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Allosteric Modulation of NMDARs Reverses Patients' Autoantibody Effects in Mice
Marija Radosevic1, Jesús Planagumà1, Francesco Mannara1
1From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M.R., J.P., F.M., A.M., E.A., L.S., J.L., A.G.-S., E.M., X.G., J.D.), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Laboratori de Neurofisiologia (X.G.), Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Sage Therapeutics (M.L.), Department of Research and Nonclinical Development, Cambridge, MA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, PA; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (J.D.), Madrid, Spain; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.
An analog of a cholesterol metabolite, SGE-301, reversed memory and synaptic deficits in an animal model of anti-NMDAR encephalitis. This suggests SGE-301 as a potential treatment for anti-NMDAR encephalitis.
Area of Science:
- Neuroscience
- Neuroimmunology
- Pharmacology
Background:
- Anti-NMDAR encephalitis causes memory and synaptic deficits.
- 24(S)-hydroxycholesterol is a brain cholesterol metabolite and NMDA receptor modulator.
- SGE-301 is a synthetic analog and positive allosteric modulator (PAM) of NMDA receptors (NMDARs).
Purpose of the Study:
- To investigate if SGE-301 can reverse memory and synaptic alterations induced by patient CSF in an animal model.
- To evaluate SGE-301's efficacy in a passive transfer model of anti-NMDAR encephalitis.
Main Methods:
- Mice received patient or control CSF via cerebroventricular pumps.
- Mice were treated with SGE-301 or vehicle.
- Assessed visuospatial memory, locomotor activity, NMDAR cluster density, LTP, and PPF.
Main Results:
- Patient CSF induced memory deficits, reduced NMDAR clusters, and impaired LTP.
- SGE-301 treatment reversed these deficits in memory, NMDAR clusters, and LTP.
- All measured parameters returned to control levels by day 26.
Conclusions:
- SGE-301, an oxysterol-based NMDAR PAM, effectively reverses synaptic and memory deficits in an anti-NMDAR encephalitis model.
- These findings support SGE-301 as a potential adjuvant therapy for anti-NMDAR encephalitis.
- Further clinical evaluation of SGE-301 is warranted.
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