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<p>Tumor necrosis factor-alpha (TNF-α) plays a detrimental role in the brain during ischemic stroke, and TNF-α inhibition has been reported to reduce ischemic brain injury. This study aimed to investigate whether TNF-α contributes to neurovascular unit (NVU) damage by modulating the calpain/NF-κB inflammatory pathway following ischemic stroke. Rats were subjected to 1.5&#xa0;h of transient middle cerebral artery occlusion (MCAO) followed by reperfusion. A TNF-α neutralizing antibody (TNF-α Ab) was administered intracerebroventricularly 15&#xa0;min before MCAO. The activation of calpain and NF-κB signaling, as well as NVU damage, was evaluated 24&#xa0;h after MCAO. TNF-α Ab dose-dependently improved neurological function and reduced infarct volumes 24&#xa0;h post-MCAO. It also attenuated apoptotic cell death, preserved the ultrastructural morphology of the NVU, and decreased blood-brain barrier permeability in the penumbra and core. Moreover, TNF-α Ab increased calpastatin levels, reduced the levels of calpain 1 and calpain 2, and suppressed calpain activity in the cytosol of both the penumbra and core. Additionally, it lowered the cytosolic levels of high mobility group box-1 and elevated cytosolic IκBα levels. TNF-α Ab also reduced cytosolic and nuclear NF-κB p65 levels. Furthermore, it down-regulated the levels of intracellular adhesion molecule-1, interleukin-1β, matrix metalloproteinase (MMP)-2, and MMP-9, and suppressed myeloperoxidase activity in the penumbra and core. These findings demonstrate the protective effects of TNF-α Ab against NVU damage in the ischemic penumbra and core, and suggest that TNF-α contributes to NVU damage by upregulating the calpain/NF-κB inflammatory pathway during ischemic stroke.</p> Graphical Abstract <p></p> <p>Contribution of TNF-α to neurovascular unit damage through up-regulating the calpain/NF-κB inflammatory pathway during ischemic stroke. The symbol “→” indicates a promoting or activating effect. The symbol “┫” indicates an inhibitory or blocking effect. <i>TNF-α</i> tumor necrosis factor-alpha, <i>TNF-α Ab</i> TNF-α neutralizing antibody, <i>TNFRs</i> TNF-α receptors, <i>PRRs</i> pattern recognition receptors, <i>NF-κB</i> nuclear factor-kappa B, <i>IκBα</i> inhibitor of kappa B alpha, <i>HMGB1</i> high mobility group box-1.</p>

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Protective Effects of TNF-α Neutralizing Antibody on the Neurovascular Unit Through Down-Regulating Calpain/NF-κB Inflammatory Pathway During Ischemic Stroke

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Chen Jin,
  • Chunyang Wang,
  • Yumei Zhao,
  • Bin Wang,
  • Ming Sun

摘要

Tumor necrosis factor-alpha (TNF-α) plays a detrimental role in the brain during ischemic stroke, and TNF-α inhibition has been reported to reduce ischemic brain injury. This study aimed to investigate whether TNF-α contributes to neurovascular unit (NVU) damage by modulating the calpain/NF-κB inflammatory pathway following ischemic stroke. Rats were subjected to 1.5 h of transient middle cerebral artery occlusion (MCAO) followed by reperfusion. A TNF-α neutralizing antibody (TNF-α Ab) was administered intracerebroventricularly 15 min before MCAO. The activation of calpain and NF-κB signaling, as well as NVU damage, was evaluated 24 h after MCAO. TNF-α Ab dose-dependently improved neurological function and reduced infarct volumes 24 h post-MCAO. It also attenuated apoptotic cell death, preserved the ultrastructural morphology of the NVU, and decreased blood-brain barrier permeability in the penumbra and core. Moreover, TNF-α Ab increased calpastatin levels, reduced the levels of calpain 1 and calpain 2, and suppressed calpain activity in the cytosol of both the penumbra and core. Additionally, it lowered the cytosolic levels of high mobility group box-1 and elevated cytosolic IκBα levels. TNF-α Ab also reduced cytosolic and nuclear NF-κB p65 levels. Furthermore, it down-regulated the levels of intracellular adhesion molecule-1, interleukin-1β, matrix metalloproteinase (MMP)-2, and MMP-9, and suppressed myeloperoxidase activity in the penumbra and core. These findings demonstrate the protective effects of TNF-α Ab against NVU damage in the ischemic penumbra and core, and suggest that TNF-α contributes to NVU damage by upregulating the calpain/NF-κB inflammatory pathway during ischemic stroke.

Graphical Abstract

Contribution of TNF-α to neurovascular unit damage through up-regulating the calpain/NF-κB inflammatory pathway during ischemic stroke. The symbol “→” indicates a promoting or activating effect. The symbol “┫” indicates an inhibitory or blocking effect. TNF-α tumor necrosis factor-alpha, TNF-α Ab TNF-α neutralizing antibody, TNFRs TNF-α receptors, PRRs pattern recognition receptors, NF-κB nuclear factor-kappa B, IκBα inhibitor of kappa B alpha, HMGB1 high mobility group box-1.