Neuroprotective effect of wild lowbush blueberry (Vaccinium angustifolium) on global cerebral ischemia/reperfusion injury in rats: Downregulation of iNOS/TNF‐α and upregulation of miR‐146a/miR‐21 expression

Abstract

This study aims to investigate the neuroprotective effect of wild lowbush blueberry on CIRI in rats. Accordingly, CIRI and reperfusion were induced in rats for 60 min and 24 h, respectively. Then, the mechanisms of the neuroprotective effects of BBE were investigated in the injury through evaluating miR-146a, miR-21, and their targets in a CIRI rat model. After that, the BBE (30, 60, and 120 mg/kg b.wt) was intraperitoneally injected for 14 days, then CIRI was induced by BCCAO for 60 min for ischemic stroke and reperfusion for 24 h. Several parameters including the oxidative stress levels in the hippocampus and serum were measured 24 h after the CIRI. The findings showed that the BBE significantly decreased the levels of malondialdehyde (MDA) and nitric oxide (NO) and increased ferric ion reducing antioxidant power (FRAP) levels in the hippocampus and serum following the stroke. The BBE also maximized the miR-146a and miR-21 expressions and moderated iNOS and TNF-α expressions in the hippocampus. Likewise, the BBE enlarged the CA1 and CA3 domains of the post-stroke pyramidal cell layers of the hippocampus. Overall, the results revealed that BBE had potent neuroprotective efficacy against CIRI via the effective modulation of neuroinflammatory cascades and protected neurons against ischemic death.blueberry extract, cerebral ischemia, iNOS, miR-146a, miR-21, TNF-α | INTRODUCTIONCerebral ischemia/reperfusion injury (CIRI) refers to a pathological process during ischemia. Through this injury, different pathways such as oxidative stress, apoptosis, inflammation, and excitotoxicity are also activated in the brain (Tian et al., 2017). The balance between sys-

Chronic and postprandial effect of blueberries on cognitive function, alertness, and mood in participants with metabolic syndrome – results from a six-month, double-blind, randomized controlled trial

“…This test requires relatively short-term, synaptic/initial memory consolidation, which is well described as occurring in the hippocampal region – with recent evidence specifically identifying a key role of the amygdala [ 52 ]. Interestingly, numerous recent animal studies have shown adaptations in neuroinflammation and neuroplasticity of the hippocampal region following blueberry extract or blueberry (poly)phenol interventions [ 49 , [53] , [54] , [55] , [56] ], which suggests this may be a priority area to focus on in future human studies.…”

The Therapeutic Effects of Blueberry-Treated Stem Cell-Derived Extracellular Vesicles in Ischemic Stroke

“…Contained in blueberry, flavonoids, and polyphenols have been reported to have therapeutic effects on neurological disease [ 78 , 79 ]. A benefit of blueberry supplements in cardiovascular disease was demonstrated using randomized controlled trials and discovered the regulating of inflammatory factors [ 51 ]. The prevention of stroke promoted by polyphenols relies mainly on their effect on ischemic stroke systems including neuroprotective roles in many cellular mechanisms [ 60 ].…”

“…In addition, a wild lowbush blueberry had neuroprotective effects on global cerebral ischemia/reperfusion injured rats through downregulation of iNOS/TNF-α and upregulation of miR-146a/miR21 expression [ 51 ]. Similarly, when neuronal cells were treated with those genes under OGD conditions, a significant increase in expression was observed in B-EVs.…”

“…Many studies on blueberries show anti-inflammatory effects on vascular diseases [ 46 , 47 , 48 ]. According to these studies, the therapeutic effects of blueberries inhibit TNF-a, IL6, and TRL4, which control and regulate inflammatory actions [ 49 , 50 , 51 ]. The beneficial effects of blueberry extract on ischemic strokes could play important roles in brain–gut signaling to modulate intestinal microbiome metabolism in the rat middle cerebral artery occlusion (MCAo) model [ 52 ].…”

Dysregulation of miR-146a: a causative factor in epilepsy pathogenesis, diagnosis, and prognosis

“…miR-146a is central to neuroinflammation by modulating the NF-κB signaling pathway activity. It substantially impacts the homeostasis of immune and brain cells, neuronal identities, identity acquisition, and immune response regulation in the nervous system (18). Abnormal expression of miR-146a can cause the uncontrolled generation of neurotoxic inflammatory factors, such as IL-1, TNF-α, nitric oxide (NO), and hydrogen peroxide (H 2 O 2 ), eventually leading to neuronal death and neurodegeneration (19,20).…”