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Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting
Xiang Li1,2, Wen Liu3, Guannan Jiang1,2
1Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China.
Insights
Celastrol, a natural compound, protects neurons and improves brain function after intracerebral hemorrhage (ICH). It works by targeting the EPAC-1 pathway to restore mitochondrial function and reduce brain injury.
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.
Abstract:
Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH-induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood-induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single-cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP-activated exchange protein-1 (EPAC-1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC-1) to inhibit its interaction with voltage-dependent anion-selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron-specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC-1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC-1 with celastrol can be a promising therapeutic approach for treating ICH-induced SBI.
