Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model

Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.

Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats

Daidzein, a plant extract, has antioxidant activity. It is hypothesized, in this study, that daidzein exhibits neuroprotective effects on cerebral ischemia. Rat models of middle cerebral artery oc- clusion were intraperitoneally administered daidzein. Biochemical and immunohistochemical tests showed that superoxide dismutase and nuclear respiratory factor 1 expression levels in the brain tissue decreased after ischemia and they increased obviously after daidzein administra- tion; malondialdehyde level and apoptosis-related cysteine peptidase caspase-3 and caspase-9 immunoreactivity in the brain tissue increased after ischemia and they decreased obviously after daidzein administration. Hematoxylin-eosin staining and luxol fast blue staining results showed that intraperitoneal administration of daidzein markedly alleviated neuronal damage in the ischemic brain tissue. These findings suggest that daidzein exhibits neuroprotective effects on ischemic brain tissue by decreasing oxygen free radical production, which validates the afore- mentioned hypothesis.

NRF1-mediated microglial activation triggers high-altitude cerebral edema

High-altitude cerebral edema(HACE)is a potentially fatal encephalopathy associated with a time-dependent exposure to the hypobaric hypoxia of altitude.The formation of HACE is affected by both vasogenic and cytotoxic edema.The over-activated microglia potentiate the damage of blood-brain barrier(BBB)and exacerbate cytotoxic edema.In light with the activation of microglia in HACE,we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE.In in vivo experiments,by exposing mice to hypobaric hypoxia(7000 m above sea level)to induce HACE model,we found that microglia were activated and migrated to blood vessels.Microglia depletion by PLX5622 obviously relieved brain edema.In in vitro experiments,we found that hypoxia induced cultured microglial activation,leading to the destruction of endothelial tight junction and astrocyte swelling.Up-regulated nuclear respiratory factor 1(NRF1)accelerated pro-inflammatory factors through transcriptional regulation on nuclearfactorkappa B p65(NF-kB p65)and mitochondrial transcription factorA(TFAM)in activated microglia under hypoxia.NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1(CAV-1)and adaptorrelated protein complex 2 subunit beta(AP2B1).The present study reveals a new mechanism in HACE:hypoxia over-activates microglia through up-regulation of NRF1,which both induces inflammatory response through transcriptionally activating NF-kB p65 and TFAM,and enhances phagocytic function through up-regulation of CAV-1 and AP2B1;hypoxia-activatedmicroglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE.

Protective efficacy of Shenge San(参蛤散) on mitochondria in H9c2 cardiomyocytes

OBJECTIVE: To investigate whether peroxisome proliferator-activated receptor γ-coactivator-1α/nuclear respiratory factor 1(PGC-1α/NRF1) activity can protect mitochondrial function in the setting of cardiac hypertrophy and improve cardiomyocyte energy metabolism. METHODS: Cardiac hypertrophy was modeled in H9c2 cells treated with isoproterenol(ISO) to assess the effects of Shenge San( 参 蛤 散, SGS) on cell viability and mitochondrial membrane potential. We assessed mitochondrial complex m RNA levels and mitochondrial oxidative phosphorylation factor m RNA and protein levels. RESULTS: Compared with the 100 μM ISO group, cell size was significantly decreased in the 0.3 mg/m L SGS and 20 μM ZLN005(PGC-1α activator) groups(P < 0.01). Compared with the SGS(0.3) +ISO group, we observed lower phosphorylated adenosine monophosphateactivated kinase(AMPK) protein levels in the ISO and ZLN005+SGS+ISO groups(P < 0.01). Compared with the compound C group, SGS significantly increased PGC-1α expression in ISO-induced cardiac hypertrophy cells(P < 0.01), and this was inhibited by compound C pretreatment(P < 0.05). Compared with the ISO group, the mitochondrial red-green fluorescence ratio increased in the 0.3 mg/m L SGS group(P < 0.05). m RNA levels of cytochrome c oxidase subunit 1(CO1) in the ISO and compound C groups were lower than those in control group(P < 0.01), and the m RNA levels of CO1 and ATP8 were significantly lower in the ISO and compound C groups versus control(P < 0.01). Compared with the SGS(0.3) +ISO group, ATP synthetase subunit 8(ATP8) m RNA was significantly decreased in the ISO group(P < 0.01) and compound C+SGS+ISO group(P < 0.05). Compared with the SGS(0.3) +ISO group, NRF1 m RNA levels were significantly decreased(P < 0.05) in the ISO and compound C+SGS+ISO groups. CONCLUSIONS: SGS can attenuate ISO-induced cardiomyocyte hypertrophy, restore the decrease in mitochondrial membrane potential, and upregulate PGC-1α/NRF1 levels. Notably, these effects can be blocked by AMPK inhibitor-compound C.