Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

Transient receptor potential vanillic acid 1 (TRPV1) is an ion channel activated by heat and inflammatory factors involved in the development of various types of pain. The P2X7 receptor is in the P2X family and is associated with pain mediated by satellite glial cells. There might be some connection between the P2X7 receptor and TRPV1 in neuropathic pain in diabetic rats. A type 2 diabetic neuropathic pain rat model was induced using high glucose and high-fat diet for 4 weeks and low-dose streptozocin (35 mg/kg) intraperitoneal injection to destroy islet B cells. Male Sprague Dawley rats were administrated by intrathecal injection of P2X7 shRNA and p38 inhibitor, and we recorded abnormal mechanical and thermal pain and nociceptive hyperalgesia. One week later, the dorsal root ganglia from the L4-L6 segment of the spinal cord were harvested for subsequent experiments. We measured pro-inflammatory cytokines, examined the relationship between TRPV1 on neurons and P2X7 receptor on satellite glial cells by measuring protein and transcription levels of P2X7 receptor and TRPV1, and measured protein expression in the PKCε/P38 MAPK/NF-κB signaling pathway after intrathecal injection. P2X7 shRNA and p38 inhibitor relieved hyperalgesia in diabetic neuropathic pain rats and modulated inflammatory factors in vivo. P2X7 shRNA and P38 inhibitors significantly reduced TRPV1 expression by downregulating the PKCε/P38 MAPK/NF-κB signaling pathway and inflammatory factors in dorsal root ganglia. Intrathecal injection of P2X7 shRNA alleviates nociceptive reactions in rats with diabetic neuropathic pain involving TRPV1 via PKCε/P38 MAPK/NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.

Background: The current treatment strategy for pain is still the application of traditional analgesic drugs to relieve pain but with many side effects. Therefore, neuropathic pain is a growing concern in the medical community, and the search for new analgesic targets for neuropathic pain has become a new hot spot. In this study, we examined whether Cx43 have the key role in response to peripheral nerve injury in P2X4 receptor-mediated neuropathic pain rats, thereby activating large numbers of satellite glial cells and neurons. Methods: A rat model of chronic compression injury of the sciatic nerve was established, and the dorsal root ganglion and serum were examined at the relevant molecular levels using western blot, quantitative fluorescent PCR, multiplex immunofluorescence and ELISA. Results: Our results confirm an important role for Cx43 in P2X4 receptor-mediated neuropathic pain. The release of ATP from Cx43 into the extracellular space activates itself and neighboring satellite glial cells and triggers a cascade amplification effect of inflammation, creating an inflammatory microenvironment that ultimately leads to neuronal sensitization of neuropathic pain in CCI rats. Conclusions: In brief, blockade of CX43 could attenuate P2X4 receptor-mediated neuropathic pain in rats suffering from CCI, and Cx43may be promising therapeutic targets for the development of novel pharmacological agents in the management of neuropathic pain.

Neuropathic pain is a growing concern in the medical community, and the search for new analgesic targets for neuropathic pain has become a new hot spot. In this study, we examined whether Cx43 has a key role in neuropathic pain mediated by P2X4 receptor- in rats after peripheral nerve injuring. Our experimental results show that ATP released via Cx43 has a crucial role in P2X4 receptor-mediated neuropathic pain in the rat model of chronic constriction injury (CCI) of the sciatic nerve, and the p38, ERK, and NF-kB signaling pathways have been shown to be involved in the development of neuropathic pain processes. In brief, blockade of CX43 could attenuateP2X4 receptor-mediated neuropathic pain in rats suffering from CCI, and Cx43 may be promising therapeutic targets for the development of novel pharmacological agents in the management of neuropathic pain.