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.