Excitotoxicity: An Organized Crime at The Cellular Level

Velasco, Manuel; Rojas-Quintero, Joselyn; Chávez-Castillo, Mervin; Rojas, Milagros; Bautista, Jordan; Martínez, María Sofía; Salazar, Juan; Mendoza, Rafael; Bermúdez, Valmore

doi:10.21767/2171-6625.1000193

Cited by 21 publications

(15 citation statements)

References 99 publications

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“…EAAT2/GLT-1 is widely distributed in the CNS, and is mainly expressed in astrocytes in the forebrain, cerebral cortex, hippocampus, and other regions [3,48]. The EAAT2 transporters are the most abundant, and absorb glutamate from the synaptic cleft, being responsible for up to 95% of its total uptake [49]. However, astrocyte dysfunction may lead to numerous neurodegenerative diseases [7].…”

Section: Eaat1 and Eaat2 Dysfunction In Astrocytes And Parkinson's DImentioning

confidence: 99%

“…However, astrocyte dysfunction may lead to numerous neurodegenerative diseases [7]. EAAT2 dysfunction leads to extracellular glutamate accumulation and is associated with many neurodegenerative diseases, like Huntington's disease [49], Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic multiple sclerosis (AMS) [39,49]. EAAT2 dysfunction is also expressed in several psychiatric diseases, such as schizophrenia, epilepsy, depression, and autism [39].…”

Section: Eaat1 and Eaat2 Dysfunction In Astrocytes And Parkinson's DImentioning

confidence: 99%

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The Potential Role of Astrocytes in Parkinson’s Disease (PD)

Gebreyesus

Gebremichael

2020

Medical Sciences

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Astrocytes are multi-functional cells, now recognized as critical participants in many brain functions. They play a critical physiological role in the clearance of neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA), and in the regulation of K+ from the space of synaptic clefts. Astrocytes also express the excitatory amino acid transporters (EAATs) and aquaporin-4 (AQP4) water channel, which are involved in both physiological functions and neurodegenerative diseases (ND). Some of the ND are the Alzheimer’s (AD), Huntington’s (HD), Parkinson’s diseases (PD), Cerebral edema, amyotrophic lateral sclerosis (ALS), and epilepsy pathological conditions in specific regions of the CNS. Parkinson’s disease is the second most common age-related neurodegenerative disorder, characterized by degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). These project to the striatum, forming an important pathway within the basal ganglia. Mostly, PD has no clear etiology, and the mechanism of dopaminergic (DA) neuron loss is not well illustrated. The results of various studies suggest that astrocytes are involved in the pathophysiology of PD. Evidence has shown that the down-regulation of EAAT-2/GLT-1 and AQP4 expression is associated with PD pathogenesis. However, controversial results were reported in different experimental studies about the expression and function of EAAT-2/GLT-1 and AQP4, as well as their colocalization in different brain regions, and their involvement in PD development. Therefore, under neurological disorders, Parkinson’s disease is related to the genetic and phenotypic change of astrocytes’ biology. In this review, the authors summarized recent their research findings, which revealed the involvement of EAAT-2/GLT-1 and AQP4 expression, the physical interaction between EAAT-2/GLT-1 and AQP4 in astrocyte function, and their potential role in the development of PD in SNpc and Subthalamic nucleus (STN) of the basal ganglia nuclei.

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Section: Eaat1 and Eaat2 Dysfunction In Astrocytes And Parkinson's DImentioning

confidence: 99%

Section: Eaat1 and Eaat2 Dysfunction In Astrocytes And Parkinson's DImentioning

confidence: 99%

The Potential Role of Astrocytes in Parkinson’s Disease (PD)

Gebreyesus

Gebremichael

2020

Medical Sciences

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“…CCH induces cellular energy imbalance and consequently, a state of excitotoxicity in the CNS 75 , 85 - 87 . Excitotoxicity is defined as the state of increased activation of neurons in response to increased levels of extracellular glutamate and subsequent calcium ion (Ca 2+ ) influx 88 . High levels of glutamate release during excitotoxicity cause a persistent activation of N-methyl-d-aspartate acid (NMDA) receptors, ∝-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors, and metabotropic glutamate receptors (mGluRs) on neurons during CCH.…”

Section: The Blood-brain Barrier In Health and Diseasementioning

confidence: 99%

Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment

Rajeev¹,

Fann²,

Dinh³

et al. 2022

Theranostics

100

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The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits from mild cognitive impairment to dementia. VCI and its most severe form, vascular dementia (VaD), is becoming a major public health concern worldwide. As growing efforts are being taken to understand VCI and VaD in animal models and humans, the pathogenesis of the disease is being actively explored. It is postulated that chronic cerebral hypoperfusion (CCH) is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain. This review outlines the molecular and cellular mechanisms that govern BBB breakdown during CCH and highlights the clinical evidence in identifying at-risk VCI patients.

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“…How neurons swell is more mysterious ("Neuronal Swelling in Response to Ischemia", "Transport (Carrier) Proteins and Neuronal Swelling" sections). Importantly, cytotoxic edema is a direct result of SD, yet SD is not even mentioned in many recent reviews of neuronal death [80][81][82][83].…”

Section: Sd Is the Common Cause Of Acute Neuronal Swellingmentioning

confidence: 99%

Neuronal Swelling: A Non-osmotic Consequence of Spreading Depolarization

Hellas

Andrew

2021

Neurocrit Care

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An acute reduction in plasma osmolality causes rapid uptake of water by astrocytes but not by neurons, whereas both cell types swell as a consequence of lost blood flow (ischemia). Either hypoosmolality or ischemia can displace the brain downwards, potentially causing death. However, these disorders are fundamentally different at the cellular level. Astrocytes osmotically swell or shrink because they express functional water channels (aquaporins), whereas neurons lack functional aquaporins and thus maintain their volume. Yet both neurons and astrocytes immediately swell when blood flow to the brain is compromised (cytotoxic edema) as following stroke onset, sudden cardiac arrest, or traumatic brain injury. In each situation, neuronal swelling is the direct result of spreading depolarization (SD) generated when the ATP-dependent sodium/potassium ATPase (the Na+/K+ pump) is compromised. The simple, and incorrect, textbook explanation for neuronal swelling is that increased Na+ influx passively draws Cl− into the cell, with water following by osmosis via some unknown conduit. We first review the strong evidence that mammalian neurons resist volume change during acute osmotic stress. We then contrast this with their dramatic swelling during ischemia. Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia.

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Excitotoxicity: An Organized Crime at The Cellular Level

Cited by 21 publications

References 99 publications

The Potential Role of Astrocytes in Parkinson’s Disease (PD)

The Potential Role of Astrocytes in Parkinson’s Disease (PD)

Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment

Neuronal Swelling: A Non-osmotic Consequence of Spreading Depolarization

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