Targeting ischemic penumbra: part I - from pathophysiology to therapeutic strategy

Abstract

Penumbra is the viable tissue around the irreversibly damaged ischemic core. The purpose of acute stroke treatment is to salvage penumbral tissue and to improve brain function. However, the majority of acute stroke patients who have treatable penumbra are left untreated. Therefore, developing an effective non-recanalizational therapeutics, such as neuroprotective agents, has significant clinical applications. Part I of this serial review on "targeting penumbra" puts special emphases on penumbral pathophysiology and the development of therapeutic strategies. Bioenergetic intervention by massive metabolic suppression and direct energy delivery would be a promising future direction. An effective drug delivery system for this purpose should be able to penetrate BBB and achieve high local tissue drug levels while non-ischemic region being largely unaffected. Selective drug delivery to ischemic stroke penumbra is feasible and deserves intensive research.

Figure 1

Infarct expansion and treatment strategies. During the first few hours after middle cerebral occlusion of a 300 gram rat, the infarct expands quickly at an average speed of 3.3 mg brain tissue per minute assuming the specific gravity of rat brain is 1.0 mg/mm³. Neuroprotective treatment should be able to penetrate the blood-brain barrier and reach penumbral zone. Such treatment should be made available to most acute stroke patients who have salvageable penumbral tissue.

Figure 2

From pathophysiology to therapeutic strategy. Salvaging penumbra is the goal for acute stroke treatment. Neuroprotection for acute ischemic stroke should target the upper stream event that determines the fate of ischemic penumbra. Bioenergetic intervention could be the therapeutic modality equivalent to recanalizational therapies at metabolic levels because the disturbance of energy metabolism after acute brain ischemia differentiates the ischemic cascades. C1-C9: pathological cycles between major events that are supported by literature; Q1-Q3: suspected pathological cycles between major events that need more literature support.

Figure 3

Correlation between energy thresholds and blood flow thresholds. The form and pathway of cell death closely are closely associated with energy state levels. Blood flow reduction causes specific metabolic disturbances at certain blood flow thresholds. The ischemic core has depleted ATP level whilst the penumbra has gradient reduction of ATP level between normal or oligemic tissue and ischemic core.