Delayed Neuroprotective Effect of Insulin-Like Growth Factor-I After Experimental Transient Focal Cerebral Ischemia Monitored With MRI

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Abstract
Background and Purpose —Insulin-like growth factor (IGF) treatment has been shown to have trophic and neuroprotective effects in vitro and in vivo in different lesion models. IGF-I has potent neuroprotective effects after hypoxic-ischemic injury and global ischemia. The role of IGF-I in focal cerebral ischemia is only partially understood. Therefore, in the present study, we evaluated, by applying MRI monitoring, whether a clinically relevant systemic administration of IGF-I can achieve a long-lasting neuroprotective effect. Methods —Male Wistar rats underwent transient occlusion of the right middle cerebral artery for 1 hour by using the suture occlusion model. Animals then were intraventricularly treated with 33.33 μg IGF-I/d for 3 days (group A, the IGF-I group [n=13]; group B, the placebo group [n=14]) or subcutaneously treated with 200 μg IGF-I/d for 7 days (group D, the IGF-I group [n=10]; group E, the placebo group [n=10]). Groups C and F served as sham-operated controls (n=5 and n=3, respectively). Treatment was begun 30 minutes after occlusion of the middle cerebral artery. Subcutaneously treated animals underwent MRI studies (diffusion-weighted imaging, perfusion imaging, and T2-weighted imaging) beginning 60 minutes after vessel occlusion at 6 hours and at days 1, 2, 5, and 7 after ischemia. The animals were weighed and neurologically assessed daily (rating scale ranged from 0, indicating no deficit, to 5, indicating death). On the third day (intraventricular trial) and on the seventh day (subcutaneous trial), animals were euthanized, and brain sections were stained with triphenyltetrazolium chloride. Results —The mean infarct volume was 52.9±25.2 mm 3 in intraventricularly treated animals versus 146.4±62.2 mm 3 in control animals ( P 3 in subcutaneously IGF-I–treated animals versus 73.1±38.1 mm 3 in control animals ( P 3 versus 38.3±19.3 mm 3 ( P =NS), increased to 168.3±49.55 mm 3 versus 105.5±33.8 mm 3 ( P 3 versus 23.3±20.2 mm 3 ( P 3 versus 115.9±56.8 mm 3 ( P 3 versus 75.7±35.8 mm 3 ( P P Conclusions —Continuous treatment with intraventricularly and subcutaneously administered IGF-I achieved a long-lasting neuroprotective effect as early as 24 hours after ischemia as measured by MRI. Therefore, IGF-I may represent a new approach to the treatment of focal cerebral ischemia.

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