The Two Pathophysiologies of Focal Brain Ischemia: Implications for Translational Stroke Research

Abstract

Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research.

Vascular plasticity in cerebrovascular disorders

“…Cell death in the core is caused primarily by a severe reduction in blood flow below the threshold of energy failure (Hossmann, 2009). In the subacute period following the stroke, an expansion of the ischemic core into the penumbral area is often seen.…”

“…In the subacute period following the stroke, an expansion of the ischemic core into the penumbral area is often seen. Mechanisms underlying the growth of an infarct into the periinfarct penumbra are not well understood, but it is thought to involve a gradual time-dependent increase in the threshold of energy failure and a delayed cell death caused by molecular disturbances in the neurons initiated by the acute ischemic insult (Hossmann, 2009).…”

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

“…First, in the t-MCAO model, primary core damage may recover, and a secondary delayed injury evolves after a free interval of up to 12 hours. This is a long therapeutic window that is not seen in human stroke, an important difference between human and experimental stroke pathways, as described by Hossmann (Hossmann, 2012). Second, we did not perform a time-dependent characterization of the inflammatory response.…”

Role of Histamine and Its Receptors in Cerebral Ischemia

“…52 Vasogenic edema then causes an increase in tissue pressure and, thereby, aggravates the primary reduction in blood flow. 53 With respect to capillary permeability, several reports indicate that blood-brain barrier permeability is regulated by brain histamine. Infusion of histamine into the carotid artery enhances the penetration of albumin through the capillary and increases the cortical water content by activating H2 receptors.…”