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.
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.
Life Sci. 2017 Mar 15;173:1-10. doi: 10.1016/j.lfs.2016.09.020. Epub 2016 Sep 28.
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.
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.
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.
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.
胰岛素/胰岛素受体信号参与认知功能。临床研究表明，鼻内给予胰岛素可改善记忆功能。然而，与改善记忆功能相关的分子机制在很大程度上仍未得到探索。因此，我们研究了鼻内胰岛素对脑室（ICV）链脲佐菌素（STZ）诱导的大鼠记忆障碍的保护作用。
大鼠双侧脑室（ICV）两次注射 STZ（3mg/kg，第 1 天和第 3 天），并连续 14 天鼻内给予胰岛素（2IU/大鼠/天）。通过 Morris 水迷宫试验评估记忆。通过激光多普勒血流仪测量脑血流（CBF）。在大鼠大脑皮质和海马进行生化和分子研究。
ICV STZ 给药导致记忆障碍，同时 CBF、ATP 水平和 Nrf-2 表达降低。鼻内给予胰岛素可显著改善记忆功能，并恢复 STZ 注射大鼠的 CBF、ATP 含量和 Nrf-2 表达。STZ 给药刺激氧化-硝化应激，表现为 ROS、丙二醛、NO 水平和诱导型一氧化氮合酶表达显著增加，谷胱甘肽水平降低；鼻内胰岛素给药可使这些指标恢复正常。STZ 诱导的胆碱能功能障碍（AChE 活性和α7-nAChR 表达）和线粒体功能障碍在很大程度上被鼻内胰岛素治疗所预防。鼻内胰岛素给药成功恢复了 STZ 注射大鼠的 BDNF 水平和 pCREB 表达。
该研究表明鼻内胰岛素对 STZ 诱导的记忆障碍具有有益作用，这归因于改善 CBF、胆碱能功能、脑能量代谢、BDNF、Nrf-2 表达和抗氧化作用。
