Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels

Dietz, Robert M.; Cruz‐Torres, Ivelisse; Orfila, James E; Patsos, Olivia P; Shimizu, Kaori; Chalmers, Nicholas; Deng, Guo-Xiong; Tiemeier, Erika; Quillinan, Nidia; Herson, Paco S.

doi:10.1007/s12975-019-00712-z

Cited by 22 publications

(49 citation statements)

References 57 publications

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“…Modeling for tatM2NX Antagonism on TRPM2. We recently showed that the peptide tatM2NX is a TRPM2 antagonist with selective neuroprotective effects in a mouse model of focal ischemia (stroke) (Shimizu et al, 2016) and global ischemia (cardiac arrest and cardiopulmonary resuscitation) (Dietz et al, 2019). To characterize the mechanism of TRPM2 inhibition by tatM2NX, we performed molecular modeling (MD) to allow prediction of tatM2NX interaction/ inhibition of activity and potential key residues responsible for efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…We next assessed the ability of tatM2NX to inhibit TRPM2mediated dephosphorylation of GSK3b (activation) because this signaling pathway has recently been shown in cell culture (Fourgeaud et al, 2019) and brain slices (Dietz et al, 2019). TRPM2 stimulation with H 2 O 2 (250 mM) activates GSK3b (dephosphorylation) in HEK293 cells (1control) compared with untreated cells (2control) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is limited by stability difficulties in the brain (Fourgeaud et al, 2019). In contrast, we recently reported that the inhibitor, tatM2NX, reduces ischemic injury when administered following focal cerebral ischemia (Shimizu et al, 2016) and global cerebral ischemia (Dietz et al, 2019) in vivo, providing evidence for clinical benefit. Therefore, the aim of this study is to characterize the TRPM2 channel inhibitor tatM2NX, a peptide designed to interact with the ADPR binding site on the NUT9-H domain.…”

Section: Introductionmentioning

confidence: 99%

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Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX

2019

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Transient receptor potential melastatin 2 (TRPM2) is a calciumpermeable channel activated by adenosine diphosphate ribose metabolites and oxidative stress. TRPM2 contributes to neuronal injury in the brain caused by stroke and cardiac arrest among other diseases including pain, inflammation, and cancer. However, the lack of specific inhibitors hinders the study of TRPM2 in brain pathophysiology. Here, we present the design of a novel TRPM2 antagonist, tatM2NX, which prevents ligand binding and TRPM2 activation. We used mutagenesis of tatM2NX to determine the structure-activity relationship and antagonistic mechanism on TRPM2 using whole-cell patch clamp and Calcium imaging in human embryonic kidney 293 cells with stable human TRPM2 expression. We show that tatM2NX inhibits over 90% of TRPM2 channel currents at concentrations as low as 2 mM. Moreover, tatM2NX is a potent antagonist with an IC 50 of 396 nM. Our results from tatM2NX mutagenesis indicate that specific residues within the tatM2NX C terminus are required to confer antagonism on TRPM2. Therefore, the peptide tatM2NX represents a new tool for the study of TRPM2 function in cell biology and enhances our understanding of TRPM2 in disease. SIGNIFICANCE STATEMENTTatM2NX is a potent TRPM2 channel antagonist with the potential for clinical benefit in neurological diseases. This study characterizes interactions of tatM2NX with TRPM2 and the mechanism of action using structure-activity analysis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX

2019

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“…Such an exclusive role of TRPM2 during reperfusion indicates that TRPM2 deficiency can only protect against brain damage induced by transient (followed by reperfusion) but not permanent (no reperfusion) [ 20 ]. The study also investigated that ischemia-induced memory deficits were mediated by the aberrant activity of TRPM2-CaN-GSK3β signaling cascade that actively inhibits synaptic plasticity [ 76 ]. Currently, mounting evidence suggested that TRPM2 worked together with diverse mechanisms, contributing to ROS‐induced neuronal cell death.…”

Section: Effects Of Trpm2 On the Pathogenesis Of Cerebral Ischemiamentioning

confidence: 99%

TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention

Wang

Liu

et al. 2021

Channels

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Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca 2+ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.

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“…Global cerebral ischemia-reperfusion injury (GCI) that occurs during the arrest period and subsequent return of spontaneous circulation (ROSC), trigger deleterious injury mechanisms including neuroinflammation [4] leading to irreversible brain damage [5]. Besides many other neurofunctional impairments [6], damage to the ischemia vulnerable brain regions such as hippocampus results in cognitive dysfunction following CA [7][8][9]. Cognitive impairment may persist up to 3 years, thereby hindering patients' daily activities and decreasing their quality of life [10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mast cell tryptase attenuates neuroinflammation via PAR-2/p38/NFκB pathway following asphyxial cardiac arrest in rats

Ocak

Huang

et al. 2020

J Neuroinflammation

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Background: Cardiac arrest survivors suffer from neurological dysfunction including cognitive impairment. Cerebral mast cells, the key regulators of neuroinflammation contribute to neuroinflammation-associated cognitive dysfunction. Mast cell tryptase was demonstrated to have a proinflammatory effect on microglia via the activation of microglial protease-activated receptor-2 (PAR-2). This study investigated the potential anti-neuroinflammatory effect of mast cell tryptase inhibition and the underlying mechanism of PAR-2/p-p38/NFκB signaling following asphyxia-induced cardiac arrest in rats. Methods: Adult male Sprague-Dawley rats resuscitated from 10 min of asphyxia-induced cardiac arrest were randomized to four separate experiments including time-course, short-term outcomes, long-term outcomes and mechanism studies. The effect of mast cell tryptase inhibition on asphyxial cardiac arrest outcomes was examined after intranasal administration of selective mast cell tryptase inhibitor (APC366; 50 μg/rat or 150 μg/rat). AC55541 (selective PAR-2 activator; 30 μg/rat) and SB203580 (selective p38 inhibitor; 300 μg/rat) were used for intervention. Short-term neurocognitive functions were evaluated using the neurological deficit score, number of seizures, adhesive tape removal test, and T-maze test, while long-term cognitive functions were evaluated using the Morris water maze test. Hippocampal neuronal degeneration was evaluated by Fluoro-Jade C staining.

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Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels

Cited by 22 publications

References 57 publications

Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX

Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX

TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention

Inhibition of mast cell tryptase attenuates neuroinflammation via PAR-2/p38/NFκB pathway following asphyxial cardiac arrest in rats

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