expression and antioxidative action. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/27693383/Intranasal_insulin_improves_cerebral_blood_flow_Nrf_2_expression_and_BDNF_in_STZ__ICV__induced_memory_impaired_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(16)30577-X DB - PRIME DP - Unbound Medicine ER -