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
AUTHORS (11)
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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