Hx of stroke
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Understanding the Impact of Hypoxia on Stroke: Blood-Brain Barrier and Neuroinflammation
Hypoxia and Blood-Brain Barrier Permeability
Protein Kinase C and Tight Junction Disruption
Hypoxia (Hx), a condition of reduced oxygen supply, is a critical factor in stroke pathology. During ischemic stroke, the restriction of blood flow and oxygen to the brain leads to significant disruptions in the blood-brain barrier (BBB). This disruption is primarily due to the breakdown of tight junction (TJ) proteins, which are essential for maintaining BBB integrity. Research has shown that hypoxia and subsequent reoxygenation (HR) phases increase vascular permeability in the hippocampus and cortex, leading to the leakage of molecules such as dextran and endogenous rat-IgG into the brain tissue.
The role of protein kinase C (PKC) isozymes in this process is significant. Activation of nPKC-θ and aPKC-ζ during hypoxia leads to the phosphorylation and disruption of TJ proteins like claudin-5, occludin, and ZO-1. This disruption results in increased BBB permeability. Inhibition of PKC with chelerythrine chloride has been shown to attenuate these effects, suggesting that PKC signaling is a key mediator in hypoxia-induced BBB disruption.
Occludin Oligomeric Assemblies and Microvascular Permeability
Further studies have highlighted the role of occludin, a transmembrane TJ protein, in maintaining BBB integrity during hypoxia and reoxygenation. Hypoxic conditions promote the disassembly of occludin oligomeric assemblies, which are crucial for the structural integrity of TJs. This disassembly leads to increased microvascular permeability and potential cerebral edema. The interaction of occludin isoforms within these assemblies allows occludin to perform both structural and signaling roles, which are disrupted under hypoxic stress.
Neuroinflammation and Stroke
Nurr1 Activation and Anti-Inflammatory Effects
Ischemic stroke not only disrupts the BBB but also triggers a massive inflammatory response that exacerbates neuronal damage. Targeting neuroinflammatory pathways has emerged as a promising therapeutic strategy. The nuclear receptor Nurr1, part of the NR4A family, has been identified as a potent modulator of inflammatory reactions. Activation of Nurr1 with the synthetic agonist HX600 has shown protective effects in stroke models. HX600 reduces the expression of proinflammatory mediators by microglia, prevents neuronal death, and alleviates motor deficits in mice subjected to permanent middle cerebral artery occlusion.
The anti-inflammatory effects of HX600 are associated with reduced immunoreactivity of markers such as Iba-1, p38, and TREM2, and protection of endogenous microglia from ischemia-induced death. Additionally, HX600 treatment decreases levels of proinflammatory metabolites like lysophosphatidylcholines (lysoPCs) and acylcarnitines, further supporting its potential as a therapeutic agent in ischemic stroke.
Conclusion
The interplay between hypoxia, BBB integrity, and neuroinflammation is crucial in the pathology of ischemic stroke. Disruption of TJ proteins and occludin assemblies under hypoxic conditions leads to increased BBB permeability, while targeting inflammatory pathways through Nurr1 activation offers a promising therapeutic approach. Understanding these mechanisms provides valuable insights into potential treatments for stroke, aiming to protect the brain from further damage and improve patient outcomes.
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