CTRP3 protects hippocampal neurons from oxygen-glucose deprivation-induced injury through the AMPK/Nrf2/ARE pathway

Abstract

Objective: C1q/TNF-related protein 3 (CTRP3), a member of CTRP family, has been found to have neuroprotective effect. In the current study, we investigated the protective role of CTRP3 in hippocampal neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R). Materials and methods: The mRNA and protein levels of CTRP3 in OGD/R-stimulated hippocampal neurons were measured using qRT-PCR and western blot analysis, respectively. CCK-8 assay was performed to assess cell viability. ROS production was measured using the fluorescence probe 2′,7′-dichlorofluorescein diacetate (H2DCFDA). The activities of SOD and GPx were determined using ELISA. Cell apoptosis was assessed. Luciferase reporter assay was carried out to assess the activation of ARE). The levels of p-AMPK and Nrf2 were measured using western blot. Results: Our results showed that the expression of CTRP3 was significantly downregulated in hippocampal neuronal cells exposed to OGD/R. Overexpression of CTRP3 improved cell viability of OGD/R-induced hippocampal neurons. In addition, overexpression of CTRP3 attenuated the OGD/R-caused oxidative stress with decreased ROS production and increased activities of SOD and GPx. Moreover, CTRP3 caused a significant increase in bcl-2 expression and decreases in bax expression and caspase-3 activity. Furthermore, CTRP3 overexpression significantly upregulated the levels of p-AMPK and Nrf2, as well induced the activation of ARE in OGD-R-induced hippocampal neurons. CTRP3 upregulated the mRNA expression levels of HO-1, NQO-1 and GPx-3. Additionally, treatment with the inhibitor of AMPK partially reversed the neuroprotective effect of CTRP3 in OGD/R-exposed neurons. Conclusion: CTRP3 exerted protective effect on OGD/R-induced cerebral injury, which was regulated by AMPK/Nrf2/ARE pathway.

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease

“…9 The overexpression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) pathways in oxygen-glucose deprivation/reperfusion-induced hippocampal neurons. 34,35 Administration of CTRP3 reduced reactive oxygen species and malondialdehyde production, increased the level of glutathione, attenuated cerebral edema and BBB disruption, promoted angiogenesis, and improved neurological defects via both protein kinase A (PKA) and AMPK/hypoxia inducing factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)…”

“…Lacking CTRP3 exacerbated depression‐type behaviors (e.g., decreased sucrose consumption and locomotor activity), neuronal death, expression of cleaved caspase‐3, and pro‐inflammatory responses by inhibiting p38 and Jun N‐terminal kinase (JNK)/mitogen‐activated protein kinase (MAPK) pathways in a depression mouse model 33 . The overexpression of CTRP3 attenuated oxidative stress, enhanced mitochondrial biogenesis, and induced changes in a series of regulatory molecules such as BCL‐2 expression, BAX expression, and Caspase‐3 activity via both AMPK/nuclear factor erythroid 2‐related factor 2 (NRF2)/antioxidant response element (ARE) and AMPK/SIRT1/peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α) pathways in oxygen–glucose deprivation/reperfusion‐induced hippocampal neurons 34,35 . Administration of CTRP3 reduced reactive oxygen species and malondialdehyde production, increased the level of glutathione, attenuated cerebral edema and BBB disruption, promoted angiogenesis, and improved neurological defects via both protein kinase A (PKA) and AMPK/hypoxia inducing factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF) pathways in an intracerebral hemorrhage rat model 36,37 .…”

CTRP3 attenuates inflammation, oxidative and cell death in cisplatin induced HK-2 cells

“…(2020) demonstrated that CTRP3 overexpression promoted cell proliferation and reduced apoptosis of AC16 cardiomyocytes treated with HG. Overexpression of CTRP3 attenuated the OGD/R-caused apoptosis with increased Bcl-2 expression and decreased Bax expression ( Ding, Wang & Song, 2021 ). These results were consistent with our findings.…”

“…CTRP3 is expressed in vascular smooth muscle cells at the cellular level ( Zhou et al, 2014 ). Recent studies have revealed that the expression level of CTRP3 decreases in the pathogenesis of acute injury in high glucose (HG)-induced H9C2 cells ( Ma et al, 2017 ) and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced hippocampal neurons ( Ding, Wang & Song, 2021 ). Furthermore, several studies have shown that CTRP3 participated in neuroprotection and cardioprotection via reducing inflammatory response, apoptosis, and oxidative stress, suggesting that CTRP3 is a potentially protective factor ( Gao, Qian & Wang, 2020 ; Ma et al, 2017 ).…”

Neuroprotective potential of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element signaling modulator cucurbitacin I upon glucose and oxygen deprivation/reperfusion (OGD/RP)

“…Based on the important action of oxidative stress in the development of oxygen-glucose deprivation/reperfusion (OGD/RP)-which lead to neuronal injury, its strict regulation is a potential master plan for alleviating neuronal injury. 17,18 The Nrf2/ARE signaling pathway has emerged as a critical regulator pathway of neuronal oxidative injury and apoptosis. 19,20 Target genes of Nrf2 include proteins involved in the regulation of the synthesis of antioxidant proteins, drug-metabolizing enzymes, pentose phosphate pathway enzymes, and enzymes involved in nucleotide syntheses, such as heme oxygenase-1 (HO-1), glutathione-S-transferase (GST), quinone oxidoreductase-1 (NQO1), thioredoxins (Trxs), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px).…”