Insulin-like growth factor (IGF)-I is a pleiotropic factor that stimulates the proliferation and differentiation of oligodendrocytes, myelinisation, synaptogenesis and the survival of neurons and glial cells. In addition, IGF-I has been shown to be neuroprotective in animal models of focal cerebral ischemia. For successful translation to clinical studies the Stroke Therapy Academic Industry Round Table (STAIR)-criteria are essential. Testing of drugs in conscious animals, the use of a co morbidity factor such as hypertension and a clinically relevant administration of the drug are three important criteria. We showed that subcutaneous administration of IGF-I in conscious rats with transient occlusion of the middle cerebral artery resulted in decreased infarct volumes. The purpose of our study is to develop and investigate a clinically relevant animal model for focal transient cerebral ischemia using conscious rats with a co morbidity factor. To this end, we tested the use of the Spontaneously Hypertensive Rat strain (SHR) in the endothelin-1 (Et-1) rat model. Using a stereotactic frame, 200 pmol Et-1 was applied in the vicinity of the middle cerebral artery of conscious controls and SHRs in order to induce a cerebral infarct. Motor/sensory functions were measured 1, 6 and 24 hours after the insult using the Neurological Deficit Score (NDS). Infarct size was assessed by cresylviolet staining. To investigate the inflammatory response, LPS was administered in the striatum of both control rats and SHR. A dose-range finding study was carried out applying 40 and 10 mg/4ml LPS. Rectal temperature was measured 1, 3 and 6 hours after the administration of 10 mg/4ml LPS. The activation of microglia and astrocytes in the striatum was investigated by immunohistochemistry using antibodies directed against ED-1 and glial fibrillary acidic protein (GFAP) 24 hours after Et-1 and LPS administration. One day after induction of focal cerebral ischemia, SHRs showed a significantly larger infarct volume (55.50 ± 4.24 mm³, n= 6) compared to the controls (39.20 ± 2.71 mm³,n=15). Accordingly, SHRs exhibited lower NDS at each time point, although these differences did not reach statistical significance. Despite the larger infarct size in SHR, microglial activation in response to the insult was reduced. Indeed, a reduced number of activated microglia (ED1⁺) in the striatum (WKY: 398 ± 50, n= 4; SHR: 195 ± 16, n= 4) as well as in the cortex (WKY: 608 ± 93, n= 4; SHR: 224 ± 56, n= 4) was observed. In contrast, activation of astrocytes, as assessed by GFAP expression, was the same in both animal models. LPS-injection resulted in an equal activation of microglia and an increased activation of astrocytes in the SHRs when 10 mg/4ml was administered (WKY: 25.3 ± 1.6, n=4; SHR: 32.1 ± 1.1, n=3). SHRs also show a significant increase in rectal temperature at every time point (1h: WKY: -0.80 ± 0.40, n=4; SHR: 0.60 ± 0.20, n=4); (3h: WKY: -0.40 ± 0.18, n=4; SHR: 0.72 ± 0.048, n=4); (6h: WKY: 0.32 ± 0.31, n= 4; SHR: 1.47 ± 0.08, n=4). We conclude that the SHR can be used to induce a clinically relevant ischemic damage. Using this model, we will further investigate the possibility to use IGF-I as a neuroprotective agent in stroke, and the possible role of immunomodulatory effects of IGF-I in neuroprotection. With respect to the differences between the normal and hypertensive model for cerebral ischemia, it remains to be established whether reduced activation of microglia is responsible for the increased infarct size in the SHR.