Abstract
N-methyl-D-aspartate receptors (NMDAR) play a key role in brain development and function, including contributing to the pathogenesis of many neurological disorders. Immunization against the GluN1 subunit of the NMDAR and the production of GluN1 antibodies is associated with neuroprotective and seizure-protective effects in rodent models of stroke and epilepsy, respectively. Whilst these data suggest the potential for the development of GluN1 antibody therapy, paradoxically GluN1 autoantibodies in humans are associated with the pathogenesis of the autoimmune disease anti-NMDA receptor encephalitis. This review discusses possible reasons for the differential effects of GluN1 antibodies on NMDAR physiology that could contribute to these phenotypes.
Highlights
Antibody-based immunotherapies form a key component of the pharmacological arsenal for treatment of cancer [1], and inflammatory diseases [2], with profound clinical success achieved for these conditions
I will provide an overview of our studies and those of others exploring the possibility of an immunoprotective approach for neurological diseases including stroke and epilepsy involving antibody-mediated targeting of the N-methyl-D-aspartate (NMDAR) subclass of glutamate receptor
Expression of heat shock protein 70 (HSP70) and brain-derived neurotrophic factor (BDNF) protein were elevated by ∼1.5-fold in the brains of the GluN1[654–800]-vaccinated animals that were protected against neuronal cell death compared to the control animals suggesting that GluN1 antibody-mediated effects at NMDAR leads to downstream upregulation of signaling pathways linked to cell survival
Summary
Antibody-based immunotherapies form a key component of the pharmacological arsenal for treatment of cancer [1], and inflammatory diseases [2], with profound clinical success achieved for these conditions. The pipeline of immunotherapies for central nervous system disorders is not as extensive and has largely been dominated by active or passive immunization approaches for Alzheimer’s disease and Parkinson’s disease that aim to modify disease progression by targeting proteins implicated in disease pathogenesis [3]. The potential of antibodies to modulate the function of other molecular targets in the central nervous system (CNS) for therapeutic benefit has not been extensively investigated. I will provide an overview of our studies and those of others exploring the possibility of an immunoprotective approach for neurological diseases including stroke and epilepsy involving antibody-mediated targeting of the N-methyl-D-aspartate (NMDAR) subclass of glutamate receptor
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