Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors

Abstract

Astrocytes are well known to play critical roles in the development and maintenance of the central nervous system (CNS). Moreover, recent reports indicate that these cells are heterogeneous with respect to the molecules they express and the functions they exhibit in the quiescent or activated state. Because astrocytes also contribute to pathology, promising new results raise the possibility of manipulating specific astroglial populations for therapeutic roles. In this mini-review, we highlight the function of metabotropic glutamate receptors (mGluRs), in particular mGluR3 and mGluR5, in reactive astrocytes and relate these to three degenerative CNS diseases: multiple sclerosis, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Previous studies demonstrate that effects of these receptors may be beneficial, but this varies depending on the subtype of receptor, the state of the astrocytes, and the specific disease to which they are exposed. Elucidating the role of mGluRs on astrocytes at specific times during development and disease will provide novel insights in understanding how to best use these to serve as therapeutic targets.

20-HETE Enzymes and Receptors in the Neurovascular Unit: Implications in Cerebrovascular Disease

“…Additionally, astrogliosis in the hippocampus caused by arterial hypertension, ischemic stroke, and Alzheimer's disease may lead to pathologic increases in 20-HETE levels exacerbating hypoxic states, inducing ROS and thus prolonging recovery. Targeting astrocytes in Alzheimer's disease and cerebrovascular disorders is becoming an emerging topic of interest ( 69 , 70 ). Therefore, inhibition of astrocyte-derived 20-HETE production or blockade of GPR75 on VSMCs and pericytes may be an attractive therapeutic target for future intervention.…”

Targeting neuroprotective functions of astrocytes in neuroimmune diseases

“…It is noteworthy that in some cases the potential beneficial effects of the neuroprotective agents on astrocytes are mediated by their action on microglia, as demonstrated for GLP1R agonists [14] and αB-crystallin [19]. Designing astrocyte-specific pharmacological agents that do not affect other CNS cell types is a significant challenge for not only neuroimmunomodulators but also for other classes of drugs with potential neuroprotective properties that target astrocytes, such as ligands of neurotransmitter and growth factor receptors, and inhibitors of transcription factors [3,9,33]. Therefore, preclinical studies should assess effects of such agents on all types of glial cells, as well as neurons.…”

Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease

“…As G-protein coupled receptors (GPCRs), they are categorized into three groups based on the signal transduction pathways and pharmacological profiles [ 95 ]. Group I contains mGluR1 and mGluR5, Gq-coupled receptors, resulting in the activation of phospholipase C (PLC), hydrolysis of phosphoinositides, release of calcium, and activation of protein kinase C (PKC) [ 96 ]. Group II (mGluR2, 3) and Group III (mGluR4, 6, 7, 8) are all Gi-coupled receptors, which are negatively coupled to adenylate cyclase [ 97 ] ( Table 1 ).…”

“…In the case of mGluR5, the intracellular signaling can regulate IP3-dependent calcium entry, increasing glutamate release from the astrocytes, which strengthens tripartite synapse consolidation in the hippocampus [ 102 ]. Even though the in vivo studies of mGluRs in AD are quite limited, it is interesting to note that Aβ increases expression of mGluR5 in an AD model [ 96 ]. mGluR3 and mGluR5 in A2 astrocytes can also increase synthesis and release of BDNF, which is a ubiquitous neurotrophic factor with a major role in neuronal plasticity, synapse formation, and long-term potentiation [ 103 ].…”