TNF-α Receptor Inhibitor Alleviates Metabolic and Inflammatory Changes in a Rat Model of Ischemic Stroke

Abstract

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms.

Jak2 Inhibitor AG490 Improved Poststroke Central and Peripheral Inflammation and Metabolic Abnormalities in a Rat Model of Ischemic Stroke

“…Therefore, the effects of AG490 on poststroke glucose metabolism were investigated. As shown in our previous reports [40][41][42][43], rats with cerebral ischemia developed hyperglycemia (Figure 3A), hyperinsulinemia (Figure 3B), and glucose intolerance (Figure 3C,D). AG490 displayed an alleviative effect on hyperglycemia (Figure 3A) and post-load glucose levels (Figure 3C,D), and augmented hyperinsulinemia (Figure 3B).…”

“…Therefore, the reduction of tissue IL-6 expression appears to be common upon beneficial intervention after cerebral ischemia. remained undetermined [40,43]. Tissues in both previous studies revealed an elevated IL-6 expression in the brain cortex, liver, and gastrocnemius of cerebral ischemia rats.…”

“…To further demonstrate the altered tissue expression of IL-6 in cerebral ischemia rats, β-adrenergic receptor antagonist propranolol (2 mg/kg) and TNF-α receptor inhibitor R-7050 (5 mg/kg) were delivered as per the same protocol of AG490. Under anesthesia with isoflurane (4%), rats were euthanized and decapitated according to our previous reports [ 40 , 43 ]. The obtained brain cortexes, livers, and gastrocnemius muscles were allocated to further analyses.…”

“…At our laboratories, we had published serial studies showing that through anti-inflammation strategies, either directly (e.g., by Tumor Necrosis Factor-α receptor (TNFR) antagonist) or indirectly (e.g., by propranolol), central neuronal injuries, hyperglycemia, insulin resistance, as well as inflammation in the brain, liver, and skeletal muscles can be reduced after acute stroke in a cerebral ischemia rodent model [ 40 , 41 , 42 , 43 ]. Accordingly, based on the multiple pathophysiological effects of IL-6, we hypothesized that increased IL-6 expression after acute stroke may be involved in the poststroke inflammation of multiple organs such as the brain, liver, and skeletal muscles, as well as in metabolic abnormalities.…”

Total Flavonoids of Chuju Decrease Oxidative Stress and Cell Apoptosis in Ischemic Stroke Rats: Network and Experimental Analyses

“…We hypothesized that TFCJ might exert its neuroprotective effects by suppressing apoptosis and oxidative stress by activating the PI3K/Akt/mTOR signaling pathway. The important predictors of IS are the neurological deficit scores and cerebral infarction ( Zhang H. et al, 2020 ; Lin et al, 2021 ; Wang et al, 2021 ). In this study, rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 24 h. In the early phase (first few minutes to a few hours) after intracerebral artery occlusion, the infarcted area containing ischemic tissue gradually spreads outwards.…”