AdipoRon Attenuates Neuroinflammation After Intracerebral Hemorrhage Through AdipoR1-AMPK Pathway.

Neuroinflammation is considered to be a critical component in the pathological process after intracerebral hemorrhage (ICH). Microglia are the foremost and earliest inflammatory cells participating in the pathological process of ICH. AdipoRon is the agonist of AdipoR1 (Adiponectin receptor 1), which enhances P-AMPK (phosphorylated AMP-activated protein kinase) activation. The activated AMPK facilitates microglia/macrophage polarization by driving the cell state from pro-inflammatory M1 state to anti-inflammatory M2 state. The study aims to investigate the role of AdipoRon in microglial polarization and neuroprotection after ICH. The experimental ICH model was established by autologous blood injection, and the treated group was done additionally by intraperitoneal injection of drugs. Flow cytometry analysis and immunofluorescence staining were performed to quantify the ratio of M1 to M2 phenotype microglia in mice. The present study indicated that AdipoRon could ameliorate neurological deficits in mice after ICH. Flow cytometric analysis demonstrated that the proportion of CD206+ cells to CD45+low CD11b+ cells (microglia isolated from the brain tissue of mice) was increased after AdipoRon treatment. AdipoR1 siRNA and AMPK inhibitor could reverse the positive effects of AdipoRon. AdipoR1 and P-AMPK expression was also significantly increased after AdipoRon treatment. The in vitro experiment showed that AdipoRon not only directly inhibited neuronal ROS overproduction, but also indirectly decreased the neuronal death in a transwell co-culture system. In summary, AdipoRon protects against ICH induced injury through promoting M2a microglia polarization and reducing neuronal death. These effects of AdipoRon rely on the activation of AdipoR1-AMPK signaling pathway.

Zheng J ，Sun Z ，Liang F ，Xu W ，Lu J ，Shi L ，Shao A ，Yu J ，Zhang J ... -  《-》

AdipoRon Protects Against Secondary Brain Injury After Intracerebral Hemorrhage via Alleviating Mitochondrial Dysfunction: Possible Involvement of AdipoR1-AMPK-PGC1α Pathway.

Yu J ，Zheng J ，Lu J ，Sun Z ，Wang Z ，Zhang J ... -  《-》

Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice.

Zhao L ，Chen S ，Sherchan P ，Ding Y ，Zhao W ，Guo Z ，Yu J ，Tang J ，Zhang JH ... -  《Journal of Neuroinflammation》

Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice.

Chen S ，Zhao L ，Sherchan P ，Ding Y ，Yu J ，Nowrangi D ，Tang J ，Xia Y ，Zhang JH ... -  《Journal of Neuroinflammation》

AdipoRon improves cognitive dysfunction of Alzheimer's disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway.

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.

Liu B ，Liu J ，Wang JG ，Liu CL ，Yan HJ ... -  《-》