Celastrol Dilates and Counteracts Ethanol-Induced Constriction of Cerebral Arteries

Abstract

The increasing recognition of the role played by cerebral artery dysfunction in brain disorders has fueled the search for new cerebrovascular dilators. Celastrol, a natural triterpene undergoing clinical trials for treating obesity, exerts neuroprotection, which was linked to its antioxidant/anti-inflammatory activities. We previously showed that celastrol fitted pharmacophore criteria for activating calcium-and voltage-gated potassium channels of large conductance ("BK") made of subunits cloned from cerebrovascular smooth muscle (SM). These recombinant BKs expressed in a heterologous system were activated by celastrol. Activation of native SM BKs is well-known to evoke cerebral artery dilation. Current data demonstrate that celastrol (1-100 µM) dilates de-endothelialized, ex-vivo pressurized middle cerebral arteries (MCA) from rats with EC 50 =45 µM and E max =100 µM, with MCA diameter reaching a 10% increase over vehicle-containing, time-matched values (P<0.05). A similar vasodilatory efficacy is achieved when celastrol is probed on MCA segments with intact endothelium. Selective BK block with 1 M paxilline blunts celastrol vasodilation. Similar blunting is achieved with 0.8 mM 4-AP, which blocks voltage-gated K + channels other than BK. Using an in-vivo rat cranial window, we further demonstrate that intracarotid injections of 45 M celastrol onto pial arteries branching from MCA mimics celastrol ex-vivo action. MCA constriction by ethanol concentrations reached in blood during moderate-heavy alcohol drinking (50 mM), which involves SM BK inhibition, is both prevented and reverted by celastrol. We conclude that celastrol could be an effective cerebrovascular dilator and antagonist of alcohol-induced cerebrovascular constriction, its efficacy being uncompromised by conditions that disrupt endothelial and/or BK function.

Alcohol Use Disorders and Their Harmful Effects on the Contractility of Skeletal, Cardiac and Smooth Muscles

“…Indeed, KCNMB1 −/− mice exhibited a significant reduction in ethanol-induced inhibition of BK-induced STOCs and its resulting vasoconstriction ( 125 ). These results identified the BK β 1 subunit as a possible therapeutic target to counteract alcohol-induced inhibition of SM BK channels and its associated cerebrovascular constriction, a proof-of-principle being obtained both in vitro and in vivo data with celastrol, a neuroprotective agent ( 145 ).…”

Celastrol Treatment Ameliorated Acute Ischemic Stroke‐Induced Brain Injury by Microglial Injury Inhibition and Nrf2/HO‐1 Pathway Activations

“…Outputs of current investigations showcased that CL treatment ameliorated AIS-induced BI by inhibiting microglial injury and Nrf2/HO-1 pathway activations. Previous investigations advised that celastrol can be used as novel drug to cause cerebral vascular dilation in cases where endothelial and/or BK channel function is impaired [ 33 ]. But if CL treatment can improve the vascular system after acute ischemic stroke is still unclear.…”

Antiinflammatory activity of natural triterpenes—An overview from 2006 to 2021

“…Jiang, Chen, et al, 2020). Triterpene 204 also revealed an antiinflammatory potential in inhibiting disorders such as rheumatoid arthritis (Xinqiang et al, 2020), mast cell-mediated allergic diseases (Zhu et al, 2021), as well as the prevention and reversal of ethanolinduced constriction in brain arteries (North et al, 2020). Recently, Q.…”

“…Commonly isolated from the species Tripterygium wilfordii , celastrol was investigated for its protective action against chondrocyte apoptosis, promoting autophagy and inhibiting the NF‐κB signaling pathway in vitro and in vivo (Feng et al, 2020) In addition, this compound exhibits antiinflammatory properties in murine macrophages treated with LPS, exerting antifibrotic effects in a model with bleomycin‐induced systemic sclerosis (X. Jiang, Chen, et al, 2020). Triterpene 204 also revealed an antiinflammatory potential in inhibiting disorders such as rheumatoid arthritis (Xinqiang et al, 2020), mast cell‐mediated allergic diseases (Zhu et al, 2021), as well as the prevention and reversal of ethanol‐induced constriction in brain arteries (North et al, 2020). Recently, Q. Zhao, Tang et al (2020) reported a new role for celastrol ( 204 ) in protecting against acute liver injury, through the modulation of peroxisome proliferator‐activated receptor‐α (PPARα) signaling.…”