Viability thresholds and the penumbra of focal ischemia

Abstract

The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought to suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolarization (< 0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.

Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

“…Annexin 2, a phospholipid-binding protein found on cell surface, has been identified as a coreceptor for both plasminogen and t-PA (Hajjar and Hamel, 1990, 1991, 1994. We have previously shown that annexin 2 is attached to endothelial cells in a calcium-dependent manner and fibrinolytic activity disappears in the absence of calcium (Ishii et al, 2001).…”

“…Brain tissues with perfusion deficits below a critical threshold (Hossmann, 1994) experience metabolic energy failure, membrane depolarization and subsequent cellular swelling. These changes precipitate a reduction in the apparent diffusion coefficient (ADC) of brain water and are manifested as hyperintense regions on DWI (Busch et al, 1997).…”

Neuroprotection for ischemic stroke: Past, present and future

“…Overview of ischemia-pathophysiology: topics and targets of neuroprotection Subject Selected Reviews General review articles (Siesjo, 1981 (Koehler, 1998;Ginsberg et al, 1998b) Transgenic and knockout mouse models (Chan et al, 1995;Liang et al, 2004) In vitro modeling of "ischemia": hippocampal slice preparation (Noraberg et al, 2005) Cerebral blood flow-determined thresholds of ischemic injury (Heiss et al, 1983;Hossmann, 1994b) Ischemic neuropathology (Graham, 1992) Selective vulnerability; delayed ischemic injury (Wieloch, 1985;Ginsberg, 1990 …”

A novel method for inducing focal ischemia in vitro

“…This disruption in ionic equilibrium, combined with the continued hypoxia and hypoglycemia, leads to a secondary stage of neuronal damage that progressively spreads to neurons located adjacent to, and well outside of, the core region (Lipton, 1999;Zheng et al, 2003;Brouns and De Deyn, 2009). This region is called the "penumbra" and is characterized by metabolic arrest, cellular stress and eventual death of neurons primarily via apoptosis (Astrup et al, 1981;Hossmann, 1994;Lipton, 1999). Together, the core and penumbra * Corresponding author.…”