Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting...

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Mitochondrial dysfunction is a key factor in secondary brain injury (SBI) after intracerebral hemorrhage (ICH).
• Celastrol, derived from Tripterygium wilfordii, shows promise for neuroprotection and mitochondrial support.

Purpose of the Study:

• To investigate the neuroprotective effects of celastrol against ICH-induced SBI.
• To elucidate the underlying molecular mechanisms of celastrol's action.

Main Methods:

• Autologous blood-induced ICH model in mice.
• In vivo and in vitro assessments of neurobehavioral and cognitive function, neuronal death, and mitochondrial function.
• Single-cell nuclear sequencing to identify signaling pathways.
• Molecular analysis of celastrol's interaction with EPAC-1 and VDAC1.
• Gene knockout studies (neuron-specific EPAC1 knockout).

Main Results:

• Celastrol administration improved neurobehavioral and cognitive outcomes in ICH mice.
• Celastrol reduced neuronal death and enhanced mitochondrial function recovery.
• Single-cell sequencing identified the cAMP/EPAC-1 pathway as a target of celastrol.
• Celastrol binds to EPAC-1, inhibiting its interaction with VDAC1 and preventing mitochondrial permeability transition pore opening.
• Neuroprotective effects of celastrol were reduced in mice lacking EPAC1 in neurons.

Conclusions:

• Celastrol ameliorates mitochondrial dysfunction in neurons following ICH.
• Celastrol exerts neuroprotection by interacting with EPAC-1, modulating the cAMP/EPAC-1 signaling pathway.
• Targeting EPAC-1 with celastrol represents a potential therapeutic strategy for ICH-induced SBI.