The effects of systemic administration of the insulin-like growth factor-I in a rat model for ischemic stroke

Abstract

Although the morbidity and mortality of stroke is very high, there is only one approved therapy by the health authorities. The insulin-like growth factor (IGF)-I has been proposed as a good candidate drug, since it is known to exerts several beneficial effects on the central nervous system. However, most experimental studies with IGF-I were carried out in inappropriate animal models or IGF-I was administered into the brain. Therefore, we have set up a clinically relevant animal model for focal cerebral ischemia and investigated the effects of systemic IGF-I injection. We first developed a stroke model for conscious rats with hypertension as a co-morbidity factor. We found that hypertensive rats showed higher infarct volumes and seemed to be less susceptible to microglial activation compared to their normotensive counterparts. Second, we tested subcutaneous (SC) administration of IGF-I in that model. It appeared that systemic administration of IGF-I reduced the infarct volume and improved the neurological deficit in normotensive rats without having an effect on the activation of glial cells. In hypertensive rats however, IGF-I was less beneficial. It turned out that in those hypertensive rats IGF-I reduced microglial activation in the cortex. To address whether systemic injection of IGF-I exerts central neuroprotective effects, we addressed the effects of central injection of the IGF-IR antagonist JB-1. It appeared that this antagonist almost completely blocked the effect of IGF-I. We conclude that systemic administration of IGF-I exerts neuroprotective effects in the brain of normotensive rats in the Et-1 model for conscious rats. We hypothesize that the reduced efficacy of IGF-I in hypertensive rats is due to reduction by IGF-I of microglial activation. Hence, treatment of patients with ischemic stroke may be feasible, but special attention should be paid to hypertension as a co-morbidity factor. Ongoing research to the differences between normotensive and hypertensive rats may provide indications for optimizing the effects of IGF-I, or other drugs, for different types of patients.

Date of Award	12 Dec 2012
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Ron Kooijman (Promotor), Jacques De Keyser (Co-promotor) & Yvette Michotte (Co-promotor)