Dissociation of nNOS from PSD‐95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes

0301 basic medicine 0303 health sciences Benzylamines GABA Plasma Membrane Transport Proteins Neuronal Plasticity Behavior, Animal Glutamate Decarboxylase Motor Cortex Nipecotic Acids Neural Inhibition Nitric Oxide Synthase Type I Anisoles Motor Activity Nitric Oxide Brain Ischemia Aminosalicylic Acids Disease Models, Animal 03 medical and health sciences Neuroprotective Agents 0302 clinical medicine Astrocytes Animals Disks Large Homolog 4 Protein Monoamine Oxidase
DOI: 10.1002/path.4999 Publication Date: 2017-10-20T13:30:12Z
ABSTRACT
Abstract Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential target, protein–protein interaction between neuronal nitric oxide synthase (nNOS) postsynaptic density protein 95 (PSD‐95), critical to acute ischaemic damage neurogenesis. We show that nNOS–PSD‐95 dissociation induced by microinjection of a recombinant fusion protein, Tat‐nNOS‐N 1–133 , or systemic administration small‐molecule, ZL006, from day 4 10 photothrombotic ischaemia in mice reduced excessive tonic inhibition peri‐infarct cortex ameliorated motor outcome. also demonstrated improved neuroplasticity including increased dendrite spine synaptogenesis reducing dissociation. Levels gamma‐aminobutyric acid (GABA) GABA transporter‐3/4 (GAT‐3/4) reactive astrocytes cortex. The GAT‐3/4‐selective antagonist SNAP‐5114 promoted function recovery, suggesting was due release reversed GAT‐3/4 astrocytes. Treatments with ZL006 inhibited astrocyte activation production, prevented reversal GAT‐3/4, consequently decreased molecular mechanisms were associated epigenetic glutamic decarboxylase 67 monoamine oxidase B expression through NO production. thus target for restoration small molecule inhibitor this interaction, promising pharmacological lead compound. Copyright © 2017 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.
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