A New Potential Strategy for Treatment of Ischemic Stroke: Targeting TRPM2–NMDAR Association

Xu, Jiayun; Zhang, Wei; Dong, Jianhong; Cao, Lei; Huang, Zhihui

doi:10.1007/s12264-022-00971-1

Cited by 11 publications

(5 citation statements)

References 18 publications

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“…Importantly, in rescue experiments using WT TRPM2 but not the silent E960D TRPM2 mutant, mitochondrial function and tumor survival were restored in vitro and in vivo , suggesting a direct link between TRPM2-mediated Ca 2+ influx, mitochondrial bioenergetics, and cancer progression ( Bao et al, 2016 ; Hirschler-Laszkiewicz et al, 2018 ). Similar observations have been made in acute myeloid leukemia (AML) ( Xu et al, 2022 ), gastric cancer ( Almasi et al, 2018 ), and breast cancer (unpublished data, El Hiani’s laboratory). Taken together, these data indicate that TRPM2 promotes cancer progression by enhancing mitochondrial function and ATP production.…”

Section: Trpm2 In Cancersupporting

confidence: 74%

“…A crucial mechanism involved in ischemic stroke is the excessive release of the neurotransmitter glutamate, which leads to overactivation of NMDA (N-methyl-D-aspartate) receptors (NMDAR) and subsequently to excessive Ca 2+ influx and overproduction of ROS in neurons ( Wu and Tymianski, 2018 ; Ge et al, 2020 ). Given the potential link between the Ca 2+ /ROS system and TRPM2 on the one hand and NMDAR-mediated ischemic stroke on the other, the role of TRPM2 in ischemic stroke has been investigated in detail ( Turlova et al, 2018 ; Zong et al, 2022a ; Xu et al, 2022 ). The first evidence linking TRPM2 with ischemic stroke was provided by Fonfria and collaborators, who showed increased TRPM2 mRNA expression and function after ischemic injury in the microglia of the transient middle cerebral artery occlusion (tMCAO) rat stroke model.…”

Section: Trpm2—the Master Of Ca 2+ and Ros Signali...mentioning

confidence: 99%

“…Mechanistically, TRPM2-mediated ischemic stroke has been associated with the expression and signalling of NMDARs ( Ge et al, 2020 ; Xu et al, 2022 ). Among the numerous subunits, GluN2A and GluN2B are the most important types of NMDARs and have been shown to control signalling pathways leading to cell survival and death, respectively ( Sun et al, 2018 ).…”

Section: Trpm2—the Master Of Ca 2+ and Ros Signali...mentioning

confidence: 99%

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TRPM2: bridging calcium and ROS signaling pathways—implications for human diseases

Maliougina

Hiani

2023

Front. Physiol.

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TRPM2 is a versatile and essential signaling molecule that plays diverse roles in Ca2+ homeostasis and oxidative stress signaling, with implications in various diseases. Research evidence has shown that TRPM2 is a promising therapeutic target. However, the decision of whether to activate or inhibit TRPM2 function depends on the context and specific disease. A deeper understanding of the molecular mechanisms governing TRPM2 activation and regulation could pave the way for the development of innovative therapeutics targeting TRPM2 to treat a broad range of diseases. In this review, we examine the structural and biophysical details of TRPM2, its involvement in neurological and cardiovascular diseases, and its role in inflammation and immune system function. In addition, we provide a comprehensive overview of the current knowledge of TRPM2 signaling pathways in cancer, including its functions in bioenergetics, oxidant defense, autophagy, and response to anticancer drugs.

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Section: Trpm2 In Cancersupporting

confidence: 74%

Section: Trpm2—the Master Of Ca 2+ and Ros Signali...mentioning

confidence: 99%

Section: Trpm2—the Master Of Ca 2+ and Ros Signali...mentioning

confidence: 99%

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TRPM2: bridging calcium and ROS signaling pathways—implications for human diseases

Maliougina

Hiani

2023

Front. Physiol.

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“…Most nascent neurons die within 2 weeks after stroke and the survival rate is only around 2% (Arvidsson et al, 2002). Various drugs, such as NMDA receptor antagonists, calcium antagonists, and antioxidants are used to enhance this effect for treatment of stroke, however, they have poor efficacy (Alonso de Lecinana et al, 2001; Xu et al, 2022). Accordingly, new treatment strategies should be developed to stimulate the restoration of the NVU (Lo, 2008) to alleviate cerebral ischemic damage.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the MAPK/Erk‐Pax6 signal pathway

