Therapeutic Efficacy Of Alpha 7 Ligands After Acute Ischaemic Stroke Is Linked To Conductive States Of Alpha 7 Nicotinic Ach Receptors

Background and Purpose Targeting alpha 7 nicotinic ACh receptors (nAChRs) in neuroinflammatory disorders including acute ischaemic stroke holds significant therapeutic promise. However, therapeutically relevant signalling mechanisms remain unidentified. Activation of neuronal alpha 7 nAChRs triggers ionotropic signalling, but there is limited evidence for it in immunoglial tissues. The alpha 7 ligands which are effective in reducing acute ischaemic stroke damage promote alpha 7 ionotropic activity, suggesting a link between their therapeutic effects for treating acute ischaemic stroke and activation of alpha 7 conductive states.Experimental Approach This hypothesis was tested using a transient middle cerebral artery occlusion (MCAO) model of acute ischaemic stroke, NS6740, a known selective non-ionotropic agonist of alpha 7 nAChRs and 4OH-GTS-21, a partial alpha 7 agonist. NS6740-like ligands exhibiting low efficacy/potency for ionotropic activity will be referred to as non-ionotropic agonists or "metagonists".Key Results 4OH-GTS-21, used as a positive control, significantly reduced neurological deficits and brain injury after MCAO as compared to vehicle and NS6740. By contrast, NS6740 was ineffective in identical assays and reversed the effects of 4OH-GTS-21 when these compounds were co-applied. Electrophysiological recordings from acute hippocampal slices obtained from NS6740-injected animals demonstrated its remarkable brain availability and protracted effects on alpha 7 nAChRs as evidenced by sustained (>8 h) alterations in alpha 7 ionotropic responsiveness.Conclusion and Implications These results suggest that alpha 7 ionotropic activity may be obligatory for therapeutic efficacy of alpha 7 ligands after acute ischaemic stroke yet, highlight the potential for selective application of alpha 7 ligands to disease states based on their mode of receptor activation.