Changes of Glycine-Aspartate Metabolism at Glutamatergic Synapses in Multiple Sclerosis: Evidence from Cerebrospinal Fluid

Metabolic changes and rearrangements of inhibitory/excitatory neurotransmitters identified since the early stages of multiple sclerosis (MS) [1] are associated with axonal loss and synaptic dysfunction at advanced stages [2]. The aim of this study was to identify a combination of biomarkers that would help to monitor MS progression at more advanced stages [3].

CSF levels of some neurotransmitters (glutamate-Glu, aspartate-Asp, glycine-Gly, GABA) in combination with markers of lipid peroxidation (MDA, 8-iso-PGF2α), the total antioxidant capacity (TAS), and specific neuronal damage (NSE) were determined in patients with MS (n=85; of which 76 had RR-MS, 9 had SP-MS), non-neurological controls (CG; n=26) and other neurological diagnoses (ONDs; n=31). The RP-HPLC method was used for the determination of neurotransmitters [4] and MDA [5]; F2-isoprostanes and NSE were determined by ELISA; TAS was determined colorimetrically [6].

Significantly higher concentrations of Gly (1.60 µmol/l vs 0.96 µmol/l p=0.0104) and Asp (0.16 µmol/l vs 0.026 µmol/l p=0.0333) in the whole cohort of MS and RR-MS patients compared to the CG and ONDs were found. Glu levels were higher in the total MS and RR subtype than in the CG (0.089 µmol/l vs 0.038 µmol/l p=0.0689; p=0.0616). Asp levels were significantly increased in EDSS≤3 compared to EDSS>3. Furthermore, Gly negatively correlated with NSE in MS and RR-MS, and positively correlated with TAS in CG. Glu levels positively correlated with 8-iso-PGF2α in MS and RR-MS.

Our results show that CSF levels of some of the studied neurotransmitters have the potential to be used as biomarkers monitoring the course of a specific pathological process in MS - Asp as an indicator of oxidative stress-induced metabolic changes in glutamatergic synapses of demyelinating lesions; Gly has potential as a cytoprotectant and immunosuppressant in the processes of remyelination [7,8].