Blocking glutamate excitoxicity maybe a way to treat the inflammatory penumbra

Sulkowski G, Dąbrowska-Bouta B, Salińska E, Strużyńska L.
Modulation of Glutamate Transport and Receptor Binding by Glutamate Receptor Antagonists in EAE Rat Brain.PLoS One. 2014 Nov 26;9(11):e113954. doi: 10.1371/journal.pone.0113954. eCollection 2014.

The aetiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. 

Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE.
Excitotoxicity is a concept that developed from the stroke field. There you have a blood clot that blocks the blood vessel and causes the nerves to die because of lack of oxygen (ischaemia). The penumbra is the area surrounding an ischaemic event, Immediately following the event, blood flow and therefore oxygen transport is reduced locally, leading to hypoxia of the cells near the location of the original insult. This can lead to hypoxic cell death (infarction) and amplify the original damage from the ischemia; however, the penumbra area may remain viable for several hours after an ischemic event due to the collateral arteries that supply the penumbral zone. However within the ischemic penumbra nerves start to fire due to glutamate release and cause excitotoxity.

Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by glutamatergic storm. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes that trigger cell suicide.
Low Ca2+ buffering and excitotoxicity under physiological stress and pathophysiological conditions in motor neuron (MNs). Low Ca2+ buffering in  S vulnerable nerves are exposes mitochondria to higher Ca2+ loads compared to highly buffered cells. Under normal physiological conditions, the neurotransmitter opens glutamate, NMDA and AMPA receptor channels, and voltage dependent Ca2+ channels (VDCC) with high glutamate release, which is taken up again by EAAT1 and EAAT2. This results in a small rise in intracellular calcium that can be buffered in the cell. In MS high Ca2+ loads and increased risk for mitochondrial damage. This triggers the mitochondrial production of reactive oxygen species (ROS), which then inhibit glial EAAT2 function. This leads to further increases in the glutamate concentration at the synapse and further rises in postsynaptic calcium levels, contributing to the selective vulnerability of nerves

The Excitatory amino-acid transporters (EAATs), also known as glutamate transporters, EAATs serve to terminate the excitatory signal by removal (uptake) of glutamate from the neuronal synaptic cleft into neuroglia and neurons. These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes.After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission. Without the activity of glutamate transporters, glutamate would build up and kill cells by excitotoxicity. In Stroke these transporters may go into reverse mode and add to the problem. It has been known for quite some time that there are alterations with the transporters in MS

This study shows that there are problems in the EAAT that may be rectified by blockade of NMDA glutamate receptors. Doing this in EAE can save nerves and it may also occur in MS but the results of treating with NMDA antagonists have been equivocal. Also other studies have suggested blockade of AMPA the other form of glutamate receptor could be neuroprotective however studies in MS have not been reported…..I suspect because blockade of AMPA is toxic…strong blockers are the wrong way to go they easily kills rodents and has sedating side effects and also surprisingly for an antagonist it causes “tolerance” so it stops working and this may contribute to NMDA not being as effective as one may think. It is a weak blocker at least.

ProfG came up with the concept of the “Inflammatory Penumbra” for problems of damage in MS

Here we have damage around the vessel that occurs due to inflammation and part of this problem will be excitotoxicity.

However there are other ways to get at the problem of the penumbra and also the problems of progression. We have invented some new drugs that may do just that. However as you know these

will be years for reaching MS. So in the shorter term we have to use what is available. 

In active inflammation, we have shown experimentally that there is a window of opportunity to make an impact in this penumbra and have used this knowledge to test the idea.  

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