Intraventricular Administration of Insulin and IGF-1 in Transient Forebrain Ischemia

Abstract

A beneficial effect of insulin in reducing cerebral ischemic damage has been recently demonstrated, and a direct central mechanism of insulin action in cerebral ischemia has been proposed. To test the hypothesis that one of the neuroprotective mechanisms of insulin action involves a direct interaction with CNS tissue via a growth factor effect, a continuous intraventricular infusion of two doses of insulin and of insulin-like growth factor 1 (IGF-1) was given to fed Wistar rats subjected to 10 min, 15 s of transient forebrain ischemia. Quantitative neuropathology after 1-week survival showed that low-dose insulin (7 IU/rat/day; n = 10) reduced selective necrosis in the striatum (p = 0.015) and one level of the hippocampus (p = 0.023) as compared with animals infused with phosphate-buffered saline (200 μl/rat/day; n = 8). IGF-1 (50 μg/rat/day; n = 8) significantly ameliorated hippocampal damage in four of the six hippocampal levels (p < 0.05). High-dose insulin infusion (23 IU/rat/day; n = 8) produced a robust reduction in cortical (p = 0.0108), striatal (p = 0.003), and hippocampal (p < 0.05) necrosis at all coronal levels. However, this high-dose insulin reduced the blood sugar significantly (p < 0.01), from 11.8 to 7.8 m M, probably by virtue of centrally administered insulin reaching the periphery. We conclude that insulin and IGF-1 offer a moderate, centrally mediated, neuroprotective effect, likely mediated at least in part via a growth factor mechanism. In addition, we confirm our earlier findings that higher doses of insulin, accompanied by lowering of peripheral blood glucose levels even within the physiologic range, yield the greatest protective effect.