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A Preclinical Model to Assess Brain Recovery After Acute Stroke in Rats
Published on: November 6, 2019
TNF-α Receptor Inhibitor Alleviates Metabolic and Inflammatory Changes in a Rat Model of Ischemic Stroke
Shih-Yi Lin1,2, Ya-Yu Wang2,3, Cheng-Yi Chang4
1Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, Taichung City 407, Taiwan.
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.
Insights
Tumor necrosis factor-alpha (TNF-α) inhibitor R-7050 shows neuroprotective effects against stroke by reducing inflammation and hyperglycemia. This anti-TNF therapy offers a promising strategy for improving stroke outcomes through combined anti-inflammatory and metabolic mechanisms.
Area of Science:
- Neuroscience
- Immunology
- Metabolic disease
Background:
- Hyperglycemia and inflammation exacerbate stroke severity and outcomes.
- Tumor necrosis factor-alpha (TNF-α) plays a critical role in both inflammatory and metabolic processes relevant to stroke.
- Targeting the TNF-α pathway presents a potential therapeutic strategy for stroke.
Purpose of the Study:
- To investigate the neuroprotective, anti-inflammatory, and antihyperglycemic effects of the TNF-α receptor inhibitor R-7050 in a rat model of ischemic stroke.
- To elucidate the molecular mechanisms underlying R-7050's effects on neuroprotection and metabolic regulation post-stroke.
Main Methods:
- Permanent cerebral ischemia was induced in rats, with some pretreated with R-7050.
- In vitro studies using bEnd.3 endothelial cells exposed to TNF-α were conducted.
- Analysis included neurological deficit scoring, brain infarction and edema measurement, oxidative stress markers, caspase 3 activity, and molecular pathway analysis (TNFRI, NF-κB, IL-6, ZO-1, insulin signaling).
- Plasma levels of metabolic markers (corticosterone, free fatty acids, CRP, FGF-15) were measured.
Main Results:
- R-7050 pretreatment significantly reduced neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation in stroke rats.
- R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and IL-6, and restored zonula occludens-1 (ZO-1) levels in injured cortical tissues.
- In vitro, R-7050 prevented TNF-α-induced reduction of ZO-1 in endothelial cells.
- R-7050 ameliorated post-stroke hyperglycemia and normalized plasma levels of corticosterone, free fatty acids, C-reactive protein, and fibroblast growth factor-15.
- In muscle tissue, R-7050 improved TNFRI/NF-κB and IL-6 pathways, oxidative stress, and insulin signaling.
Conclusions:
- R-7050 demonstrates significant neuroprotective effects in a rat stroke model, acting through anti-inflammatory and metabolic pathways.
- The drug effectively targets key molecular players like TNFRI, NF-κB, and IL-6, while also improving endothelial barrier function.
- R-7050's ability to counteract hyperglycemia and metabolic dysregulation post-stroke highlights its potential as a comprehensive therapeutic agent.
