likviriton and Neuralgia

Wu-tou decoction (WTD), a classic Traditional Chinese medicine formula, has been extensively used in the treatment of neuropathic pain (NP) such as chronic inflammatory pain, trigeminal neuralgia, and cancer-induced pain. Our previous studies have shown that the severity of mechanical allodynia and thermo hypersensitivity in NP rats are reduced by WTD, of which analgesic candidates are paeoniflorin (Pae) and liquiritin (Liq). The aim of this study was to clarify the molecular mechanisms of WTD, Pae and Liq against NP based on the primary rat glial cells in vitro. The gene expression levels of neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Artemin and C-C chemokine receptor type 5 (CCR5) were augmented by inflammatory cytokines, while chemokines increased only CCR5 gene expression. The constitutive and cytokine-augmented neurotrophic factor gene expression was enhanced by WTD, Pae, and Liq through PI3K- and PKA-dependent pathways in rat glial cells, leading to the increase of NGF and BDNF production. Furthermore, the CCR5 gene expression under basal and chemokine-treated conditions was suppressed by these reagents, in which signal pathway(s) was independent on the activation of PI3K and PKA. Moreover, there was no cytotoxicity in the WTD, Pae, and Liq treatments in glial cells. Thus, these results provide a novel evidence that WTD may exert the anti-NP actions by predominantly increasing the production of neurotrophic factors through PI3K- and PKA-signaling pathways in rat glial cells. Furthermore, Pae and Liq may play as analgesic candidates in WTD-mediated NP management.

Topics: Animals; Cells, Cultured; Cytokines; Drugs, Chinese Herbal; Flavanones; Gene Expression Regulation; Glucosides; Inflammation Mediators; Monoterpenes; Nerve Growth Factors; Neuralgia; Neuroglia; Rats, Sprague-Dawley; Receptors, CCR5; RNA, Messenger; Signal Transduction

Topics: Animals; Chemokines; Disease Models, Animal; Drug Discovery; Drug Therapy, Combination; Flavanones; Glucosides; Humans; Monoterpenes; Neuralgia; Rats; Signal Transduction

Managing of neuropathic pain remains clinically challenging because the existing pharmacotherapies are either ineffective or non-specific. Therefore, developing novel alternatives is essential for better treatment. Liquiritin is an active component extracted from Glycyrrhizae radix and has potential neuroprotective action. This study aimed to investigate the protective efficacy of liquiritin on chronic constriction injury (CCI)-induced neuropathic pain in mice. Liquiritin (30, 60, and 120mg/kg) and pregabalin (40mg/kg) were administered intragastrically for 7 consecutive days starting on the 8th day post-surgery. Behavioral parameters and sciatic functional index were assessed on days 0, 7, 8, 10, 12, and 14. Electrophysiological and histopathological changes were analyzed on the 14th day. Immunofluorescence and Western blot were used to evaluate the expression of glial cells and the protein levels of inflammatory cytokines in the spinal cord, respectively. Results showed that liquiritin dose-dependently reduced hyperalgesia and allodynia and increased the sciatic functional index and motor nerve conduction velocities. Moreover, liquiritin restored the injured axon and myelin sheath, inhibited the activation of astrocyte and microglia, down-regulated the pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL-6, and IL-1β), and simultaneously up-regulated the anti-inflammatory cytokine IL-10. Our study revealed that liquiritin exerted a neuroprotective effect on CCI-induced neuropathic pain, which might be attributed to its direct protective effect on damaged nerves and its anti-inflammatory activity at the level of the spinal cord. Therefore, liquiritin shows promise as a compound for the development of novel analgesic agents that can be used to effectively treat intractable neuropathic pain.

Topics: Animals; Chronic Disease; Constriction; Flavanones; Glucosides; Mice; Mice, Inbred ICR; Neuralgia; Neuroprotective Agents; Pain Measurement; Random Allocation; Sciatic Neuropathy; Treatment Outcome