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GLP-1 directed NMDA receptor antagonism for obesity treatment

ABSTRACT: The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Roger Moreno Justicia

LAB HEAD: Atul Deshmukh

PROVIDER: PXD045816 | Pride | 2024-04-26

REPOSITORIES: Pride

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NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine

Project description:Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models amenable for studying the neurobiology of schizophrenia may contribute to fill the gaps led by the widely employed animal models. Here we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to resective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass- spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia.

2024-02-06 | PXD046944 | Pride

Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK801-Exposed C57BL/6 Mice.

Project description:MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia(SCZ). However, the effects of MK-801 treatment on gene expression in prefrontal cortex (PFC) are largely unknown. We have established MK-801 animal models to explore the etiology and pathophysiology of schizophrenia. Transcriptome analysis of the prefrontal cortex reveals that the differentially expressed genes mainly aggregate in chemical synaptic transmission and immune system process. Gene association patterns which are involved in synaptic vesicle cycle and mitochondrial electron transport chain have also been altered. Together, these observations underscore that dysfunction in glutamatergic synaptic vesicle cycle and mitochondrial electron transport chain has an impact on the pathogenesis of SCZ.

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Investigating the Succinylome and Malonylome of Schizophrenia

Project description:The succinylome and malonylome of human oligodendrocyte precursors (MO3.13 line) and postmortem brain tissue (whole lysates and mitochondrial enrichments) were studied with shotgun mass spectrometry. The goal was to determine what changes in oligodendrocytes are induced with the addition of the NMDA receptor antagonist MK-801 and compare this with schizophrenia brain tissue; to visualize the changes that antipsychotics have on the succinylome and malonylome and how this may relate to their side effects; to see what changes induced by MK-801 are returned to more control-like levels and how this may relate to mechanisms of drug action; and to see what changes in these PTMs may exist in vivo in patients with schizophrenia compared to healthy controls.

2022-10-13 | PXD014188 | Pride

Investigating the Succinylome and Malonylome of Schizophrenia

2022-08-11 | PXD014149 | Pride

Effects of the Co-Administration of MK-801 and Clozapine on MiRNA Expression Profiles in Rats

Project description:Background: microRNAs (miRNAs) are small, non-coding RNAs, which can silence the expression of various target genes via binding their mRNAs, thus miRNAs serve and regulate a wide range of crucial functions in the body. However, the miRNAs expression profile after the antipsychotics mediation in schizophrenia is largely unknown. Methods: Noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonists like as MK-801 had been shown to provide a useful animal model to investigate these effects of schizophrenia-like symptoms in rodent animals. In this study, the rat hippocampal miRNA expression profiles were examined after the antipsychotic clozapine (CLO) treated the MK-801-pretreated Sprague Dawley rats. The total RNA samples from their hippocampus of three rat groups were sequenced using next generation sequencing (NGS), then processed bioinformatic analysis. Results: Successfully, we identified 8 miRNAs’ expressions were significantly different in the MK-801 group comparing the VEH control group. Interestingly, 14 miRNAs were largely changed expression in CLO+MK-80-treated group comparing the MK-801-pretreated group, in which the rno-miR-184 was up-regulated significantly. Subsequently, further analyses suggested these miRNAs could modulate their target genes involving in the regulation of endocytosis, ubiquitin mediated proteolysis and regulation of actin cytoskeleton, which might be involved in the important mechanism of schizophrenia. Conclusion: Our results suggested the altered miRNA expressions might play an important role in the complex pathophysiology of schizophrenia, and subsequently impacted on brain functions.

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Project description:Aminoglycosides remain in current use because of the benefits, including the broad-spectrum, inexpensiveness to produce, and a relatively small incidence of allergic reactions. However, aminoglycosides may induce irreversible hearing loss. Recently, tacrine, an acetylcholineesterase inhibitor originally developed to treat Alzheimer’s disease, was found to be protective to neomycin-induced hair cell damage in zebrafish and mouse. However, the protection mechanism remain to be largely unknown. In this study, we revealed that tacrine significantly suppressed the expression of tnf mRNA and ROS production induced by neomycin. Reduction of tnf expression by the antisense morpholino or transcription activator-like effectors nuclease significantly suppressed the hair cell damage but not ROS production induced by neomycin. In zebrafish treated with an antagonist of NMDA receptor MK-801 or a mitochondrial ROS inhibitor acetyl-L-carnitine, ROS production, tnf expression, and hair cell damage induced by neomycin were also significantly reduced. These levels of suppression were not significantly different from those of co-treatment of tacrine and MK-801 or acetyl-L-carnitine. These findings suggest that activation of NMDA receptor followed by ROS production and subsequent tnf expression are involved in neomycin-induced hair cell damage and that tacrine ameliorate neomycin-induced hair cell damage through inhibition of the signaling pathway.

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Effects of developmental N-Methyl D-aspartate (NMDA) receptor antagonism on adulthood hypothalamic gene expression in female C57Bl/6J mice.

Project description:AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. This data will compliment on-going studies into the effect of developmental NMDA receptor antagonism on aspects of the Hypothalamic-Pituitary-Adrenal (HPA) axis.

2019-12-13 | GSE108042 | GEO

Effects of developmental N-Methyl D-aspartate (NMDA) receptor antagonism on adulthood adrenal gene expression in female C57Bl/6J mice.

Project description:AIM: to examine changes in adrenal gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. This data will compliment on-going studies into the effect of developmental NMDA receptor antagonism on aspects of the Hypothalamic-Pituitary-Adrenal (HPA) axis.

2019-12-13 | GSE108032 | GEO

MK-DG vs MK C+S-DG

Project description:MK: MK-801. Young male C57BL/6J mice received an injection of MK-801 (300 micro-g per g body weight). RNA from control mice were extracted 1hr, 2hr, 4hr, and 6hr after MK experimental mice received their last shock treatment. MK C+S: MK-801 & Context + Shock: Young male C57BL/6J mice received an injection of MK-801 (300 micro-g per g body weight) 1 h prior to contextual fear conditioning that consisted of: Placement into a novel spatial context for 2 min. After 2 min, a 1 sec (0.5 mA) shock was administered through a floor grid. The 2 min-1 sec shock paradigm was repeated for a total of 3 shocks. 1 min after the last shock, animals were removed to their homecage. RNA was extracted 1hr, 2hr, 4hr, and 6hr after the last shock treatment. Keywords: time-course

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