cell death pathways, respectively has contributed to ongoing efforts to develop subunit-selective NMDAR antagonists

cell death pathways, respectively has contributed to ongoing efforts to develop subunit-selective NMDAR antagonists. conditions. Monoclonal antibody therapies have several desirable attributes over traditional small molecule drugs including long half-lives and high specificity for 1-Methyladenosine the target molecular disease driver leading to reduced off-target 1-Methyladenosine toxicity and a lower adverse effect profile. 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 1-Methyladenosine proteins implicated in disease pathogenesis (3). Different strategies have been employed including using antibodies to neutralize the actions of putative neurotoxic protein species or to promote clearance of the offending disease protein. Clinical trials have shown some promise (4), but much work is still required to improve the therapeutic efficacy of these approaches. 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. In this review, 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. == The NMDA Receptor == The NMDAR plays a pivotal role in brain development, neuronal survival, and synaptic plasticity associated with learning and memory. The receptor is a hetero-tetramer composed of two obligatory GluN1 subunits of which there are eight distinct splice variants, and two variable subunits from the GluN2 (GluN2A-2D) or GluN3 (GluN3A-3B) subunit families. The combination of GluN1 Mouse monoclonal to Flag Tag.FLAG tag Mouse mAb is part of the series of Tag antibodies, the excellent quality in the research. FLAG tag antibody is a highly sensitive and affinity PAB applicable to FLAG tagged fusion protein detection. FLAG tag antibody can detect FLAG tags in internal, C terminal, or N terminal recombinant proteins with different GluN2/3 family members provides for the creation of diverse NMDAR subtypes varying in their regional distribution and functional properties. The majority of native NMDAR are triheteromeric, with GluN1/GluN2A/GluN2B receptors being the most common subtype in forebrain excitatory neurons (5). The subunits are transmembrane-spanning and arranged to form an ion channel pore that is gated in a ligand- and voltage-dependent manner. The extracellular regions of the receptor resembling two clamshell structures with binding sites for glutamate on the GluN2 subunit and sites for glycine binding on the GluN1 subunit. The interaction between the distal amino terminal domain (ATD) of the receptor and other proteins regulate subtype-specific receptor assembly and receptor trafficking and sites for allosteric modulation of NMDAR function are also found in the ATD. The cytoplasmic C-terminus domain engages in interactions with scaffold proteins and intracellular messenger systems in the postsynaptic density. The importance of NMDAR in the maintenance of physiological brain function is underpinned by observations that NMDAR-mediated hypofunction caused by either receptor loss, or altered distribution at synapses, is implicated in neurodevelopmental (autism spectrum disorders) (6) and neuropsychiatric disorders (schizophrenia) (7). Moreover, excessive glutamate release that leads to NMDAR overactivation contributes to neurodegeneration in acute or chronic neurodegenerative diseases including Alzheimer’s disease (8,9). The centrality of the NMDAR in the pathophysiology of a broad range of conditions makes these receptors an attractive drug target but human trials of NMDAR antagonists of different compound classes and at different sites of receptor action have been disappointing and are associated with a narrow therapeutic index and an unacceptable adverse effect profile (10). Greater insight into NMDAR function, and the discovery that synaptic and extrasynaptic NMDAR may be differentially linked to cell survival vs. cell death pathways, respectively has contributed to ongoing efforts to develop subunit-selective NMDAR antagonists. Weaker GluN2B-selective blockers that may preferentially target extrasynaptic NMDAR have a much-improved side-effect profile in humans than early generation broad spectrum antagonists (11)..