Urolithin A Prevents Focal Cerebral Ischemic Injury via Attenuating Apoptosis and Neuroinflammation in Mice.

Neuroinflammation contributes to neuronal death in cerebral ischemia. Urolithin A (UA), a gut microbial metabolite of ellagic acid, has emerged as a potential anti-inflammatory agent. However, its roles and precise mechanisms in stroke remain unknown. Here we found that UA treatment ameliorated infarction, neurological deficit scores, and spatial memory deficits after cerebral ischemia. Furthermore, UA significantly reduced neuron loss and promoted neurogenesis after ischemic stroke. We also found that UA attenuated apoptosis by regulating apoptotic-related proteins. Meanwhile, UA treatment inhibited glial activation via affecting inflammatory signaling pathways, specifically by enhancing cerebral AMPK and IκBa activation while decreasing the activation of Akt, P65NFκB, ERK, JNK, and P38MAPK. Our findings reveal a key role of UA against ischemic stroke through modulating apoptosis and neuroinflammation in mice.

PPARα Agonist Fenofibrate Ameliorates Learning and Memory Deficits in Rats Following Global Cerebral Ischemia.

Increasing evidence demonstrates that local inflammation contributes to neuronal death following cerebral ischemia. Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exhibit many pharmacological effects including anti-inflammatory functions. The aim of this study was to investigate the neuroprotective effects of PPARα agonist fenofibrate on the behavioral dysfunction induced by global cerebral ischemia/reperfusion (GCI/R) injury in rats. The present study showed that fenofibrate treatment significantly reduced hippocampal neuronal death, and improved memory impairment and hippocampal neurogenesis after GCI/R. Fenofibrate administration also inhibited GCI/R-induced over-activation of microglia but not astrocytes and prevented up-regulations of pro-inflammatory mediators in hippocampus. Further study demonstrated that treatment with fenofibrate suppressed GCI/R-induced activations of P65 NF-κB and P38 MAPK. Our data suggest that the PPARα agonist fenofibrate can exert functional recovery of memory deficits and neuroprotective effect against GCI/R in rats via triggering of neurogenesis and anti-inflammatory effect mediated by inhibiting activation of P65 NF-κB and P38 MAPK in the hippocampus, which can contribute to improvement in neurological deficits.

Valproic acid alleviates memory deficits and attenuates amyloid-ß deposition in transgenic mouse model of Alzheimer's disease.

In the brains of patients with Alzheimer's disease (AD) and transgenic AD mouse models, astrocytes and microglia activated by amyloid-ß (Aß) contribute to the inflammatory process that develops around injury in the brain. Valproic acid (VPA) has been shown to have anti-inflammatory function. The present study intended to explore the therapeutic effect of VPA on the neuropathology and memory deficits in APPswe/PS1ΔE9 (APP/PS1) transgenic mice. Here, we report that VPA-treated APP/PS1 mice markedly improved memory deficits and decreased Aß deposition compared with the vehicle-treated APP/PS1 mice. Moreover, the extensive astrogliosis and microgliosis as well as the increased expression in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the hippocampus and cortex of APP/PS1 transgenic mice were significantly reduced following administration of VPA, which attenuated neuronal degeneration. Concomitantly, VPA alleviated the levels of p65 NF-κB phosphorylation and enhanced the levels of acetyl-H3, Bcl-2, and phospho-glycogen synthase kinase (GSK)-3ß that occurred in the hippocampus of APP/PS1 transgenic mice. These results demonstrate that VPA could significantly ameliorate spatial memory impairment and Aß deposition at least in part via the inhibition of inflammation, suggesting that administration of VPA could provide a therapeutic approach for AD.