Tuesday, 25 September 2012

Research: Glutamate Receptors as a new target to control MS

Someone wrote and asked about a post on mGluR4 and EAE. This was a company post about some new variants of those used previously in this post.

Fallarino F, Volpi C, Fazio F, Notartomaso S, Vacca C, Busceti C, Bicciato S, Battaglia G, Bruno V, Puccetti P, Fioretti MC, Nicoletti F, Grohmann U, Di Marco R. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat Med. 2010 ;16(8):897-902. Epub 2010 Jul 25

High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (T(reg)) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.

                                                              AMPA receptor
Glutamate is the major excitatory neurotransmitter, so it is involved in transmitting nerve signals along the nerve. It can also be made by white blood cells and astrocytes are involved in hoovering excess glutamate and converting it to glutamine. Whilst we need glutamate, too much and it becomes damaging and can cause nerves to die. The way that glutamate is because it docks with glutamate receptors.
There are some called iontrophic glutamat receptors that signal down nerves by causing ions (an type of atom with and electrical charge) to to be releasd or moved There are whole families of glutamate receptors their are ionotrophic receptors. One type is called the N-methyl-D-aspartate (NMDA) receptor The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function. Then there are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is a non-NMDA-type ionotropictransmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Blocking thes may be useful thing to do in MS. Then there is another iontrophic receptor called kainate receptors. There are five types of kainate receptor subunits, GluR5 (GRIK1), GluR6 (GRIK2), GluR7 (GRIK3), KA1 (GRIK4) and KA2 (GRIK5), which are similar to AMPA and NMDA receptor subunit. there are many others.

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. There are at least eight different types of mGluRs, labeled mGluR1 to mGluR8 (GRM1 to GRM8), are divided into groups I, II, and III. GluR1 and GluR5 are group I mGLuR and are involved in the control of nerve impulse transmission, mGLuR2 and Glur3 are group II and  mGluR4, mGlur 6, 7, and 8 are group III. So now you can see that glutamate must be able to do looks of different things and this depends on the type of glutamate receptors expressed.
This study looked as mGlur4 and they found that if you do not have an mGlur4 receptor you get worse autoimmunity in mices with an MS-like disease. In this case they think that dendritic cells that control how T cells become stimulated to cause disase can be controleed when glutatamate stimulates the mGlur4 receptor. This study then uses a drug that stimulates the mGluR4 and this stopped the MS-disease from developing. This indicates that mGlur4 may be providing a break to stop autoimmunity from developing. This is a new exciting target to try and control EAE
We showed previously that mGluR can have other functions activation of microglial Group II mGluR exacerbated nerve killing whilst activation of group III mGluR was neuroprotective. We tried to get some funding to look at mGluR for a few years but nobody seemed to be interested at the time and have some interesting studies with Group I and Group III stimultors but that's for another day.

A company has just announced that they have produced some mGluR4 reactive drugs and these also work in animal models of MS. We will have to watch this space to see if they are safe in humans and whether they work. The mGluR are relatively unexplored set of targets that could act an many stages of the disease process.
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