Brain transient receptor potential channels and stroke

Zhang, Eric; Liao, Ping

doi:10.1002/jnr.23529

Cited by 49 publications

(42 citation statements)

References 235 publications

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“…death). Nonetheless, in light of recent data (14-16,23,33,35,36), these data suggest an important role for the Sur1-Trpm4 channel in pathophysiology of post-ischemic cell death and implicates pharmacological blockade of the Sur1-Trpm4 channel as a possible novel therapeutic strategy to mitigate neuronal loss and malignant cerebral edema in patients who sustain large, territorial cerebral infarction.…”

Section: Discussionmentioning

confidence: 81%

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

Mehta

Tosun

Ivanova

et al. 2015

J Neuropathol Exp Neurol

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In animal models of stroke, spinal cord injury, and subarachnoid hemorrhage, transient receptor potential melastatin 4 (Trpm4), a non-selective monovalent cation channel, is transcriptionally upregulated in neural and vascular cells. In these contexts, Trpm4 has been shown to co-associate with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which play a critical role in cytotoxic edema, accidental necrotic (oncotic) cell death, blood-brain barrier (BBB) breakdown and formation of vasogenic edema. To date, the expression and molecular interactions of Trpm4 within human cerebral infarcts have not been systematically evaluated. In this study, we examined Trpm4 expression in postmortem specimens obtained from 15 patients within the first 31 days after onset of focal cerebral ischemia. Significant upregulation of Trpm4 protein was found in all cases, relative to controls. De novo transcriptional upregulation of Trpm4 protein was confirmed using in situ hybridization for Trpm4 mRNA. Trpm4 co-localized and co-associated with Sur1 within ischemic endothelial cells and neurons which exhibited membrane thickening and irregularities characteristic of necrotic cell death. Sur1 and Trpm4 co-expression in abnormal endothelial cells also was associated with vasogenic edema, as evidenced by upregulated perivascular TNFα, perivascular extravasation of serum immunoglobulin G and associated inflammation. Upregulated Trpm4 protein persisted up to one month post onset of cerebral ischemia. Furthermore, pharmacological channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, was found to mitigate perivascular TNFα labeling in a rat middle cerebral artery occlusion (MCAo) stroke model. We conclude that the Sur1-Trpm4 channel is upregulated and associated with BBB disruption and cerebral edema formation in human cerebral infarcts. These data suggest that pharmacological targeting of this channel may represent a promising therapeutic strategy for clinical management of ischemic stroke.

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Section: Discussionmentioning

confidence: 81%

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

Mehta

Tosun

Ivanova

et al. 2015

J Neuropathol Exp Neurol

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“…Moreover, calcium influx may be promoted following ischemic processes related to TBI [ 19 ]. In particular, the anaerobic environment after ischemia activates sodium–calcium exchangers (NCX), acid-sensing ion channels (ASIC) and transient receptor potential channels (TRPM), thus increasing intracellular calcium levels and consequently activating excitotoxic pathways and cell death processes independently of glutamate [ 25 , 26 , 27 , 28 ]. Calcium is generally transported in the endoplasmic reticulum by a pump called SERCA (sarcoplasmic/endoplasmic reticulum calcium-ATPase); its activity is based on the exchange of two calcium ions for every ATP molecule [ 29 ], therefore, SERCA may contribute to excitotoxicity, increasing cytosolic calcium concentration through ryanodine receptors (RyR) and inositol-1,4,5-trisphosphate receptors RyR (IP3R) which are activated following TBI [ 30 , 31 ].…”

Section: Pathophysiology Of Tbimentioning

confidence: 99%

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

Irrera

Russo

Pallio

et al. 2020

IJMS

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Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1β, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.

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“…These include the acid-sensing ion channel 1a (ASIC1a) 24 , proton-sensitive cation channels, ion exchangers 25 and transient receptor potential (TRP) channels. The latter include transient receptor potential canonical (TRPC) 3/4/6 channels, transient receptor potential melastatin (TRPM) 2/4/7 channels and transient receptor potential vanilloid (TRPV) 1/3/4 channels 26 , 27 , 28 , 29 , 30 . Thus drugs that act through non-glutamate–related mechanisms may represent an alternative strategy for stroke drug discovery.…”

Section: Drugs Discontinued In Clinical Trialsmentioning

confidence: 99%

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

Chen

Wang

2016

Acta Pharmaceutica Sinica B

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Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators (rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995–2015 and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

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Brain transient receptor potential channels and stroke

Cited by 49 publications

References 235 publications

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

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