Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Abstract

The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain’s central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

Stroke-related gene expression profiles across species: A meta-analysis

“…For instance, the molecular signature of the stroke core may considerably vary from the penumbra and different cell types may contribute to gene expression changes. However, there are only a limited number of studies that have thoroughly investigated these differences [17]. Novel advancements with single cell/nucleus and spatially resolved transcriptomics may provide further insights in near future [18,19].…”

Stroke in the Time of Circadian Medicine

“…The immediate effects of vessel occlusion in stroke are the rapid development of tissue hypoxia resulting in a mismatch between metabolic supply and demand. 36,37 The transcription factor HIF (hypoxia-inducible factor) 1α is a master regulator of the cellular response to the hypoxic environment and has been extensively studied in stroke, particularly in the ischemic penumbra. [36][37][38][39] There are multiple reciprocal interactions between HIF1α and the core clock machinery 40 (Figure 1C).…”

“…36,37 The transcription factor HIF (hypoxia-inducible factor) 1α is a master regulator of the cellular response to the hypoxic environment and has been extensively studied in stroke, particularly in the ischemic penumbra. [36][37][38][39] There are multiple reciprocal interactions between HIF1α and the core clock machinery 40 (Figure 1C). First, oxygen levels in the blood and in tissues of mice show a timeof-day-dependent rhythm, and oxygen fluctuations synchronize cellular clocks.…”

“…36,37 Strong excitotoxicity triggers rapid necrosis, whereas less intense exposure to excitotoxic stimuli (as in the penumbra 36 ) results in delayed apoptosis, mediated by the direct activation of BAX 49,104 and other proteins associated with apoptosis. 36,105 Apoptosis is further amplified as a result of reperfusion. 36 Importantly, cell death pathways are known to intersect and overlap with other signaling pathways.…”

“…Cells in the penumbra, however, encounter hypoxic conditions that lead to mitochondrial dysfunction. 36 Mitochondria, the cell's energy-producing organelles, are at the center stage of the hypoxia response. 130 Mitochondria are not only directly involved in apoptotic signaling (see above), but also fulfil critical metabolic functions such as oxidative phosphorylation, fatty acid and amino acid metabolism.…”