PMID- 32830245 OWN - NLM STAT- MEDLINE DCOM- 20210216 LR - 20210216 IS - 1460-2156 (Electronic) IS - 0006-8950 (Linking) VI - 143 IP - 9 DP - 2020 Sep 1 TI - Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis. PG - 2709-2720 LID - 10.1093/brain/awaa195 [doi] AB - 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. CI - (c) The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Mannara, Francesco AU - Mannara F AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Radosevic, Marija AU - Radosevic M AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Planaguma, Jesus AU - Planaguma J AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Soto, David AU - Soto D AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. AD - Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. FAU - Aguilar, Esther AU - Aguilar E AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Garcia-Serra, Anna AU - Garcia-Serra A AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Maudes, Estibaliz AU - Maudes E AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Pedreno, Marta AU - Pedreno M AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Paul, Steven AU - Paul S AD - Sage Therapeutics, Cambridge, MA, USA. AD - Departments of Psychiatry and Neurology, Washington University School of Medicine, St Louis, USA. FAU - Doherty, James AU - Doherty J AD - Sage Therapeutics, Cambridge, MA, USA. FAU - Quirk, Michael AU - Quirk M AD - Sage Therapeutics, Cambridge, MA, USA. FAU - Dai, Jing AU - Dai J AD - Sage Therapeutics, Cambridge, MA, USA. FAU - Gasull, Xavier AU - Gasull X AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. AD - Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain. FAU - Lewis, Mike AU - Lewis M AD - Sage Therapeutics, Cambridge, MA, USA. FAU - Dalmau, Josep AU - Dalmau J AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. AD - Department of Neurology, University of Pennsylvania, Philadelphia, USA. AD - Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Autoantibodies) RN - 0 (Hydroxycholesterols) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Allosteric Regulation/drug effects/physiology MH - Animals MH - Anti-N-Methyl-D-Aspartate Receptor Encephalitis/*metabolism/*therapy MH - Autoantibodies/*administration & dosage/*cerebrospinal fluid MH - Cells, Cultured MH - HEK293 Cells MH - Hippocampus/drug effects/metabolism MH - Humans MH - Hydroxycholesterols/chemistry/pharmacology/therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Organ Culture Techniques MH - Receptors, N-Methyl-D-Aspartate/*metabolism OTO - NOTNLM OT - SGE-301 OT - animal model OT - anti-NMDAR encephalitis OT - treatment EDAT- 2020/08/25 06:00 MHDA- 2021/02/17 06:00 CRDT- 2020/08/25 06:00 PHST- 2019/12/05 00:00 [received] PHST- 2020/04/03 00:00 [revised] PHST- 2020/04/22 00:00 [accepted] PHST- 2020/08/25 06:00 [pubmed] PHST- 2021/02/17 06:00 [medline] PHST- 2020/08/25 06:00 [entrez] AID - 5896262 [pii] AID - 10.1093/brain/awaa195 [doi] PST - ppublish SO - Brain. 2020 Sep 1;143(9):2709-2720. doi: 10.1093/brain/awaa195.