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Updated: Nov 10, 2025
Quantification of Neurovascular Protection Following Repetitive Hypoxic Preconditioning and Transient Middle Cerebral Artery Occlusion in Mice
Published on: May 4, 2015
Triptolide protects against white matter injury induced by chronic cerebral hypoperfusion in mice
Yu-Shan Wan1, Yi You1, Qian-Yun Ding1,2
1Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Abstract:
White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3β pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 μg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.
Insights
Triptolide protects against white matter injury and cognitive decline in chronic cerebral hypoperfusion models. It reduces oligodendrocyte apoptosis and microglial activation without causing toxicity, suggesting potential for treating vascular dementia.
Area of Science:
- Neuroscience
- Pharmacology
- Pathology
Background:
- Subcortical ischemic vascular dementia (SIVD) is characterized by white matter injury due to chronic cerebral hypoperfusion.
- This injury involves demyelination, oligodendrocyte apoptosis, and microglial activation, leading to cognitive impairment.
- Triptolide is known for its anti-inflammatory and immunosuppressive properties.
Purpose of the Study:
- To investigate the therapeutic effects of triptolide on white matter injury and cognitive deficits in a mouse model of chronic cerebral hypoperfusion.
- To elucidate the underlying mechanisms of triptolide's protective actions.
Main Methods:
- Chronic cerebral hypoperfusion was induced using right unilateral common carotid artery occlusion (rUCCAO) in mice.
- Triptolide treatment effects on white matter integrity, cognitive function (novel object recognition, Morris water maze), oligodendrocyte apoptosis, and microglial activation were assessed.
- In vitro studies used primary oligodendrocytes and BV2 microglial cells subjected to oxygen-glucose deprivation (OGD).
Main Results:
- Triptolide administration significantly alleviated demyelination, axonal injury, and oligodendrocyte loss in hypoperfused mice, improving cognitive function.
- Triptolide protected primary oligodendrocytes from OGD-induced apoptosis by enhancing the Src/Akt/GSK3β pathway phosphorylation.
- Triptolide suppressed microglial activation and pro-inflammatory cytokine expression in vivo and in vitro.
Conclusions:
- Triptolide effectively mitigates white matter injury and cognitive impairment associated with chronic cerebral hypoperfusion.
- Its protective effects stem from direct oligodendrocyte protection and indirect inhibition of neuroinflammation.
- Triptolide demonstrates potential as a therapeutic agent for SIVD and related conditions without significant hepatotoxicity or nephrotoxicity.
