GLUTAMATE SCAVENGING RESTORES GLUTAMATE HOMEOSTASIS AND PREVENTS CELL DEATH IN MURINE NEUROINFLAMMATION

Glutamate excitotoxicity is a pathological hallmark of many neurological disease. However, therapeutic approaches often interfere with glutamate receptor signaling, leading to a variety of side effects. Our aim is to investigate the beneficial effects of Glutamate scavenging in a mouse model of Multiple sclerosis (MS), primarily focusing on neuronal cell death.
Therefore, BL6 mice were subjected to Experimental autoimmune encephalomyelitis (EAE), the mouse model of Multiple sclerosis. Mice were treated with PBS or a combination of Glutamate-oxaloacetate transaminase (GOT) and Oxaloacetate (OxAc). By lowering blood glutamate levels, these substances can reduce excess extracellular glutamate in the brain. This approach is referred to as glutamate scavenging. To verify the efficiency of the substances, we analyzed glutamate concentrations in serum and cerebrospinal fluid samples, using an enzymatic assay. In addition, we removed the central nervous system and performed western blot and histological analysis to investigate the regulation of different cell death pathways. Furthermore, Neurofilament light chain (NFL) levels were analyzed in serum samples.
Our findings show that Glutamate scavenging improves the clinical score in EAE animals. This improvement is accompanied by a decrease of cell death markers in GOT/OxAc treated animals compared to control animals. In addition, treated animals show a reduction of serum glutamate and a lower concentration of serum NFL levels, indicating a decrease of neuronal cell death.
Our results underline that glutamate excitotoxicity is a primary contributor to disease progression in the mouse model of MS. Diminishing glutamate excitotoxicity with glutamate scavenging improves clinical symptoms and reduces neurodegeneration.