Theaflavin attenuates cerebral ischemia/reperfusion injury by abolishing miRNA‑128‑3p‑mediated Nrf2 inhibition and reducing oxidative stress

Abstract

Theaflavin has been proven to own strong antioxidative capacity; however, the molecular mechanism underlying its protective effect against cerebral ischemia-reperfusion (I/R) injury remains unclear. Therefore, the present study was designed to elucidate the neuroprotective effects of theaflavin on cerebral I/R injury and its underlying molecular mechanisms. To investigate the effects of theaflavin on neurological function, neurogenesis, and oxidative stress, experiments were performed using a cerebral I/R injury rat model, and neural stem cells (NSCs) were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). Further, the expression profiles of miRNA-128-3p and the regulatory function of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) were evaluated in these models. We found that theaflavin treatment significantly reduced infarct volume and neuronal injury, and thus improved the impaired memory and learning ability. Furthermore, theaflavin treatment significantly enhanced the increase in NSC proliferation, reduction in the apoptotic rate and inhibition of oxidative stress. Mechanistically, theaflavin targeted miRNA-128-3p and further activated the Nrf2 pathway to reduce oxidative stress. In summary, theaflavin has a strong ability to attenuate cerebral I/R injury through miRNA-128-3p-mediated recovery of the impaired antioxidant defense system, which suggests that it could be a potential drug candidate for ischemic stroke.

Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?

“…Among polyphenols, catechins are the main ones in green tea, while the black tea contains theaflavins [ 27 ]. Li et al evidenced that theaflavin (C 29 H 24 O 12 ; CAS number 4670-05-7; Figure 1 (1)) exerted beneficial effects both in in vivo and in vitro models of I/R abolishing miRNA-128-3p-induced Nrf2 suppression and thus decreasing oxidative stress [ 28 ]. In particular, in rats subjected to MCAO, theaflavin administration lowered infarct volume and neuronal damage, and ameliorated neurological abilities.…”

“…These enzymes have an important role in counteracting oxidative stress: SOD catalyzes the reaction of dismutation of the superoxide radical leading to the formation of O 2 and hydrogen peroxide (H 2 O 2 ), while GPx eliminates H 2 O 2 forming water and O 2 , through the oxidation of glutathione (GSH). The antioxidant effects of theaflavin may be due to its capacity to increase dose-dependently Nrf2 expression reducing miRNA-128-3p levels in vivo and in vitro [ 28 ]. It is important to mention that MDA shows some limits in order to be considered as a marker of oxidative stress.…”

MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models

“…Theaflavin as a neuroprotective agent declined the I/R‐induced upregulation of miRNA‐128‐3p, whereas it upgraded Nrf2 protein level in an animal model of stroke. Theaflavin ameliorated oxidative stress and potentiated learning and memory in the MCAO rat model (R. Li et al, 2019). miR‐134 is the next downregulated miRNA in the MCAO mice's peri‐infarct area (C. Liu et al, 2012).…”

Long non-coding RNA LOC366613 alleviates the cerebral ischemic injury via regulating the miR-532-5p/phosphatase and tensin homolog axis

“…Liang et al found that miRNA-320 promotes cerebral I/R injury in mice by inhibiting IGF-1 expression [20]. Similarly, miRNA-128-3p promotes cell proliferation by regulating Nrf2, which inhibits cell apoptosis and alleviates oxidative stress [21]. miRNA-128-3p also has a protective effect against cerebral I/R injury.…”