GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes

Abstract

Oligodendrocytes are the myelin forming cells of the central nervous system, and their vulnerability to excitotoxicity induced by glutamate contributes to the pathogenesis of neurological disorders including brain ischemia and neurodegenerative diseases, such as multiple sclerosis. In addition to glutamate receptors, oligodendrocytes express GABA receptors (GABAR) that are involved in their survival and differentiation. The interactions between glutamate and GABAergic systems are well documented in neurons, under both physiological and pathological conditions, but this potential crosstalk in oligodendrocytes has not been studied in depth. Here, we evaluated the protective effect of GABAR agonists, baclofen (GABAB) and muscimol (GABAA), against AMPA-induced excitotoxicity in cultured rat oligodendrocytes. First, we observed that both baclofen and muscimol reduced cell death and caspase-3 activation after AMPA insult, proving their oligoprotective potential. Interestingly, analysis of the cell-surface expression of calcium-impermeable GluR2 subunits in oligodendrocytes revealed that GABAergic agonists significantly reverted GluR2 internalization induced by AMPA. We determined that baclofen and muscimol also impaired AMPA-induced intracellular calcium increase and subsequent mitochondrial membrane potential alteration, ROS generation, and calpain activation. However, AMPA-triggered activation of Src, Akt, JNK and CREB was not affected by baclofen or muscimol. Overall, our results suggest that GABAR activation initiates alternative molecular mechanisms that attenuate AMPA-mediated apoptotic excitotoxicity in oligodendrocytes by interfering with expression of GluR subunits in membranes and with calcium-dependent intracellular signaling pathways. Together, these findings provide evidence of GABAR agonists as potential oligodendroglial protectants in central nervous system disorders.

Quinolinic acid links kidney injury to brain toxicity

“…QA interacts with NMDA receptors, competing with glutamate and contributes to excitotoxicity and neuronal damage (21, 33–36). Moreover, our finding of decreased GABA levels in the brain cortex is consistent with other studies showing GABA as a suppressor of inflammation and excitotoxic damage (37, 38) and its decrease in the brain is associated with various neurological disorders (39, 40)…”

“…QA interacts with NMDA receptors, competing with glutamate and contributes to excitotoxicity and neuronal damage (21,(33)(34)(35)(36). Moreover, our finding of decreased GABA levels in the brain cortex is consistent with other studies showing GABA as a suppressor of inflammation and excitotoxic damage (37,38) and its decrease in the brain is associated with various neurological disorders (39,40) Our novel spatial metabolomics approach overlaying MALDI-MSI ion images to post-MALDI H&E-stained brain tissue evealed an interesting pattern wherein QA colocalized with ependymal cells in one of the MDM2cKO brains. Ependymal cells are glial cells that line the cerebral ventricles and secrete and circulate CSF.…”

Mitochondrial Dysfunction as the Major Basis of Brain Aging

“…Inhibition of calpain diminishes microglial and astroglial responsivity and reduces the extent of the neuropathological changes and behavioral decline of aged transgenic mice modeling Alzheimer's disease [18][19][20] and Parkinson's disease [21,22]. Glutamate receptors that respond to excess activation are also found in oligodendrocytes which can be damaged by excitotoxic events [23]. NMDA receptor stimulation also induces activation of NADPH oxidase 2, a magnitude relation enzyme that leads to production of reactive oxygen species which can harm surrounding cells [24].…”

The Effect of Oral GABA on the Nervous System: Potential for Therapeutic Intervention

“…These cells are exceptionally vulnerable to excitotoxicity triggered by glutamate, leading to their dysfunction and cell death. Glutamate overactivation primarily targets ionotropic glutamate receptors, such as AMPA and kainate receptors, in oligodendrocytes, resulting in sustained calcium influx that disrupts mitochondrial function, triggering the generation of reactive oxygen species (ROS) and initiating apoptotic pathways ultimately leading to oligodendroglia and neuronal death [63] (Figure 2).…”