Hypertension as a co-morbidity factor in a stroke model for conscious animals: effects on infarct size, neurological deficit and activation of glial cells

Background: IGF-I is a pleiotropic growth factor that stimulates the proliferation, differentiation and survival of neurons and glial cells. IGF-I has been shown to be neuroprotective in animal models of stroke. For successful translation to the clinic, drugs have to be administered in a clinically relevant way in conscious animals with a co morbidity factor, such as hypertension or diabetes (STAIR-criteria). Material: A cerebral infarct was induced by application of 200 pmol Et-1 in the vicinity of the middle cerebral artery of conscious controls and spontaneously hypertensive rats (SHRs). Motor/sensory functions were measured 1, 6 and 24 hours after the insult using the Neurological Deficit Score. The infarct size was assessed by cresylviolet staining. The activation of microglia and astrocytes was investigated by immunohistochemistry using antibodies directed against ED-1 and glial fibrillary acidic protein (GFAP) 24 hours after Et-1 administration.Results: First, we showed that subcutaneous administration of IGF-I in conscious rats with transient occlusion of the middle cerebral artery resulted in decreased infarct volumes in control rats. Second, induction of a cerebral infarct inSHRs resulted in a significantly larger infarct volume at 24 hr compared to controls. Accordingly, SHRs exhibited lower NDS at each time point, although these differences did not reach significance. Despite the larger infarct size in SHR, microglial activation in response to the insult was markedly reduced. Indeed, a reduced number of activated microglia in striatum and cortex was found. The activation of astrocytes, as assessed by GFAP expression, was the same in both animal models.
Conclusion: We conclude that subcutaneous administration of IGF-I after the insult can be neuroprotective in rats and that the SHR can be used to induce a clinically relevant ischemic infarct to further test therapeutic value of IGF-I.