TRPM2 ion channel is involved in the aggravation of cognitive impairment and down regulation of epilepsy threshold in pentylenetetrazole-induced kindling mice

Qin, Zheng; Zhu, Tao; Hu, Hui; Zhao, Yisha; Ying, Yingchao; Luo, Xiaoying; Ling, Yinjie; Chen, Zhiyue; Ji, Haoran; Jiang, Peifang

doi:10.1016/j.brainresbull.2019.11.018

Cited by 26 publications

(10 citation statements)

References 49 publications

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“…Additionally, TRPM2 KO markedly improves neurological outcomes such as learning and memory following transient focal or global ischemic insult (Perraud et al, 2001;Ye et al, 2014), further indicating a critical role for TRPM2-assocated delayed neuronal death in cognitive dysfunction. Recently, pharmacological inhibition of TRPM2 channels was shown to obviously attenuate cognitive deficits in rodent models of diabetes (Thapak et al, 2020), global ischemia (Dietz et al, 2020), chronic cerebral hypoperfusion (Miyanohara et al, 2018), aging (Kakae et al, 2019), epilepsy (Zheng et al, 2020) and AD . Based on these novel findings, it was hypothesized that TRPM2 could be targeted in a therapeutic strategy for alleviating brain injury and cognitive impairment associated with the above conditions.…”

Section: Discussionmentioning

confidence: 99%

Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats

Zhu

Qiu

et al. 2021

Front. Behav. Neurosci.

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Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur’s effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.

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Section: Discussionmentioning

confidence: 99%

Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats

Zhu

Qiu

et al. 2021

Front. Behav. Neurosci.

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“…The TRPM2 channel is widely distributed throughout the body and is highly sensitive to activation by OS-inducing stimuli [ [31] , [32] , [33] ]. A large number of studies have been carried out over the past decades that provide compelling evidence to show that the TRPM2 channel is a key mechanism mediating OS-induced alteration in intracellular Ca 2+ and Zn 2+ homeostasis to disrupt various cellular functions and further support a significant role for aberrant TRPM2 channel activity in diverse OS-associated pathologies [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] ]. A well-established mechanism, among others, by which the TRPM2 channel contributes to these pathological processes, is to mediate OS-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Malko

Jiang

2020

Redox Biology

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Oxidative stress resulting from the accumulation of high levels of reactive oxygen species is a salient feature of, and a well-recognised pathological factor for, diverse pathologies. One common mechanism for oxidative stress damage is via the disruption of intracellular ion homeostasis to induce cell death. TRPM2 is a non-selective Ca 2+ -permeable cation channel with a wide distribution throughout the body and is highly sensitive to activation by oxidative stress. Recent studies have collected abundant evidence to show its important role in mediating cell death induced by miscellaneous oxidative stress-inducing pathological factors, both endogenous and exogenous, including ischemia/reperfusion and the neurotoxicants amyloid-β peptides and MPTP/MPP + that cause neuronal demise in the brain, myocardial ischemia/reperfusion, proinflammatory mediators that disrupt endothelial function, diabetogenic agent streptozotocin and diabetes risk factor free fatty acids that induce loss of pancreatic β-cells, bile acids that damage pancreatic acinar cells, renal ischemia/reperfusion and albuminuria that are detrimental to kidney cells, acetaminophen that triggers hepatocyte death, and nanoparticles that injure pericytes. Studies have also shed light on the signalling mechanisms by which these pathological factors activate the TRPM2 channel to alter intracellular ion homeostasis leading to aberrant initiation of various cell death pathways. TRPM2-mediated cell death thus emerges as an important mechanism in the pathogenesis of conditions including ischemic stroke, neurodegenerative diseases, cardiovascular diseases, diabetes, pancreatitis, chronic kidney disease, liver damage and neurovascular injury. These findings raise the exciting perspective of targeting the TRPM2 channel as a novel therapeutic strategy to treat such oxidative stress-associated diseases.

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“…19 The neuroprotective effect of TRPM2 knockout could decrease neuronal apoptosis via PARP-1/BNIP3/AIF in epilepsy. 36 KIF4 mutations increased the affinity of binding with PARP1 and contributed to epilepsy susceptibility. 37 In this study, SV2A protected mitochondria, inhibiting the translocation of AIF to the nucleus, subsequently inhibiting parthanatos, and ultimately protecting DNA from degradation.…”

Section: Discussionmentioning

confidence: 99%

“… 19 The neuroprotective effect of TRPM2 knockout could decrease neuronal apoptosis via PARP‐1/BNIP3/AIF in epilepsy. 36 KIF4 mutations increased the affinity of binding with PARP1 and contributed to epilepsy susceptibility. 37…”

Section: Discussionmentioning

confidence: 99%

Synaptic vesicle protein 2A mitigates parthanatos via apoptosis‐inducing factor in a rat model of pharmacoresistant epilepsy

Li,

Wang,

Ren

et al. 2024

CNS Neurosci Ther

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AimsSynaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure‐induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis‐inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF.MethodsAn intraperitoneal injection of lithium chloride‐pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF.ResultsParthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ‐H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction.SignificanceSV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.

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TRPM2 ion channel is involved in the aggravation of cognitive impairment and down regulation of epilepsy threshold in pentylenetetrazole-induced kindling mice

Cited by 26 publications

References 49 publications

Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats

Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Synaptic vesicle protein 2A mitigates parthanatos via apoptosis‐inducing factor in a rat model of pharmacoresistant epilepsy

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