Therapeutic efficacy of α7 ligands after acute ischaemic stroke is linked to conductive states of α7 nicotinic ACh receptors

Abstract

Funding information UNTHSC Background and Purpose: Targeting α7 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 α7 nAChRs triggers ionotropic signalling, but there is limited evidence for it in immunoglial tissues. The α7 ligands which are effective in reducing acute ischaemic stroke damage promote α7 ionotropic activity, suggesting a link between their therapeutic effects for treating acute ischaemic stroke and activation of α7 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 α7 nAChRs and 4OH-GTS-21, a partial α7 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 α7 nAChRs as evidenced by sustained (>8 h) alterations in α7 ionotropic responsiveness. Conclusion and Implications: These results suggest that α7 ionotropic activity may be obligatory for therapeutic efficacy of α7 ligands after acute ischaemic stroke yet, highlight the potential for selective application of α7 ligands to disease states based on their mode of receptor activation.

Electroacupuncture ameliorates gastrointestinal dysfunction by modulating DMV cholinergic efferent signals to drive the vagus nerve in p-MCAO rats

“…The a7nAchR is recognized as a key target in CAP because its activation effectively mitigates both central and peripheral inflammatory damage [ 20 , 54 ]. Studies have demonstrated that EA can alleviate decreased intestinal motility and intestinal inflammation resulting from postoperative intestinal obstruction through the α7nAchR-mediated JAK2/STAT3 signaling pathway [ 22 ].…”

“…A permanent MCAO ( p -MCAO) model was established under isoflurane anesthesia utilizing the modified Longa thread occlusion method [ 20 ]. The rats were anesthetized and placed in a supine position on an operating Table An incision is made on the left side of the neck along the midline to expose the common carotid artery (CCA).…”

“…Subsequently, ACh is enzymatically degraded into acetate and choline by acetylcholinesterase (AChE), thereby terminating neural signaling and its associated anti-inflammatory effects [ 17 ]. Both animal studies and long-term clinical evidence have suggested the effectiveness of AChE inhibitors and α7nAChR agonists in improving neurological deficits and cognitive deficits after stroke [ [18] , [19] , [20] ].…”

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

“…In recent years, it has been shown that besides affecting cognitive functions, GTS 21 (and its active metabolite) effectively suppresses inflammation, demonstrating positive effects in a number of pathological conditions, such as acute ischemic stroke [ 70 ], sepsis [ 71 , 72 ], burns [ 73 ], acute lung injury [ 74 ], chronic obstructive pulmonary disease [ 75 ], airway inflammation [ 76 ] and atherosclerosis [ 77 ]. In clinical trials, the anti-inflammatory effects of GTS-21 were investigated in healthy human volunteers during experimental endotoxemia [ 78 ].…”

Protective effects and mechanisms of auricular vagus nerve stimulation in the alleviation of acute ischemic cerebral injury in mice

“…Activation of nAChRs protects neurons from neurodegenerative diseases [13]. Some studies demonstrated that activation of α7-nAChR could reduce ischemic injury [14,15]. However, there is limited studies mentioned that α4-nAChR play the role in ischemic stroke.…”