Excitotoxicity

Last updated December 04, 2023

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca²⁺) to enter the cell. Ca²⁺ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.^[1]^[2] In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.^[3]^[4]

Excitotoxicity may be involved in cancers, spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity), and in neurodegenerative diseases of the central nervous system such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism, alcohol withdrawal or hyperammonemia and especially over-rapid benzodiazepine withdrawal, and also Huntington's disease.^[5]^[6] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia. Blood sugars are the primary glutamate removal method from inter-synaptic spaces at the NMDA and AMPA receptor site. Persons in excitotoxic shock must never fall into hypoglycemia. Patients should be given 5% glucose (dextrose) IV drip during excitotoxic shock to avoid a dangerous build up of glutamate around NMDA and AMPA neurons.^{[ citation needed ]} When 5% glucose (dextrose) IV drip is not available high levels of fructose are given orally. Treatment is administered during the acute stages of excitotoxic shock along with glutamate antagonists. Dehydration should be avoided as this also contributes to the concentrations of glutamate in the inter-synaptic cleft^[7] and "status epilepticus can also be triggered by a build up of glutamate around inter-synaptic neurons."^[8]

History

The harmful effects of glutamate on the central nervous system were first observed in 1954 by T. Hayashi, a Japanese scientist who stated that direct application of glutamate caused seizure activity,^[9] though this report went unnoticed for several years.^{[ citation needed ]} D. R. Lucas and J. P. Newhouse, after noting that "single doses of [20–30 grams of sodium glutamate in humans] have ... been administered intravenously without permanent ill-effects", observed in 1957 that a subcutaneous dose described as "a little less than lethal", destroyed the neurons in the inner layers of the retina in newborn mice.^[10] In 1969, John Olney discovered that the phenomenon was not restricted to the retina, but occurred throughout the brain, and coined the term excitotoxicity. He also assessed that cell death was restricted to postsynaptic neurons, that glutamate agonists were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate antagonists could stop the neurotoxicity.^[11]

In 2002, Hilmar Bading and co-workers found that excitotoxicity is caused by the activation of NMDA receptors located outside synaptic contacts.^[12] The molecular basis for toxic extrasynaptic NMDA receptor signaling was uncovered in 2020 when Hilmar Bading and co-workers described a death signaling complex that consists of extrasynaptic NMDA receptor and TRPM4.^[13] Disruption of this complex using NMDAR/TRPM4 interface inhibitors (also known as ‚interface inhibitors‘) renders extrasynaptic NMDA receptor non-toxic.^{[ citation needed ]}

Pathophysiology

Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is also the major excitatory neurotransmitter in the central nervous system of mammals.^[14] During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds.^[15] When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis.^[16]^[17]

This pathologic phenomenon can also occur after brain injury and spinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate.^[18] Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need for oxygen and glucose) and save energy to be used to remove glutamate actively. (The main aim in induced comas is to reduce the intracranial pressure, not brain metabolism).^{[ citation needed ]}

Increased extracellular glutamate levels leads to the activation of Ca²⁺ permeable NMDA receptors on myelin sheaths and oligodendrocytes, leaving oligodendrocytes susceptible to Ca²⁺ influxes and subsequent excitotoxicity.^[19]^[20] One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleaved caspase processing.^[20] Another damaging result of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release reactive oxygen species and other proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium. In addition, production of adenosine triphosphate (ATP) may be stopped, and ATP synthase may in fact begin hydrolysing ATP instead of producing it,^[21] which is suggested to be involved in depression.^[22]

Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintenance of these ion gradients to remove glutamate from the extracellular space. The loss of ion gradients results in not only the halting of glutamate uptake, but also in the reversal of the transporters. The Na⁺-glutamate transporters on neurons and astrocytes can reverse their glutamate transport and start secreting glutamate at a concentration capable of inducing excitotoxicity.^[23] This results in a buildup of glutamate and further damaging activation of glutamate receptors.^[24]

On the molecular level, calcium influx is not the only factor responsible for apoptosis induced by excitoxicity. Recently,^[25] it has been noted that extrasynaptic NMDA receptor activation, triggered by both glutamate exposure or hypoxic/ischemic conditions, activate a CREB (cAMP response element binding) protein shut-off, which in turn caused loss of mitochondrial membrane potential and apoptosis. On the other hand, activation of synaptic NMDA receptors activated only the CREB pathway, which activates BDNF (brain-derived neurotrophic factor), not activating apoptosis.^[25]^[26]

