Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis

Abstract

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients’ NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient’s CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients’ or controls’ CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient’s CSF antibodies, but not those infused with controls’ CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy

“…Positive Allosteric Modulation as a Therapeutic Strategy NMDAR antibodies binding in patients result in NMDAR loss and hypofunction. Preliminary work suggests that allosteric binding of compounds such as synthetic oxysterols to extracellular regulatory sites of the NMDAR (distinct from the agonist binding and channel permeating sites) can restore NMDAR function in cultured rat hippocampal neurons and prevent the pathogenic effects of NMDAR auto-antibodies in a mouse model, suggesting a potential new strategy to counteract abnormal NMDAR function (129).…”

In vivo NMDA receptor function in people with NMDA receptor antibody encephalitis

“…If validated in larger and longitudinal studies, [ 18 F]GE-179 PET could have the potential for tracking NMDAR function -the key predicted feature of disease activity -and guide accurate prognostication and escalation of immunotherapies or administration of NMDAR-active agents (23), in addition to providing novel insights into the principle biological disease mechanism.…”

Blocking Placental Class G Immunoglobulin Transfer Prevents NMDA Receptor Antibody Effects in Newborn Mice

“… 1 The absence of other brain-specific antibodies was established using previously reported experiments 13 , 22 in which patients' NMDAR antibodies were immunoabsorbed, resulting in abrogation of patients' IgG effects in cultured neurons. 23 …”

“…We recently reported this technique applied to the current model of placental transfer of NMDAR antibodies. 16 , 23 …”