Metabotropic glutamate receptors are exciting therapeutic targets due to their involvement in cardiovascular and neurological diseases, and their widespread expression.
Oligodendrocytes are Protected by Glial Cells
Group III metabotropic glutamate receptors have drawn a great deal of attention because of their involvement in neuroinflammation, which occurs in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, among others.
A major part of neuroinflammation involves damage to oligodendrocytes, and activation of glial cells within the central nervous system (CNS). Inflammatory responses and glutamatergic signaling link neuroinflammation with excitotoxicity.
Metabotropic glutamate receptor 4 (mGlu4) has been demonstrated to be capable of modulating the immune response in the peripheral nervous system. Activation of astrocytic mGlu4 speeds up oligodendrocyte maturation and enhances oligodendrocyte survival after excitotoxic damage in the CNS.
Treating oligodendrocytes with the agonist of mGlu4, L-AP4, protected them from kainate-induced excitotoxicity in the presence of astrocytes. The mGlu4 positive allosteric modulator (PAM), PHCCC. mimicked this. Treatment with CPPG, the mGlu4 antagonist, lessened this neuroprotective effect.
Following stimulation of mGlu4, transforming growth factor β (TGF-β) secreted from astrocytes mediated the protective effects against excitotoxic insult. Neuroinflammatory conditions could therefore be managed by compounds targeting mGlu4 on glial cells.
Depression is often associated with glutamatergic signaling through the metabotropic glutamate receptor 5 (mGlu5), though there is not much research on its role in stress, which may lead to depression.
Resilience to chronic stress has been shown to be promoted by mGlu5, by the induction of the transcription factor ΔFoSB2 found within the nucleus accumbens (NAc). Knockout mice (mGluR5−/−) where used, employing multiphasic stress-based models of depression in addition to modified single-session tests to simulate chronic stress
Mice missing mGlu5 showed obvious depression-like behaviors that were reduced following lentiviral rescue of mGlu5. mGluR5−/− mice also showed defective ΔFoSB induction, while pharmacological activation of mGlu5 with CDPPB improved ΔFoSB expression.
The induction of ΔFoSB, and activation of mGlu5 in the NAc are both needed, but enough, to promote chronic stress resistance in mice. This is the first discovered proof that mGlu5 mediates stress resilience. A stress-resilience-promoting receptor like mGlu5 has great potential as a drug target to prevent chronic depression, rather than just temporarily treating it.
Protecting Against Ischemic Damage
Cardiac arrest and hypovolemic shock can cause selective neurodegeneration in vulnerable regions of the brain, resulting in Transient cerebral global ischemia. Implicated in this neuronal vulnerability to ischemic damage is the metabotropic glutamate receptor 2 (mGlu2).
Recently highlighted by researchers, global ischemia epigenetically down-regulates mGlu2 expression in vulnerable neurons of the CA1 hippocampal region, though not in the CA3 region. Neuronal death was sometimes preceded by this down-regulation during the development of ischemic damage, so it was found that it could represent a neuroprotective mechanism to constrain neuronal damage. Levels of mGlu2 mRNA were much higher in CA1 regions than in CA3 regions, perhaps contributing to that area’s protection from ischemic damage.
Treatment with an mGlu2 negative allosteric modulator (NAM) was highly neuroprotective, while treatment with an mGlu2 PAM increased neuronal damage in the CA1 region and caused neuronal death in CA3 region. Therefore, mGlu2 NAMs may be useful in the treatment of hypovolemic shock, cardiac arrest, severe hypotension or other pathologies that damage vulnerable hippocampal neurons.
- Spampinato, S. F., Merlo, S., Chisari, M., Nicoletti, F. & Sortino, M. A. Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes. Front. Cell. Neurosci. 8, 462 (2015).
- Shin, S. et al. mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress. Nat. Neurosci. 18, 1017–1024 (2015).
- Motolese, M. et al. Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage. Mol. Brain 8, 66 (2015).
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