Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Cerebral ischemic/reperfusion (I/R) injury causes significant mitochondrial dysfunction and neurovascular impairment.
• Understanding the mechanisms underlying I/R injury is crucial for developing effective stroke therapies.
• Tetrahydrocurcumin (THC) is being investigated for its potential therapeutic benefits.

Purpose of the Study:

• To elucidate the mechanism of mitochondrial dysfunction in cerebral I/R injury.
• To evaluate the therapeutic potential of tetrahydrocurcumin (THC) in mitigating mitochondrial dysfunction and neurovascular damage in an experimental stroke model.

Main Methods:

• Middle cerebral artery occlusion (MCAO) model in C57BL/6 mice.
• Treatment with Tetrahydrocurcumin (THC) post-ischemia.
• Assessment of functional recovery, neuroscore, infarct volume, brain edema, microvascular leakage, mitochondrial function, oxidative stress, mitophagy, and gene/protein expression (DNMT1, TIMP-2).

Main Results:

• THC treatment significantly improved functional capacity, reduced neuroscore, infarct volume, brain edema, and microvascular leakage.
• I/R injury altered homocysteine levels, mitochondrial function (ATP production, O2 consumption), MMP-9 activity, and tight junction proteins.
• THC normalized these functional and molecular changes, including epigenetic alterations in TIMP-2 promoter methylation via DNMT1.

Conclusions:

• Tetrahydrocurcumin (THC) demonstrates significant neuroprotective effects in a mouse model of ischemic stroke.
• THC ameliorates mitochondrial dysfunction and vascular impairment through epigenetic mechanisms, specifically by modulating TIMP-2 expression.
• This study highlights the potential of THC as a therapeutic agent for ischemic stroke by targeting epigenetic pathways.