We have previously demonstrated the therapeutic potential of inducing a humoral response with autoantibodies to the N-methyl D-aspartate (NMDA) receptor using a genetic approach. In this study, we generated three recombinant proteins to different functional domains of the NMDA receptor, which is implicated in mediating brain tolerance, specifically NR1[21–375], NR1[313–619], NR1[654–800], and an intracellular scaffolding protein, Homer1a, with a similar anatomical expression pattern. All peptides showed similar antigenicity and antibody titers following systemic vaccination, and all animals thrived. Two months following vaccination, rats were administered the potent neurotoxin, kainic acid. NR1[21–375] animals showed an antiepileptic phenotype but no neuroprotection. Remarkably, despite ineffective antiepileptic activity, 6 of 7 seizing NR1[654–800] rats showed absolutely no injury with only minimal changes in the remaining animal, whereas the majority of persistently seizing rats in the other groups showed moderate to severe hippocampal injury. CREB, BDNF, and HSP70, proteins associated with preconditioning, were selectively upregulated in the hippocampus of NR1[654–800] animals, consistent with the observed neuroprotective phenotype. These results identify NR1 epitopes important in conferring anticonvulsive and neuroprotective effects and support the concept of an immunological strategy to induce a chronic state of tolerance in the brain. 1. Introduction The N-methyl D-aspartate (NMDA) receptors are one of the major subclasses of glutamatergic receptors that have critical roles in normal physiological processes such as neuronal proliferation [1], migration [2], and plasticity [3], as well as in pathological conditions, such as epilepsy and neurodegeneration [4, 5]. Following observations indicating NMDA receptor as an important mediator of glutamate-induced excitotoxicity [6] and that excessive NDMA receptor activation contributes to neuronal death in both acute trauma and chronic neurodegenerative diseases [7, 8], intense research was directed to develop NMDA receptor antagonists as neuroprotective agents. However, despite the wealth of preclinical studies demonstrating the therapeutic efficacy of NMDA receptor antagonists in various animal models of neurological disorders, most of these antagonists failed to produce positive results in clinical trials [9]. One of the reasons underlying the poor outcome of these clinical trials was the early termination and failure to reach therapeutic doses due to significant adverse effects by the antagonists [10].
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