Effect of Bufalin-PLGA Microspheres in the Alleviation of Neuropathic Pain via the CCI Model

Abstract

The treatment of neuropathic pain (NPP) is considered challenging, while the search for alternative medication is striving. NPP pathology is related with the expression of both the purinergic 2X7 (P2X7) receptor and the transient receptor potential vanilloid 1 receptor (TRPV1). Bufalin is a traditional Chinese medication derived from toad venom with pronounced antitumor, analgesic, and anti-inflammatory properties. However, poor solubility, rapid metabolism, and the knowledge gap on its pain alleviation mechanism have limited the clinical application of bufalin. Hence, the purpose of this study is to illustrate the NPP alleviation mechanism of bufalin via chronic constriction injury (CCI). To address the concern on fast metabolism, bufalin-PLGA microspheres (MS) were prepared via membrane emulsification to achieve prolonged pain-relieving effects. Western blot, real-time PCR, immunofluorescence, and molecular docking were employed to demonstrate the therapeutic action of bufalin on NPP. The results showed enhanced thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) after the administration of both bufalin and bufalin-PLGA MS in the CCI rats. Prolonged pain-relieving effects for up to 3 days with reduced dose frequency was achieved via bufalin-PLGA MS. In the CCI rats treated with bufalin-PLGA MS, the expression levels of protein and mRNA in TRPV1 and P2X7, both localized in the dorsal root ganglion (DRG), were reduced. Moreover, bufalin-PLGA MS effectively reduced the levels of IL-1β, IL-18, IL-6, and TNF-α in the CCI group. The results from molecular docking suggested a possible mechanism of NPP alleviation of bufalin through binding to P2X7 receptors directly. The administration of bufalin-PLGA MS prepared by membrane emulsification demonstrated promising applications for sustained effect on the alleviation of NPP.

Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats

“…Therefore, a diabetic neuropathic pain rat model was successfully established in this study by measuring thermal, mechanical pain and sciatic nerve conduction velocity in rats (Figures 1 and 2) to study its pathogenesis. Many studies have reported that both TRPV1 and P2X7 are involved in the formation of DNP [15,28], and some have reported that they are related between P2X7 and TRPV1 [8,17]. However, how they are related is still unknown, and our study is designed to fill that gap and provide a basis for future treatment.…”

“…P2X7R has been found to have a good association with TRPV1 in esophageal inflammation because of their closed correlated gene expression [16]. Meanwhile, long et al [17] reported that neuropathic pain is related to the expression of P2X7R and TRPV1. Injection of P2X7 inhibitors can reduce TRPV1 expression associated with diabetic neuropathic pain [8].…”

Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases

“…Bufalin : Is a cardiotonic digoxin-like steroid that is extracted from the skin and parotid venom glands of the Chinese toad species Bufo melanostictus and Bufo gargarizans , also known as Chan Su. This TCM material has been used for centuries as a painkiller and for the treatment of heart failure, cancer, and other diseases ( Long et al, 2022 ). Bufalin is one of the major active components of Chan Su, alongside other bufadienolides such as bufalon, resibufagin, gambufotalin, bufataline, and cinobufotalin ( Wei et al, 2019 ).…”

Advances on Delivery System of Active Ingredients of Dried Toad Skin and Toad Venom

“… 71 The positive charge of PLGA can facilitate electrostatic interactions between the microspheres and negatively charged tissue or cell receptors, thereby increasing the residence time of the microspheres at the target site and enabling controlled drug release. 72 Based on the analgesic effect of BU, Long et al 48 prepared bufalin-PLGA MS to elucidate the drug’s effect and mechanism of action. bufalin-PLGA MS exhibited a slow drug release profile, extending the duration of action in vivo (within 48 h, in vitro cumulative release rate: 26.2%).…”