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Vasoconstrictive neurovascular coupling during focal ischemic depolarizations.
Hwa Kyoung Shin1, Andrew K Dunn, Phillip B Jones
1Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Summary
Repetitive periinfarct spreading depolarizations (PIDs) worsen stroke by reducing blood flow. Inhibiting cortical spreading depression (CSD) reduced hypoperfusion and infarct size in mice, suggesting a new neuroprotection strategy.
Area of Science:
- Neuroscience
- Cerebrovascular Biology
- Ischemic Stroke Research
Background:
- Ischemic depolarizing events, like periinfarct spreading depolarizations (PIDs), exacerbate stroke by increasing metabolic demand.
- This can lead to a critical mismatch between cerebral blood flow (CBF) and metabolism, worsening infarct size.
Purpose of the Study:
- To investigate the impact of anoxic depolarization (AD) and PIDs on CBF in an experimental stroke model.
- To evaluate the neuroprotective potential of drugs inhibiting cortical spreading depression (CSD) by examining their effect on CBF and infarct size.
Main Methods:
- Utilized a distal middle cerebral artery occlusion model in mice to induce focal ischemia.
- Measured CBF and quantified the area of severely hypoperfused cortex during AD and PIDs.
- Administered drugs targeting NMDA receptors (MK-801) and sigma-1 receptors (dextromethorphan, carbetapentane) or AMPA receptors (NBQX) to assess their effects.
Main Results:
- AD and PIDs caused significant vasoconstriction, abruptly reducing CBF in the ischemic cortex and increasing severely hypoperfused areas by 140%.
- CSD inhibitors (MK-801, dextromethorphan, carbetapentane) did not alter PID frequency but reduced hypoperfusion severity and prevented infarct expansion.
- NBQX, an AMPA receptor antagonist that doesn't inhibit CSD, did not improve CBF or reduce infarct size, unlike MK-801.
Conclusions:
- AD and PIDs critically expand the CBF deficit in ischemic brain, negatively impacting lesion development.
- Mitigating vasoconstrictive neurovascular coupling during ischemic depolarizations via CSD inhibitors offers a novel hemodynamic neuroprotection mechanism.
- Targeting CSD may be a promising therapeutic strategy for acute ischemic stroke.