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Currently, there is no pharmacological treatment available to limit progressive neuronal death after stroke. A major mechanism causing ischemia\u2010induced neuronal death is the excessive release of glutamate and the associated overexcitation of neurons (excitotoxicity). Normally, GABA<jats:sub>B<\/jats:sub> receptors control neuronal excitability in the brain via prolonged inhibition. However, excitotoxic conditions rapidly downregulate GABA<jats:sub>B<\/jats:sub> receptors via a CaMKII\u2010mediated mechanism and thereby diminish adequate inhibition that could counteract neuronal overexcitation and neuronal death. To prevent the deleterious downregulation of GABA<jats:sub>B<\/jats:sub> receptors, we developed a cell\u2010penetrating synthetic peptide (R1\u2010Pep) that inhibits the interaction of GABA<jats:sub>B<\/jats:sub> receptors with CaMKII. Administration of this peptide to cultured cortical neurons exposed to excitotoxic conditions restored cell surface expression and function of GABA<jats:sub>B<\/jats:sub> receptors. R1\u2010Pep did not affect CaMKII expression or activity but prevented its T286 autophosphorylation that renders it autonomously and persistently active. Moreover, R1\u2010Pep counteracted the aberrant downregulation of G protein\u2010coupled inwardly rectifying K<jats:sup>+<\/jats:sup> channels and the upregulation of N\u2010type voltage\u2010gated Ca<jats:sup>2+<\/jats:sup> channels, the main effectors of GABA<jats:sub>B<\/jats:sub> receptors. The restoration of GABA<jats:sub>B<\/jats:sub> receptors activated the Akt survival pathway and inhibited excitotoxic neuronal death with a wide time window in cultured neurons. Restoration of GABA<jats:sub>B<\/jats:sub> receptors and neuroprotective activity of R1\u2010Pep was verified by using brain slices prepared from mice after middle cerebral artery occlusion (MCAO). Treatment with R1\u2010Pep restored normal GABA<jats:sub>B<\/jats:sub> receptor expression and GABA receptor\u2010mediated K<jats:sup>+<\/jats:sup> channel currents. This reduced MCAO\u2010induced neuronal excitability and inhibited neuronal death. These results support the hypothesis that restoration of GABA<jats:sub>B<\/jats:sub> 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.<\/jats:p>","DOI":"10.1111\/bpa.13099","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T03:07:38Z","timestamp":1655176058000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Targeting the interaction of GABA<sub>B<\/sub> receptors with CaMKII with an interfering peptide restores receptor expression after cerebral ischemia and inhibits progressive neuronal death in mouse brain cells and slices"],"prefix":"10.1111","volume":"33","author":[{"given":"Karthik","family":"Balakrishnan","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich  Zurich 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