Evaluating the window of opportunity for intranasal insulin therapy in a rat model of cerebral ischemia

Intranasal insulin (InI) demonstrates clinical efficacy in mitigating cognitive deficits. Its neuroprotective potential in cerebral ischemia is of growing research interest. For the first time, this study investigates the therapeutic window for InI in a rat model of transient global cerebral ischemia. Cerebral ischemia was induced in male Wistar rats via 10-min bilateral common carotid artery occlusion with hypotension (40 mm Hg) (I/R). Sham-operated (SO) controls underwent surgery without occlusion or hypotension. InI (0.5 IU/rat) was administered at 2 or 4 hours after ischemia, followed by once-daily dosing for 7 days. Hippocampal gene expression and neuronal survival were assessed using RT-PCR and Nissl staining, respectively. InI at 2 h post-ischemia more effectively prevented body weight loss in I/R rats compared to the 4 h regimen. Blood glucose levels remained unchanged across groups. Increased gene expression of GFAP, a marker of astrocytes, and IBA-1, a marker of microglia, was found in the hippocampus of I/R rats, which may indicate astrogliosis and microgliosis. InI, administered at 2 h, normalized the expression of these genes. Moreover, only the 2 h InI treatment group exhibited a significant neuroprotective effect, with a higher density of Nissl-positive neurons in the hippocampal CA1 region compared to untreated I/R rats, consistent with the levels observed in SO animals. This study is the first to define a critical window of opportunity for InI treatment in transient cerebral ischemia. Administration initiated within 2 hours post-ischemia provides neuroprotection and attenuates glial activation, while delayed treatment (4 h) is markedly less effective.

The work is supported by the IEPhB Research Program No. 075-00967-23-00.