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 pKi= 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 4, demonstrated
the ability to reduce mitochondrial dysfunction, regulate intracellular
calcium levels, decrease caspase 3 levels, and promote neurite outgrowth
in in vitro assays. In an animal model, compound 4 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.