VX-765 attenuates secondary damage and β-amyloid accumulation in ipsilateral thalamus after experimental stroke in rats

Yu-Bin Liang; Ri-Xin Luo; Zhen Lu; Ying Mao; Ping-Ping Song; Qiao-Wei Li; Zhi-Qiang Peng; Yu-Sheng Zhang

doi:10.1016/j.expneurol.2024.115097

VX-765 attenuates secondary damage and β-amyloid accumulation in ipsilateral thalamus after experimental stroke in rats

Exp Neurol. 2024 Dec 6:385:115097. doi: 10.1016/j.expneurol.2024.115097. Online ahead of print.

Authors

Yu-Bin Liang¹, Ri-Xin Luo², Zhen Lu³, Ying Mao⁴, Ping-Ping Song⁵, Qiao-Wei Li², Zhi-Qiang Peng⁶, Yu-Sheng Zhang⁷

Affiliations

¹ Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China.
² Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China.
³ Postgraduate Cultivation Base of Guangzhou University of Chinese Medicine, Panyu Central Hospital, Guangzhou, China.
⁴ Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519,041, China.
⁵ Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China.
⁶ Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Postgraduate Cultivation Base of Guangzhou University of Chinese Medicine, Panyu Central Hospital, Guangzhou, China. Electronic address: pengzhiqiang@pyhospital.com.cn.
⁷ Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China. Electronic address: zhangys@jnu.edu.cn.

PMID: 39647574
DOI: 10.1016/j.expneurol.2024.115097

Abstract

Focal cortical infarction can result both in the accumulation of Aβ in as well as further secondary damage and inflammation within the ipsilateral thalamus. VX-765 is a potent and selective small-molecule capable of inhibiting caspase-1, which has been shown to exhibit active neuroprotection properties in multiple disease. However, the neuroprotection efficacy of VX-765 as a means of attenuating secondary damage after MCAO remains uncertain. As such, we sought to determine the ability of VX-765 to alter thalamic Aβ accumulation, secondary damage, and sensory deficits in rats of focal cortical infarction. A rat model of distal branch of middle cerebral artery occlusion (dMCAO) was used to evaluate the effects of the VX-765 on the secondary damage and β-amyloid accumulation in ipsilateral thalamus after dMCAO in rats. The activation of astrocyte and microglia, loss of neuron, and damage to sensory function were detected weekly till 4 weeks after modeling. VX-765 was injected intraperitoneally delayed after 7 days injury and the status of secondary damage, inflammation and β-amyloid accumulation in ipsilateral thalamus after dMCAO were examined.Our results revealed that VX-765 markedly reduce sensory deficits in these rats, suppressing secondary damage through reductions in APP and accumulations of Aβ with an accompanying reduction in both neuronal loss, astrocyte and microglia activation. VX-765 markedly inhibited NLRP3 and caspase-1, and downregulation of ASC, GSDMD, IL-1β, and IL-18 in the ipsilateral thalamus after MCAO. Our results further suggested that VX-765 may regulate secondary damage via control inflammation and suppressing the production of pro-inflammatory factors such as iNOS, TNF-α, IL-6 and COX2 that are produced downstream NF-κB signaling. Taken together, VX-765 is well-suited to attenuate secondary damage and accumulations of Aβ, improving recovery from sensory deficits and cognitive deficits after MCAO, at least in part via suppressing pyroptosis and inflammation.

Keywords: Inflammation; Ischemic stroke; Pyroptosis; Secondary damage; VX-765; β-Amyloid.