Exogenous excitotoxins

Exogenous excitotoxins refer to neurotoxins that also act at postsynaptic cells but are not normally found in the body. These toxins may enter the body of an organism from the environment through wounds, food intake, aerial dispersion etc.^[27] Common excitotoxins include glutamate analogs that mimic the action of glutamate at glutamate receptors, including AMPA and NMDA receptors.^[28]

BMAA

The L-alanine derivative β-methylamino-L-alanine (BMAA) has long been identified as a neurotoxin which was first associated with the amyotrophic lateral sclerosis/parkinsonism–dementia complex (Lytico-bodig disease) in the Chamorro people of Guam.^[29] The widespread occurrence of BMAA can be attributed to cyanobacteria which produce BMAA as a result of complex reactions under nitrogen stress.^[30] Following research, excitotoxicity appears to be the likely mode of action for BMAA which acts as a glutamate agonist, activating AMPA and NMDA receptors and causing damage to cells even at relatively low concentrations of 10 μM.^[31] The subsequent uncontrolled influx of Ca²⁺ then leads to the pathophysiology described above. Further evidence of the role of BMAA as an excitotoxin is rooted in the ability of NMDA antagonists like MK801 to block the action of BMAA.^[29] More recently, evidence has been found that BMAA is misincorporated in place of L-serine in human proteins.^[32]^[33] A considerable portion of the research relating to the toxicity of BMAA has been conducted on rodents. A study published in 2016 with vervets (Chlorocebus sabaeus) in St. Kitts, which are homozygous for the apoE4 (APOE-ε4) allele (a condition which in humans is a risk factor for Alzheimer's disease), found that vervets orally administered BMAA developed hallmark histopathology features of Alzheimer's Disease including amyloid beta plaques and neurofibrillary tangle accumulation. Vervets in the trial fed smaller doses of BMAA were found to have correlative decreases in these pathology features. This study demonstrates that BMAA, an environmental toxin, can trigger neurodegenerative disease as a result of a gene/environment interaction.^[34] While BMAA has been detected in brain tissue of deceased ALS/PDC patients, further insight is required to trace neurodegenerative pathology in humans to BMAA.^{[ citation needed ]}

Related Research Articles

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg²⁺ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Neuroprotection</span> Relative preservation of neuronal structure and/or function

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

The mitochondrial permeability transition pore is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Opening allows increase in the permeability of the mitochondrial membranes to molecules of less than 1500 daltons in molecular weight. Induction of the permeability transition pore, mitochondrial membrane permeability transition, can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca²⁺ signaling, although recent research has questioned the role of Ca²⁺ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

Glutamate [NMDA] receptor subunit 3A is a protein that in humans is encoded by the GRIN3A gene.

Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

<span class="mw-page-title-main">Eliprodil</span> Chemical compound

Eliprodil is an NMDA antagonist drug candidate which selectively inhibits the NR2B (GLUN2B) subtype NMDA receptor at submicromolar concentrations. Eliprodil failed a Phase III clinical trial for the treatment of acute ischemic stroke in 1996, sponsored by Synthélabo Recherche.

<span class="mw-page-title-main">Nitromemantine</span> Chemical compound

Nitromemantine is a derivative of memantine developed in 2006 for the treatment of Alzheimer's disease. It has been shown to reduce excitotoxicity mediated by over-activation of the glutamatergic system, by blocking NMDA receptors.

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

<span class="mw-page-title-main">Hilmar Bading</span> German physician and neuroscientist

Hilmar Bading is a German physician and neuroscientist. He is a member of the German National Academy of Science Leopoldina.

Acquired neuroprotection is a synaptic-activity-dependent form of adaptation in the nervous system that renders neurons more resistant to harmful conditions. The term was coined by Hilmar Bading. This use-dependent enhancement of cellular survival activity requires changes in gene expression triggered by neuronal activity and nuclear calcium signaling. In rodents, components of the neuroprotective gene program can reduce brain damage caused by seizure-like activity or by a stroke. In acute and chronic neurodegenerative diseases, gene regulatory events important for acquired neuroprotection are antagonized by extrasynaptic NMDA receptor signaling leading to increased vulnerability, loss of structural integrity, and bioenergetics dysfunction.

Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal cell surface. In contrast to synaptic NMDA receptors that promote acquired neuroprotection and synaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways. Extrasynaptic NMDA receptors are responsible for initiating excitotoxicity and have been implicated in the etiology of neurodegenerative diseases, including stroke, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).

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