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

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. ; group E, the placebo group [nϭ10]). Groups C and F served as sham-operated controls (nϭ5 and nϭ3, 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. (PϽ0.05) at day 7 for control and IGF-I-treated animals, respectively. The relative regional cerebral blood volume was reduced to 50% before reperfusion in all regions of interest except for region of interest 1 (vessel territory of anterior cerebral artery), recovered during reperfusion, but was not different between the control and the growth factor-treated group at any imaging time point. There was no significant difference in weight loss. There was less neurological deficit after ischemia in intraventricularly and subcutaneously IGF-I-treated animals compared with control animals (PϽ0.05). Conclusions-Continuous treatment with intraventricularly and subcutaneously administered IGF-I achieved a longlasting 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. Methods-Male Results-The

Insulin-Like Growth Factor I

“…34 Infarct volume was also reduced by IVC injection of 33 g IGF-I per day during 3 days starting 30 minutes after MCAO. 35 Improved functional outcome in this study was observed at Days 1, 2, and 3. When IGF-I was given subcutaneously at a dose of 200 g/day during 7 days starting from 30 minutes after the insult, the infarct volume was reduced and significant improvement of functional outcome was detected at Days 1 and 3 to 7.…”

“…When IGF-I was given subcutaneously at a dose of 200 g/day during 7 days starting from 30 minutes after the insult, the infarct volume was reduced and significant improvement of functional outcome was detected at Days 1 and 3 to 7. 35 It remains to be established whether IGF-I treatment at later time points reduces or delays functional outcome. Taken together, these results indicate that further studies to the window of opportunity for different ways of administration at different doses are required.…”

“…35,38 One study has tested IGF-I gene transfer using adenoassociated virus-IGF-I constructs in mice. 39 In this study, the construct was introduced in the caudate nucleus 3 weeks before MCAO and proved to stimulate neurogenesis, neovascularization, and improved functional outcome.…”

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

“…Along with other growth factors (Schabitz et al, 2001(Schabitz et al, , 2003, G-CSF has been previously reported to reduce lesion volume after ischemia in mice (Six et al, 2003) and the rat (Schabitz et al, 2003). In these studies, 50 or 60 mg/kg G-CSF was administered via a single subcutaneous injection, and their findings formed the basis for the present study.…”

Growth factors and stroke

“…for 3 days, or 200 g/d s.c. for 7 days) beginning 30 minutes after the onset of one hour of ischemia. 32 Infarct volume was reduced by 64% in intracerebroventricularly-treated and by 42% in subcutaneously-treated rats. Another group studied the N-terminal tripeptide of IGF-1, Gly-Pro-Glu (GPE).…”