Lei

Chen

et al. 2023

Glia

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Reactive astrocytes can be transformed into new neurons. Vascular endothelial growth factor (VEGF) promotes the transformation of reactive astrocytes into neurons in ischemic brain. Therefore, in this study, the molecular mechanism of VEGF's effect on ischemia/hypoxia-induced astrocyte to neuron transformation was investigated in the models of rat middle cerebral artery occlusion (MCAO) and in astrocyte culture with oxygen and glucose deprivation (OGD). We found that VEGF enhanced ischemia-induced Pax6, a neurogenic fate determinant, expression and Erk phosphorylation in reactive astrocytes and reduced infarct volume of rat brain at 3 days after MCAO, which effects could be blocked by administration of U0126, a MAPK/Erk inhibitor. In cultured astrocytes, VEGF also enhanced OGD-induced Erk phosphorylation and Pax6 expression, which was blocked by U0126, but not wortmannin, a PI3K/Akt inhibitor, or SB203580, a MAPK/p38 inhibitor, suggesting VEGF enhanced Pax6 expression via activation of MAPK/Erk pathway. OGD induced the increase of miR365 and VEGF inhibited the increase of OGD-induced miR365 expression. However, miR365 agonists blocked VEGF-enhanced Pax6 expression in hypoxic astrocytes, but did not block VEGF-enhanced Erk phosphorylation. We further found that VEGF promoted OGD-induced astrocyte-converted to neuron. Interestingly, both U0126 and Pax6 RNAi significantly reduced enhancement of VEGF on astrocytes-toneurons transformation, as indicated Dcx and MAP2 immunopositive signals in reactive astrocytes. Moreover, those transformed neurons become mature and functional. We concluded that VEGF enhanced astrocytic neurogenesis via the MAPK/Erk-miR-365-Pax6 signal axis. The results also indicated that astrocytes play important roles in the reconstruction of neurovascular units in brain after stroke.

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“…Pathologies that favor the occurrence of transient ischemic, ischemic or hemorrhagic accidents are represented by heart diseases (heart failure, congenital heart malformations, heart infections, heart rhythm disorders), obstructive sleep apnea syndrome [ 83 ]. Recent studies showed the involvement of TRPM2 in pathogenesis factors of ischemic stroke as follows: by reducing oxidative stress in cardiomyocytes, TRPM2 reduces inflammation and stimulates the remodeling of the atria; it models endothelial dysfunction by deregulating the influx of calcium ions, mediates the damaging effects of ROS on the endothelium and favors hypertension; induces the death of pancreatic β cells that secrete insulin, thus promoting the development of diabetes; promotes the aggregation of platelets and favors the appearance of vascular thrombus [ 84 – 86 ]. In the case of hepatic ischemia–reperfusion (IR) injury, it may be considered a clinically important pathological disorder complicating liver surgery and transplantation.…”

Section: Trpm2 In Ischemic Reperfusion Injurymentioning

confidence: 99%

TRPM2-mediated Ca2+ signaling as a potential therapeutic target in cancer treatment: an updated review of its role in survival and proliferation of cancer cells

Ali

Chakrabarty

Ramproshad³

et al. 2023

Cell Commun Signal

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The transient receptor potential melastatin subfamily member 2 (TRPM2), a thermo and reactive oxygen species (ROS) sensitive Ca2+-permeable cation channel has a vital role in surviving the cell as well as defending the adaptability of various cell groups during and after oxidative stress. It shows higher expression in several cancers involving breast, pancreatic, prostate, melanoma, leukemia, and neuroblastoma, indicating it raises the survivability of cancerous cells. In various cancers including gastric cancers, and neuroblastoma, TRPM2 is known to conserve viability, and several underlying mechanisms of action have been proposed. Transcription factors are thought to activate TRPM2 channels, which is essential for cell proliferation and survival. In normal physiological conditions with an optimal expression of TRPM2, mitochondrial ROS is produced in optimal amounts while regulation of antioxidant expression is carried on. Depletion of TRPM2 overexpression or activity has been shown to improve ischemia–reperfusion injury in organ levels, reduce tumor growth and/or viability of various malignant cancers like breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, T-cell and acute myelogenous leukemia. This updated and comprehensive review also analyzes the mechanisms by which TRPM2-mediated Ca2+ signaling can regulate the growth and survival of different types of cancer cells. Based on the discussion of the available data, it can be concluded that TRPM2 may be a unique therapeutic target in the treatment of several types of cancer.

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A New Potential Strategy for Treatment of Ischemic Stroke: Targeting TRPM2–NMDAR Association

Cited by 11 publications

References 18 publications

TRPM2: bridging calcium and ROS signaling pathways—implications for human diseases

TRPM2: bridging calcium and ROS signaling pathways—implications for human diseases

Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the MAPK/Erk‐Pax6 signal pathway

TRPM2-mediated Ca2+ signaling as a potential therapeutic target in cancer treatment: an updated review of its role in survival and proliferation of cancer cells

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