Abstract
AbstractBackgroundIntranasal insulin (INI) represents a potential treatment for age‐related cognitive decline (ARCD), as numerous studies and multi‐center clinical trials have demonstrated that it enhances memory. However, the mechanism underlying these pro‐cognitive changes is unknown. Several methods were implemented to begin to uncover a neurochemical/molecular basis underlying the effects of acute and subchronic INI.MethodNeurochemical and molecular techniques were employed in adult male Sprague‐Dawley rats following acute and/or subchronic INI. The animals received bilateral hippocampal injections of a lentiviral vector containing a selective insulin receptor antisense sequence (LV‐IRAS) or a control virus (LV‐Con). To measure neurotransmitter efflux following INI, probes were inserted into the medial prefrontal cortex (mPFC) and hippocampus for in vivo microdialysis. Levels of acetylcholine and glutamate were measured for three hours following acute INI or IN vehicle. To investigate insulin receptor signaling following acute and subchronic INI, a separate cohort of animals (no virus) were administered INI or IN vehicle for 10 days. The next day they were given another dose of INI to stimulate insulin signaling and euthanized at various time points post‐administration. Olfactory bulb and hippocampal extracts were processed for immunoblot analysis to assess changes in central insulin signaling.ResultBaseline levels of glutamate were significantly decreased in LV‐IRAS animals compared to LV‐Con in the hippocampus but not the mPFC. Additionally, INI administration appeared to increase hippocampal glutamate efflux. Finally, a time‐dependent increase in insulin signaling in response to INI was observed after subchronic INI administration.ConclusionThese results begin to uncover a mechanistic basis for the pro‐cognitive effects of INI. The effects of acute INI may be partially mediated by a neurochemical mechanism, specifically involving glutamate. This study also revealed that molecular changes were dependent on timing and length of dose; therefore a more chronic INI administration may affect neurotransmission differently. More studies are needed to fully understand the mechanistic changes following INI and to determine the most effective clinical dose and dosing regimen. It is important to understand the mechanism of action, as INI could eventually be used in the broader clinical setting to treat ARCD.
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