Preferential Synaptic Type of GABA-A Receptor Ligands Enhancing Neuronal Survival and Facilitating Functional Recovery After Ischemic Stroke
Selective enhancement of synaptic GABA signaling mediated by GABA-A receptors has been previously reported to promote functional recovery after ischemic stroke, while tonic GABA signaling has been detrimental. To identify agents that enhance synaptic signaling, we synthesized GABA-A ligands based on three chemotypes with affinity values p<i>K</i><sub>i</sub>= 6.44-8.32. Representative compounds showed a preference in functional responses toward synaptic type of GABA-A receptors, compared to the extrasynaptic ones. In a cellular ischemia model (OGD), selected compounds showed the potential to improve neuronal recovery. The selected lead, compound <b>4</b>, demonstrated the ability to reduce mitochondrial dysfunction, regulate intracellular calcium levels, decrease caspase 3 levels, and promote neurite outgrowth in <i>in vitro</i> assays. In an animal model, compound <b>4</b> enhanced motor recovery and showed neuroprotective activity by reducing infarct volume and decreasing poststroke acidosis. These findings underscore the value of selective ligands modulating synaptic GABA-A receptors in promoting recovery from ischemic stroke.
Authors
- Elżbieta Pękala (ORCID: https://orcid.org/0000-0002-1260-4253)
- Paweł Żmudzki (ORCID: https://orcid.org/0000-0003-3594-1241)
- Maciej Gawlik (ORCID: https://orcid.org/0000-0002-0808-4603)
- Magdalena Jastrzębska‐Więsek
- Jakub Jończyk (ORCID: https://orcid.org/0000-0002-9731-908X)
- Alicja Skórkowska (ORCID: https://orcid.org/0000-0002-1167-7610)
- Monika Marcinkowska (ORCID: https://orcid.org/0000-0002-4948-6617)
- Agata Siwek (ORCID: https://orcid.org/0000-0001-5321-9266)
- Barbara Mordyl (ORCID: https://orcid.org/0000-0001-7906-0353)
- Weronika Krzyżanowska (ORCID: https://orcid.org/0000-0003-1166-6126)
- Maria Walczak (ORCID: https://orcid.org/0000-0002-5670-9866)
- Marcin Kołaczkowski (ORCID: https://orcid.org/0000-0001-8402-1121)
- Bartosz Pomierny (ORCID: https://orcid.org/0000-0002-5352-5324)
- Tadeusz P. Karcz (ORCID: https://orcid.org/0000-0003-4035-659X)
- Nikola Fajkis-Zajączkowska
- Karolina Słoczyńska (ORCID: https://orcid.org/0000-0002-7366-2676)
- Katarzyna Szafrańska
- Magdalena Smolik (ORCID: https://orcid.org/0000-0003-1619-0913)
- Monika Głuch‐Lutwin (ORCID: https://orcid.org/0000-0003-1632-6569)
- Jakub Jurczyk (ORCID: https://orcid.org/0000-0002-0308-5981)
- Aleksandra Sałach
Institutions
- Jagiellonian University (PL)
- Medicina (PL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01578
- Citations
- 3
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Narodowe Centrum Nauki