Autoantibodies to NR2A Peptide of the Glutamate/NMDA Receptor in Patients with Seizure Disorders in Neuropsychiatric Systemic Lupus Erythematosus

Objective. Seizure disorders are one of the most disabling, life-threatening, and the least understood syndromes associated with neuropsychiatric SLE (NPSLE). N-Methyl-D-aspartate (NMDA) receptors are a subgroup of the glutamate receptor family, whose NR2A subunit was found on neuronal cells (anti-NR2A) in NPSLE patients with different types of epilepsy. The present study was conducted to determine the serum levels of anti-NR2A antibodies in a large group of SLE patients, to investigate the possible correlation between the presence of the NR2A specific antibodies and NPSLE-related seizure disorders.Methods and Results. The study population consisted of 107 SLE patients and 43 age- and sex-matched healthy controls. 73 SLE patients had active disease. 36 of these had NPSLE. NMDA levels were measured by ELISA. Clinical and serological parameters were assessed according to routine procedures. The levels of anti-NR2A antibodies were significantly higher in NPSLE patients, compared with non-NPSLE patients and healthy controls. Furthermore, the levels of NPSLE in patients with seizure disorders were shown to be higher than in those with cognitive dysfunction and other CNS symptoms, however, without significance. Increase in serum anti-NR2A antibodies levels correlated to anti-dsDNA antibody and SLEDAI as well as complement levels.Conclusion. We suggest that anti-NR2A antibodies play a role in the pathogenesis of NPSLE with seizure disorders.

AMPA Ionotropic Glutamate Receptors Pathogenesis Symptomatic Epilepsy in Gliomas of the Cerebral Hemispheres

The purpose of the research is to study the role of AMPA receptors of glutamate in the mechanisms of the development of epi-lepsy in the patients with gliomas of the big hemispheres of a brain. Materials and methods: 92 patients with gliomas of the big hemispheres of a brain have been examined. Immune enzyme method of semi-quantitative determination of the level of auto-antibodies to NR2A subunit of NMDA and GluR1 subunit of AMPA receptors of glutamate was used. Results: The frequency and clinical features of symptomatic epilepsy have been studied. The reaction of NMDA and of AMPA receptors of glutamate depending on localization and degree of malignance and features of clinical course of the disease, have been examined. Conclusion: A high-technology of patho-morphological research of brain tumors made in recent years has revealed that glial tumors start releasing glutamate by themselves, as their anaplasia level increases, which causes exitotoxical effect in anatomical lines of peritumoral area. Such blastomastoma growth features form specificity of clinical aspect of disease, including epileptic syndrome. It is shown dominative increase the level of auto-antibodies to GluR1 subunit of AMPA receptors of glutamate in the patients with gliomas, current with epileptic syndrome. Under the effect of the tumor on the frontal and temporal share the maximum level of autoantibodies, mainly to GluR1 subunit of AMPA receptors of glutamate is registered.

Аlterationdegree of NMDA and AMPA receptors of glutamate in the pathogenesis of the disease and technological peculiarities of surgical treatment of the hemispheric glioma-swith the epileptic syndrome

The development of effective approaches to the treatment of patients with symptomatic tumor epilepsy was determined by the level of our fundamental knowledge of the basic mechanisms of epileptogenesis on cellular and molecular level. 92 patients with gliomas of the cerebral hemisphereswere examined. Immunoenzyme method ofsemiquantitative determination of the level of autoantibodies to NR2A subunit of NMDA and GluR1 subunit of AMPA receptors of glutamate was used. The reaction of NMDA and AMPA glutamate receptors depending on the availability of an epileptic syndrome in the clinical picture of the disease and the extent of radical surgery has been studied. Pre-emptive increase of the level of autoantibodies to GluR1 subunit of AMPA receptors of glutamate in patients with hemispheric gliomaswith epileptic syndrome was demonstrated. It was foundonly the total removal of the tumor reduced significantly the level of autoantibodies to ionotropic glutamate receptors.

Identification of an N-Methyl-d-aspartate Receptor in Isolated Nervous System Mitochondria

NMDA ionotropic glutamate receptors gate the cytoplasmic influx of calcium, which may, depending on the intensity of the stimulus, subserve either normal synaptic communication or cell death. We demonstrate that when isolated mitochondria are exposed to calcium and NMDA agonists, there is a significant increase in mitochondrial calcium levels. The agonist/antagonist response studies on purified mitochondria suggest the presence of a receptor on mitochondria with features similar to plasma membrane NMDA receptors. Immunogold electron microscopy of hippocampal tissue sections revealed extensive localization of NR2a subunit immunoreactivity on mitochondria. Transient transfection of neuronal GT1-7 cells with an NR1-NR2a NMDA receptor subunit cassette specifically targeting mitochondria resulted in a significant increase in mitochondrial calcium and neuroprotection against glutamate-induced cell death. Mitochondria prepared from GT1-7 cells in which the NR1 subunit of NMDA receptors was silenced demonstrated a decrease in calcium uptake. Our findings are the first to demonstrate that mitochondria express a calcium transport protein that shares characteristics with the NMDA receptor and may play a neuroprotective role.