Spreading depression: imaging and blockade in the rat neocortical brain slice

Area of Science:

• Neuroscience
• Cellular Biology

Background:

• Spreading depression (SD) is a significant neuronal event occurring in conditions like migraine aura, stroke, and head trauma.
• While not damaging in migraine, SD can exacerbate neuronal damage in stroke and head trauma.
• Existing treatments targeting N-methyl-D-aspartate (NMDA) receptors are not ideal for therapeutic use.

Purpose of the Study:

• To develop and validate a novel superfused brain slice preparation for studying spreading depression (SD).
• To investigate potential therapeutic agents for blocking SD using this new model.
• To identify drugs that can block SD without relying on NMDA receptor antagonism.

Main Methods:

• Utilized a superfused rat neocortical slice preparation to repeatedly induce and image spreading depression (SD).
• Evoked SD using elevated potassium artificial cerebrospinal fluid (ACSF) and monitored via DC shifts and light transmittance.
• Tested the efficacy of NMDA receptor antagonists, non-NMDA glutamate receptor antagonists, and sigma-one receptor (sigma(1)R) agonists and antagonists.

Main Results:

• The brain slice preparation successfully supported repeated, non-damaging SD evocation and imaging.
• NMDA receptor antagonists blocked SD, but sigma-one receptor (sigma(1)R) agonists (dextromethorphan, carbetapentane, 4-IBP) provided a more promising block.
• Sigma-one receptor (sigma(1)R) agonists also reduced general cell swelling and their effect was reversible with specific antagonists.

Conclusions:

• Sigma-one receptor (sigma(1)R) agonists represent a novel and effective therapeutic strategy for blocking spreading depression (SD).
• These findings suggest sigma(1)R ligands could be valuable in treating conditions associated with SD, including migraine, stroke, and head trauma.
• Further research into potent, therapeutically tolerated sigma(1)R ligands is warranted.