Abstract: Although stroke is a major global health problem, a pharmacological treatment to inhibit ongoing neuronal death in patients is still lacking. In cerebral ischemia, the prevailing form of stroke, severely reduced blood supply by obstruction of blood vessels deprives neurons from oxygen and glucose, eventually leading to metabolic derailment and death of neurons in the affected brain area. Currently, the only available treatment for acute ischemic stroke is thrombolytic drugs (Alteplase, Tenecteplase) to break down blood clots to restore blood circulation and thrombectomy to mechanically remove the occlusion. Even after the successful restoration of blood flow, progressive neuronal death remains a major concern. One of the main causes for ongoing neuronal death is excitotoxicity induced by excessive glutamate release and overactivation of glutamate receptors resulting in chronic overexcitation of neurons (Choi, 2020). Under physiological conditions, neuronal excitability and elevated glutamate release are controlled by the heterodimeric G protein-coupled γ-aminobutyric acid type B (GABAB) receptors. However, under ischemic conditions, GABAB receptors are downregulated and can no longer counteract the overexcitation of neurons. Therefore, restoring GABAB receptor expression to normal levels after an ischemic insult is a promising strategy to limit overexcitation and the associated excitotoxic death of neurons. We recently showed that targeting protein-protein interactions involved in the aberrant downregulation of GABAB receptors with specific interfering peptides restored GABAB receptor expression, counteracted neuronal overexcitation, and provided neuroprotection with a potentially wide time window (Balakrishnan et al., 2022; Bhat et al., 2022; Hleihil et al., 2022). Besides cerebral ischemia, this approach could also be a promising strategy to address other neurological diseases associated with an excitation/inhibition imbalance and downregulation of GABAB receptors, e.g. addiction and neurodegenerative diseases.