NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage

Abstract

SignificanceWhy the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke.

Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury

“…Endothelial cells are sensitive pathological events in early stage of cerebral ischemia, which elicit critical impact on barrier stability [17,19,26,27]. Here we found OGD insult of endothelial cells led to continuous elevation of FKBP25 nuclear protein levels at least until 24 h after treatments.…”

Calcium-dependent reactive oxygen formation and blood-brain barrier breakdown by NOX5 limits post-reperfusion outcome in stroke

“…Distinct NOX isoforms, i.e. NOX2 and NOX4, have been described as key players in stroke ROS-dependent patho-mechanism [5,14], however, no specific role of NOX5 has been defined so far. Thus, to examine whether NOX5 causes acute cerebral post-reperfusion/re-oxygenation ROS formation, we first studied in vitro organotypic hippocampal cultures (OHC) of NOX5 KI mice.…”

“…Since current innovative clinical approaches suggest to perform the thrombectomy procedure in presence of the pharmacological agent, we added the NOX5 inhibitor in the acute state before re-oxygenation. However, NOX4 is induced 4h post-re-oxygenation (Fig S2) although it also affects BBB disruption [14]. Then, HBMECs were treated both acutely and post-re-oxygenation with the relatively NOX4-specific inhibitor, M13 (0.2 μM) in order to mimic pre- and post-thrombectomy neuroprotective treatment.…”

“…Therapeutically, one additional aspect is worth considering, i.e. the previous identification of neuronal (and endothelial) NOX4 in stroke [14,26]. This enzyme does not contribute to the here investigated early stages of BBB opening.…”

The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial

“…Interaction OR: 1.03, 95% CI 1.00-1.06, p = 0.03 decrease, leading to the disruption of normal myocardial cellular homeostasis [6]. Unlike the heart, the brain is more sensitive to tissue ischaemia as it has no myoglobin oxygen stores [23,24]. Furthermore, CPR and vasopressors may be less effective at restoring mitochondrial function in the brain than it is at restoring cardiac mitochondrial performance [25].…”