Targeting the interaction of GABA B receptors with CaMKII with an interfering peptide restores receptor expression after cerebral ischemia and inhibits progressive neuronal death in mouse brain cells and slices.

Autor: Balakrishnan K; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland., Hleihil M; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland., Bhat MA; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland., Ganley RP; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland., Vaas M; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland., Klohs J; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.; Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland., Zeilhofer HU; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.; Drug Discovery Network Zurich, Zurich, Switzerland.; Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland., Benke D; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.; Drug Discovery Network Zurich, Zurich, Switzerland.
Jazyk: angličtina
Zdroj: Brain pathology (Zurich, Switzerland) [Brain Pathol] 2023 Jan; Vol. 33 (1), pp. e13099. Date of Electronic Publication: 2022 Jun 13.
DOI: 10.1111/bpa.13099
Abstrakt: Cerebral ischemia is the leading cause for long-term disability and mortality in adults due to massive neuronal death. Currently, there is no pharmacological treatment available to limit progressive neuronal death after stroke. A major mechanism causing ischemia-induced neuronal death is the excessive release of glutamate and the associated overexcitation of neurons (excitotoxicity). Normally, GABA B receptors control neuronal excitability in the brain via prolonged inhibition. However, excitotoxic conditions rapidly downregulate GABA B receptors via a CaMKII-mediated mechanism and thereby diminish adequate inhibition that could counteract neuronal overexcitation and neuronal death. To prevent the deleterious downregulation of GABA B receptors, we developed a cell-penetrating synthetic peptide (R1-Pep) that inhibits the interaction of GABA B receptors with CaMKII. Administration of this peptide to cultured cortical neurons exposed to excitotoxic conditions restored cell surface expression and function of GABA B receptors. R1-Pep did not affect CaMKII expression or activity but prevented its T286 autophosphorylation that renders it autonomously and persistently active. Moreover, R1-Pep counteracted the aberrant downregulation of G protein-coupled inwardly rectifying K + channels and the upregulation of N-type voltage-gated Ca 2+ channels, the main effectors of GABA B receptors. The restoration of GABA B receptors activated the Akt survival pathway and inhibited excitotoxic neuronal death with a wide time window in cultured neurons. Restoration of GABA B receptors and neuroprotective activity of R1-Pep was verified by using brain slices prepared from mice after middle cerebral artery occlusion (MCAO). Treatment with R1-Pep restored normal GABA B receptor expression and GABA receptor-mediated K + channel currents. This reduced MCAO-induced neuronal excitability and inhibited neuronal death. These results support the hypothesis that restoration of GABA B receptor expression under excitatory conditions provides neuroprotection and might be the basis for the development of a selective intervention to inhibit progressive neuronal death after ischemic stroke.
(© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)
Databáze: MEDLINE
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