Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
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.
N
N
Rajasekar
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.
Chandishwar
C
Nath
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.
Kashif
K
Hanif
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.
Rakesh
R
Shukla
D000281:Administration, Intranasal; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000009:adverse effects* / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000096:biosynthesis
D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D064569:alpha7 Nicotinic Acetylcholine Receptor; D013311:Streptozocin
Acetylcholinesterase; CREB activation; Cerebral blood flow; Insulin; Oxidative stress