Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission.
Por:
Santos-Gómez A, Julià-Palacios NA, Rejano-Bosch A, Marí-Vico R, Miguez-Cabello F, Masana M, Soto D, Olivella M, Garcia-Cazorla A and Altafaj X
Publicada:
1 mar 2025
Resumen:
GRIN-related disorders (GRD) developmental and epileptic encephalopathies (DEEs) display a clinical spectrum including developmental delay, hypotonia, intellectual disability, epilepsy, and autistic traits. The presence of de novo pathogenic variants in the GRIN genes alters the N-methyl D-aspartate receptor (NMDAR) function, with a genotype-phenotype relationship. Despite recent advances to elucidate GRD pathophysiological mechanisms and to find treatments, to date, GRD therapeutic arms are still scarce and with limited efficacy. Herein, we investigated whether the natural polyamine spermine-positive allosteric modulators of GluN2B subunit-containing NMDARs-or its precursor spermidine might rescue NMDAR hypofunctionality. In heterologous cell systems, administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits. Functionally, the putative therapeutic benefit of spermidine (spermine precursor) was assessed in constitutive Grin2b(+/-) heterozygous mice, a GRIN2B-LoF genetic murine model recapitulating GRD-like synaptic, motor, and cognitive alterations. Chronic spermidine administration in young adult Grin2b(+/-) mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of Grin2b(+/-) mice, supporting the cognitive improvement observed in behavioral phenotyping. Based on these preclinical findings, a case study was conducted in two pediatric patients harboring mild GRIN2B-LoF variants. Importantly, in line with preclinical findings, 18 months of spermidine treatment resulted in the amelioration of adaptive behavior (notably in the younger treated patient), with the absence of noticeable side effects. Overall, our findings provide both preclinical and clinical data supporting the benefit of spermidine for the treatment of GRD in individuals harboring GRIN2B-LoF variants.
Filiaciones:
Santos-Gómez A:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
Julià-Palacios NA:
Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu-CIBERER, Barcelona, Spain
Rejano-Bosch A:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
Marí-Vico R:
Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu-CIBERER, Barcelona, Spain
Miguez-Cabello F:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
Masana M:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Soto D:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
Olivella M:
Bioinformatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Vic, Spain
Institute for Research and Innovation in Life and Health Sciences (IRIS-CC), University of Vic-Central University of Catalonia, Vic, Spain
Garcia-Cazorla A:
Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu-CIBERER, Barcelona, Spain
Altafaj X:
Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain
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