The biological efficacy of Apelin against focal transient cerebral ischemia-reperfusion injury. A systematic review and meta-analysis of animal studies.

BACKGROUND: Apelin has been extensively studied, and emerging experimental evidence suggests that Apelin may have effects on stroke by reducing infarct volume and neurological deficits, inhibiting the apoptosis process and reducing brain water content. However, the credibility of the evidence is uncertain. Thus, we aimed to perform a systematic review and meta-analysis to evaluate preclinical studies that used Apelin for the treatment of transient focal cerebral ischemia. METHODS: Electronic bibliographic databases including PubMed, EMBASE, Scopus, and Google Scholar were searched for finding relevant studies from January 2000 to July 2023. The methodological quality and risk of bias scores for animal studies were calculated based on the CAMARADES and the SYRCLE's RoB tools, respectively. The effect sizes were assessed using Comprehensive Meta-Analysis (CMA) software. RESULTS: A total of twelve eligible studies were used for the systematic review and meta-analysis. The median scores of study quality and risk of bias were 7.5 out of 10, and 5 out of 10, respectively. Apelin treatment effectively decreased infarct volume (primary outcome) [Hedges' g = 2.72, 95 % CI (1.93, 3.51), p < 0.001], neurological deficit [Hedges' g = 1.76, 95 % CI (0.96, 2.55), p < 0.001], cleaved caspase 3 [Hedges' g = 2.16, 95 % CI (0.87, 3.44), p = 0.001], and apoptotic cell number [Hedges' g = 4.07, 95 % CI (1.25,6.89), p = 0.005] compared with the control group. According to subgroup analysis, more notable neuroprotective effects were observed with intravenous administration than with intracerebroventricular (ICV) administration. Moreover, we determined that effect size of infarct volume was markedly related to the species. The combined measurement of two studies demonstrated that Apelin could reduce BCL2 and TNF-α levels as well as brain water content compared with the control group. However, pooled measurement of two studies showed that no relevancy was discovered between CHOP and altering infarct volume. CONCLUSION: The present meta-analysis was conducted to assess preclinical studies related to Apelin treatment in rodent ischemic stroke. Apelin can exert promising neuroprotective effects by reducing infarct volume, neurological deficit, caspase 3, apoptotic cell number, TNF- α and brain water content and increasing BCL2. The current evidence supports the anti-apoptotic and anti-inflammatory properties of Apelin, but its effectiveness in decreasing CHOP level in animal models of ischemic stroke needs further elucidation. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42023460926.

The Effects of Mouse Recombinant Resistin on mRNA Expression of Proinflammatory and Anti-Inflammatory Cytokines and Heat Shock Protein-70 in Experimental Stroke Model.

BACKGROUND: Our recent research showed that resistin has a neuroprotective effect against stroke-induced injury through suppressing apoptosis and oxidative stress. However, the molecular mechanism of neuroprotection of resistin is unclear. This work was designed to examine the effect of mouse recombinant resistin on mRNA expression of Tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), Interleukin-10 (IL-10), Transforming growth factor-ß1 (TGF- ß1), and Heat shock protein-70 (HSP-70) in mouse model of stroke. MATERIALS AND METHODS: Transient focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) in mice. TNF-α, IL-1ß, IL-10, TGF-ß1, and HSP-70 mRNA were detected at sham (0 hour), 3 hours, 6 hours, 12 hours, and 24 hours after MCAO using real-time QRT-PCR method. Moreover, animals were treated with resistin at the dose of 400ng/mouse at the commencement of MCAO, and mRNA expression of the cytokines and HSP-70 was measured 24 hours after MCAO. RESULTS: Tumor necrosis factor-α and IL-1ß mRNA expression markedly increased at 12-hour time point and then returned to the basal level at 24 hours after MCAO; but HSP-70 mRNA expression increased at 24-hour time point. Furthermore, resistin (400 ng/mouse) significantly increased TGF-ß1 and IL-10 and decreased HSP-70 gene expression at 24 hours after MCAO. CONCLUSIONS: Our findings revealed that a molecular mechanism of attenuating ischemic damage by resistin administration probably is increased mRNA expression of anti-inflammatory cytokines. However, applying resistin in the clinical settings for the treatment of stroke deserves further researches in the future.

Irisin Peptide Protects Brain Against Ischemic Injury Through Reducing Apoptosis and Enhancing BDNF in a Rodent Model of Stroke.

Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice.

Neuroprotective nature of adipokine resistin in the early stages of focal cerebral ischemia in a stroke mouse model.

New evidence suggests that resistin may have a therapeutic potential effect in management of neurodegenerative disease; but its role in the pathophysiology of stroke-induced injuries is not understood. However, further investigations are required to elucidate the effect of resistin and explore its possible molecular mechanisms on the ischemic reperfusion injury. Transient focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) in mice. Animal treated with resistin at doses of 25, 50, 100, 200, and 400 ng/mouse, on the MCAO commencement. Neurological function, infarct size, brain edema and Blood-brain barrier (BBB) disruption were measured. Additionally, content of malondialdehyde (MDA), TUNEL-positive cells and apoptosis-related proteins were assessed by immunohistochemistry and western blot techniques. Resistin mRNA was detected at 3 h, 6 h, 12 h and 24 h after MCAO using real-time QRT-PCR method. Central administration of resistin only at doses of 200 and 400 ng/mouse considerably reduced the infarct size and promoted neurological function (p < 0.001). In addition, resistin (400 ng/mouse) significantly decreased brain edema (p < 0.001), evans blue (EB) leakage (p < 0.05), MDA content (p < 0.005), apoptotic cells and apoptosis-related proteins (p < 0.001). Resistin mRNA expression markedly increased at 12-h time point and then returned to basal level at 24 h after MCAO. Our findings revealed that treatment with resistin could attenuate ischemic damage in a dose-dependent approach via suppressing apoptosis and oxidative stress. Application of resistin in clinical settings to treat stroke and brain ischemia warrants further research.