The window of opportunity for neuronal rescue with insulin-like growth factor-1 after hypoxia-ischemia in rats is critically modulated by cerebral temperature during recovery

Insulin-like growth factor (IGF-I) is induced in damaged brain tissue after hypoxia-ischemia, and exogenous administration of IGF-I shortly after inju ry has been shown to be neuroprotective. However, it is unknown whether tre atment with IGF-I delayed by more than a few hours after injury may be prot ective. Hypothermia after brain injury has been reported to delay the devel opment of ischemic neuronal death. The authors therefore hypothesize that a reduction in the environmental temperature during recovery from hypoxia-is chemia could prolong the window of opportunity for IGF-I treatment. Unilate ral brain damage was induced in adult rats using a modified Levine model of right carotid artery ligation followed by brief hypoxia (6% O-2, for 10 mi nutes). The rats were maintained in either a warm (31 degrees C) or cool (2 3 degrees C) environment for the first 2 hours after hypoxia. All rats were subsequently transferred to the 23 degrees C environment until the end of the experiment. A single dose of IGF-I (501 mu g) or its vehicle was given intracerebroventricularly at either 2 or 6 hours after hypoxia. Histologic outcome in the lateral cortex was quantified 5 days after hypoxia. Finally, cortical temperature was recorded from 1 hour before and 2 hours after hyp oxia in separate groups of rats exposed to the "warm" and "cool" protocols. In rats exposed to the warm recovery environment, IGF-1 reduced cortical d amage (P < 0.05) when given 2 hours but not 6 hours after insult. In contra st, with early recovery in the cool environment, a significant protective e ffect of IGF-1 in the lateral cortex (P < 0.05) was found with administrati on 6 hours after insult. In conclusion, a reduction in cerebral temperature during the early recovery phase after severe hypoxia-ischemia did not sign ificantly reduce the severity of injury after 5 days' recovery; however, it markedly shifted and extended the window of opportunity for delayed treatm ent with IGF-I.