Disrupted Ionic Homeostasis in Ischemic Stroke and New Therapeutic Targets

Hu, Hui-Jie; Song, Mingke

doi:10.1016/j.jstrokecerebrovasdis.2017.09.011

Cited by 58 publications

(38 citation statements)

References 136 publications

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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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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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“…Kir4.1 is dependent on adenosine triphosphate (ATP) (Nwaobi et al, 2016 ). Under K + -starvation, Kir4.1 may be inactive as a result of ATP depletion in response to brain ischemia and low pH due to the acidosis that occurs in response to ischemia (Pessia et al, 2001 ; Hu and Song, 2017 ). As a result, Kir4.1 is no longer activated in a PI3K-dependent manner (as suggested below) and mTORC1 no longer prevents autophagic cell death.…”

Section: Potential Mechanisms Involved In Mediating Kir41 Functionalmentioning

confidence: 99%

It's All about Timing: The Involvement of Kir4.1 Channel Regulation in Acute Ischemic Stroke Pathology

Milton

Smith

2018

Front. Cell. Neurosci.

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An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009). For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+) and chloride channels (Vella et al., 2015). This astroglial swelling may be overwhelmed, under ischemic conditions, due to the increased levels of glutamate and extracellular K+ (Lai et al., 2014; Vella et al., 2015). The increase in extracellular K+ contributes to neuronal damage and loss through the initiation of harmful secondary cascades (Nwaobi et al., 2016). Reducing the amount of extracellular K+ could, in theory, limit or prevent neuronal damage and loss resulting in an improved prognosis for individuals following ischemic stroke. Kir4.1, an inwardly rectifying K+ channel, has demonstrated an ability to regulate the rapid reuptake of this ion to return the cell to basal levels allowing it to fire again in rapid transmission (Sibille et al., 2015). Despite growing interest in this area, the underlying mechanism suggesting that neuroprotection could occur through modification of the Kir4.1 channel's activity has yet to be described. The purpose of this review is to examine the current literature and propose potential underlying mechanisms involving Kir4.1, specially the mammalian target of rapamycin (mTOR) and/or autophagic pathways, in the pathogenesis of ischemic stroke. The hope is that this review will instigate further investigation of Kir4.1 as a modulator of stroke pathology.

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“…Under the ischemic condition, disruption of brain homeostasis is disturbed and cell death mechanisms are initiated. This cerebral injury leads to an alteration in ionic balance within the intra-extracellular space [ 6 ], reactive oxygen species (ROS) production [ 7 ], microglia [ 8 ] and astrocyte [ 9 ] activation, zinc accumulation [ 10 ], and neuronal cell degeneration [ 11 , 12 , 13 ] in the brain. Blockage of blood flow to the brain by ischemic insult causes tissue infarction, dysfunction of ionic balance, and intracellular calcium overload [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death

Hong

Kho

Lee

et al. 2020

IJMS

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A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.

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Disrupted Ionic Homeostasis in Ischemic Stroke and New Therapeutic Targets

Cited by 58 publications

References 136 publications

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

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

It's All about Timing: The Involvement of Kir4.1 Channel Regulation in Acute Ischemic Stroke Pathology

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death

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