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Background: Endogenous cannabinoid anandamide (AEA) protects neurons from oxidative injury in rodent models; however the mechanism of AEA-induced neuroprotection remains to be determined. Activation of neuronal NADPH oxidase 2 (Nox2) contributes to oxidative damage of the brain, and inhibition of Nox2 can attenuate cerebral oxidative stress. We aimed to determine whether the neuronal Nox2 was involved in protection mediated by AEA., Methods: The mouse hippocampal neuron cell line HT22 was exposed to hydrogen peroxide (H2O2) to mimic oxidative injury of neurons. The protective effect of AEA was assessed by measuring cell metabolic activity, apoptosis, lactate dehydrogenase (LDH) release, cellular morphology, intracellular reactive oxygen species (ROS), and antioxidant and oxidant levels and Nox2 expression., Results: HT22 cells exposed to H2O2 demonstrated morphological changes, decreased LDH release, reduced metabolic activity, increased levels of intracellular ROS and oxidized glutathione (GSSG), reduced levels of superoxide dismutase (SOD), and reduced glutathione (GSH) and increased expression of Nox2. AEA prevented these effects, a property abolished by simultaneous administration of CB1 antagonist AM251 or CB1-siRNA., Conclusion: Nox2 inhibition is involved in AEA-induced cytoprotection against oxidative stress through CB1 activation in HT22 cells.

Neuroinflammation contributes to the progression of cerebral ischemia/reperfusion (I/R) damage. Scutellarin (SL) is a glucuronide flavonoid that has apoptotic, anti‐inflammatory, and anti‐tumor properties. It is anti‐oxidant and anti‐inflammatory mechanism as a neuroprotective against ischemic brain injury is unknown. The purpose of the study was to examine the role and mechanism of SL in preventing I/R damage in a rat model. SL (40 and 80 mg/kg) was given to the rats for 14 days before the ischemic stroke. SL administration prevented I/R mediated brain injury, and neuronal apoptosis. Malondialdehyde, superoxide dismutase, glutathione, IL‐6, and IL‐1β and nitric oxide were modulated by SL. SL suppressed the p65 and p38 expressions in particular. The findings show that SL protects rats from cerebral damage caused by I/R through the nuclear factor kappa‐B p65 and p38 mitogen‐activated protein kinase signaling pathway. Thus, SL protected the brain of rats from ischemic injury by inhibiting the inflammatory process. [ABSTRACT FROM AUTHOR]

• TRIM8 expression is increased in OGD/R-exposed neurons. • TRIM8 inhibition protects from OGD/R-induced neuronal injury. • TRIM8 inhibition enhances Nrf2 signaling by regulating AMPK. • TRIM8 regulates OGD/R-induced neuronal injury by AMPK/Nrf2 signaling. Tripartite motif 8 (TRIM8) has emerged as a crucial regulator of cell survival, apoptosis, and oxidative stress in various pathological processes. However, TRIM8's involvement in regulating neuronal injury in cerebral ischemia/reperfusion injury remains largely uncharacterized. In the present study, we aimed to investigate the potential function and molecular mechanism of TRIM8 in regulating neuronal apoptosis and oxidative stress induced by oxygen–glucose deprivation/re-oxygenation (OGD/R) in an in vitro model to study cerebral ischemia/reperfusion injury. Herein, we found that TRIM8 expression was upregulated in neurons exposed to OGD/R. Knockdown of TRIM8 improved the viability and decreased the apoptosis and reactive oxygen species (ROS) generation in OGD/R-exposed neurons, whereas TRIM8 overexpression showed the opposite effect. Notably, TRIM8 inhibition increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Moreover, TRIM8 inhibition promoted the transcriptional activity of the Nrf2/antioxidant response element (ARE). However, AMPK inhibition partially reversed TRIM8 downregulation-mediated Nrf2/ARE activation and the neuroprotective effect in OGD/R-exposed neurons. Additionally, silencing of Nrf2 also markedly abrogated TRIM8 downregulation-mediated neuroprotection. Overall, these results demonstrate that downregulation of TRIM8 protects from OGD/R-induced neuronal injury by reinforcing the activation of Nrf2/ARE antioxidant signaling via AMPK, suggesting a potential role for TRIM8 in cerebral ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]