Triptolide protects against white matter injury induced by chronic cerebral hypoperfusion in mice

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 concentrationdependent 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.

Fo-Shou-San Ameliorates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment in Mice by Regulating NRF2/HO-1 Pathway Against Ferroptosis

“…The same process without carotid ligation was operated on the sham group. Body temperature was sustained until mice were woken from anesthesia [39][40][41][42][43].…”

The therapeutic potential of triptolide and celastrol in neurological diseases

“…In addition, right unilateral common carotid artery occlusion (rUCCAO), which simulates chronic cerebral hypoperfusion, can also be used for cerebral ischemia related research ( Yoshizaki et al, 2008 ). A recent study using rUCCAO and OGD reported the therapeutic effects of triptolide in vitro and in vivo , including alleviating white matter injury, protecting against oligodendrocyte apoptosis directly, and inhibiting microglial inflammation indirectly, and the related mechanism was to increase the phosphorylation of the Src/AKT/GSK 3β singnaling pathway ( Wan et al, 2022 ).…”

L‐ascorbyl‐2‐phosphate alleviates white matter injury caused by chronic hypoxia through the PRMT5/P53/NF‐κB pathway

“…Moreover, the WMI model lacks an in vitro model; therefore, we used an OGD model to mimic demyelination in vivo. Although the OGD model has been widely used to investigate the proliferation and differentiation of oligodendrocytes (Dai et al., 2020; Wan et al., 2022; Wu et al., 2014), it is not a perfect fit for the chronic hypoxia‐induced WMI model and cannot fully capture the complex pathogenesis observed in vivo. A more appropriate in vitro model is looked forward to.…”