DMXB-Anabaseine

Sepsis is a common clinical syndrome in intensive care unit (ICU) with high morbidity and high mortality, making it a global health issue. The estimated global incidence of sepsis is 437/100 000, with an in-hospital mortality of 17%, which is higher in developing countries and underdeveloped regions. Despite some progress in sepsis treatment in recent years, the complexity of its pathophysiology limits therapeutic effectiveness. The cholinergic anti-inflammatory pathway (CAP), a neuro-immune regulatory pathway, plays a crucial role in sepsis through key components such as the vagus nerve, central M-type muscarinic receptor, the spleen and splenic sympathetic nerves, acetylcholine, and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR). This article explores the potential mechanisms and roles of CAP in sepsis, focusing on CAP-related cell signaling pathways, including nuclear factor-κB (NF-κB) signaling pathway, Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, and cyclooxygenase (COX) and prostaglandin E2 (PGE2) signaling pathways. Potential applications of CAP in sepsis treatment include stimulating the vagus nerve (e.g., through pharmacological, electrical, or acupuncture stimulation), using α7nAChR agonists (e.g., nicotine, GTS-21, and PNU-282987), adrenergic receptor agonists (e.g., dexmedetomidine and salbutamol), or other drugs and bioactive substances (e.g., buprenorphine and traditional Chinese medicine components). These approaches aim to activate CAP, suppress inflammatory responses, and improve sepsis prognosis, providing a theoretical basis for treatment and promoting the development of related drugs.

Parkinson's disease (PD) is a neurological disorder that causes a gradual decrease in mobility. Abnormal α-synuclein (α-syn) levels and aggregation contribute to PD development. The dissemination of α-synuclein pathology via the gut-brain axis has emerged as a critical aspect in α-synucleinopathies, including PD. Recently, α7 nicotinic acetylcholine receptor (α7nAchR) agonists have been proposed as promising agents for treating PD, owing to their biological properties such as anti-inflammatory effects. This study aims to investigate whether activation of α7nAchR improves α-synuclein pathology in the brain and gut of a mouse model of PD. We found that α7nAchR agonists, GTS-21 and PNU-282987, induced behavioral recovery and improved nigrostriatal dopaminergic neurotransmission in a subacute MPTP mouse model of PD. In addition, GTS-21 and PNU-282987 facilitated α-syn clearance in the brain and distal colon, as evidenced by a considerable reduction in the accumulation of pathogenic forms of α-syn. Accordingly, GTS-21 and PNU-282987 were found to promote the AMPK-mTOR autophagy signaling pathway. Furthermore, GTS-21 and PNU-282987 exerted anti-inflammatory effects, reducing the levels of proinflammatory mediators such as inducible nitric oxide synthase, interleukin-6, and tumor necrosis factor-α in both the brain and gut. To validate the specific effects of α7nAchR agonists, subacute MPTP mice were pretreated with methyllycaconitine (MLA), a selective α7nAchR antagonist before GTS-21 administration. Pretreatment with MLA abolished the GTS-21-elicited behavioral recovery, α-syn clearance, and anti-inflammatory effects in the brain and gut. Therefore, α7nAchR activation may be a potential candidate strategy for the treatment of PD by altering α-syn aggregation in the brain and gut.