Rhodojaponin Ⅵ indirectly targets Cav2.2 channels via N-ethylmaleimide-sensitive fusion protein to alleviate neuropathic pain

Neuropathic pain is a chronic disease that severely afflicts the life and emotional status of patients,but currently available treatments are often ineffective.Novel therapeutic targets for the alleviation of neuropathic pain are urgently needed.Rhodojaponin Ⅵ,a grayanotoxin from Rhododendron molle,showed remarkable antinociceptive efficacy in models of neuropathic pain,but its biotargets and mechanisms are unknown.Given the reversible action of rhodojaponin Ⅵ and the narrow range over which its structure can be modified,we perforwmed thermal proteome profiling of the rat dorsal root ganglion to determine the protein target of rhodojaponin Ⅵ.N-Ethylmaleimide-sensitive fusion(NSF) was confirmed as the key target of rhodojaponin Ⅵ through biological and biophysical experiments.Functional validation showed for the first time that NSF facilitated trafficking of the Cav2.2 channel to induce an increase in Ca2+current intensity,whereas rhodojaponin Ⅵ reversed the effects of NSF.In conclusion,rhodojaponin Ⅵ represents a unique class of analgesic natural products targeting Cav2.2 channels via NSF.

Construction of meloxicam and bupivacaine co-delivery nanosystem based on the pathophysiological environment of surgical injuries for enhanced postoperative analgesia

Besides peripheral nerve injury,the acute inflammation is one of the pathological features of tissues after surgery,which exacerbates the postoperative pain,especially in the first 48 h after the surgery.Multimodal analgesia(MMA),such as the combination of non-steroidal anti-inflammatory drugs(NSAIDs)with local anesthetics,has shown enhanced potency compared with the usage of local anesthetics alone.However,rare formulations can provide long-term analgesia at a single dose.Herein,bupivacaine(BUP,a local anesthetic)loading poly(lactic-co-glycolic acid)(PLGA)nanoparticles(NPB)were coated with meloxicam(MLX,an NSAID)loading lipid bilayer(LPM),forming a core–shell nanosystem(NPB@LPM)to provide enhanced and long-term analgesia to treat postoperative pain.MLX was encapsulated in the lipid shell,which enabled high dose MLX to be released in the first 48 h after surgery to reduce the acute inflammation induced pain.BUP was encapsulated in the PLGA core to provide a long-term release for the nerve block.This nanosystem provided a 7-day(whole recovery cycle)effective analgesia in the Brennan’s plantar incision rat model.The tissue reactions of NPB@LPM are benign.This work will provide feasible strategies on designing drug delivery systems for postoperative pain management.

Focal-type,but not Diffuse-type,Amyloid Beta Plaques are Correlated with Alzheimer’s Neuropathology,Cognitive Dysfunction,and Neuroinflammation in the Human Hippocampus

Amyloid beta(Aβ)plaques are one of the hallmarks of Alzheimer’s disease(AD).However,currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans.It has been found that there are different types of Aβplaque(diffuse and focal types)in the postmortem human brain.In this study,we aimed to investigate the correlations among different types of Aβplaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China.The results indicated that focal plaques,but not diffuse plaques,significantly increased with age in the human hippocampus.We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes(measured by the“ABC”scoring system)and cognitive decline(measured by the Everyday Cognitive Insider Questionnaire).Furthermore,most of the focal plaques were co-localized with neuritic plaques(identified by Bielschowsky silver staining)and accompanied by microglial and other inflammatory cells.Our findings suggest the potential of using focal-type but not general Aβplaques as biomarkers for the neuropathological evaluation of AD.