In a focal model of brain ischemia in the spontaneously hypertensive rat (SHR), microvascular perfusion, accumulation of inflammatory mediators, and indices of cellular injury have been correlated spatially and temporally by means of multiple label immunohistochemistry in order to study their role in acute stroke. The findings clearly demonstrate that progressive impairment of microcirculation occurs in regions of brain that undergo progressive damage in the early hours of ischemia. Inhibition of tumor necrosis factor-alpha (TNF-alpha) with TNF-binding protein reduces brain infarct volume in middle cerebral artery occlusion (MCAO) models in the rat and mouse. In addition, TNF-binding protein attenuates the progressive impairment of microvascular perfusion that occurs during the early hours of focal brain ischemia. These findings implicate TNF-alpha as a mediator of progressive brain damage during acute stroke. Lipopolysaccharide (LPS) pretreatment has been demonstrated to induce tolerance to focal brain ischemia in the MCAO model in the SHR. TNF binding protein blocks this tolerance implicating TNF-alpha as the mediator. One feature of this form of tolerance is that the degree of microcirculatory perfusion impairment in brain is reduced. Preconditioning with TNF by intracisternal injection of TNF has been demonstrated to induce tolerance to ischemia in the Balb/C mouse. These findings implicate TNF as a stress cytokine that can induce a state of resistance to brain ischemia in rat and mouse models. A recent Phase III clinical stroke trial with an antibody to ICAM-1, an adhesion molecule for leukocytes, caused an excess of morbidity and death in the treated group. Preclinical studies as they had been conducted in other laboratories did not predict this result. Additional studies in rat stroke models are being performed to identify the injury mechanisms responsible for the results of this study and to suggest ways to make preclinical models more predictive.
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