koumine and Disease-Models--Animal

Gelsemium elegans Benth. is a toxic plant that has been used as an ancient Chinese herbal remedy for rheumatoid arthritis (RA) and nervous pain, spasticity, skin ulcers, and cancers. Koumine, one of its representative alkaloids, shows numerous promising pharmacological activities, including anti-inflammatory and analgesic activities. Here, we investigated the analgesic effect of koumine on the collagen-induced arthritis (CIA) rat model of RA and explored the potential pharmacological mechanisms underlying the analgesia. In the CIA rats, repeated koumine treatments significantly reduced pain compared to controls and attenuated the collagen-induced increase in levels of glial fibrillary acidic protein (GFAP) and the pro-inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Cultured astrocytes showed reduced astrocyte reactivation and decreased production of both tested cytokines. Based on our results, koumine exerted both analgesic and anti-inflammatory effects on the CIA rat model that were apparently mediated by inhibiting astrocyte reactivation and pro-inflammatory cytokine production.

Topics: Analgesics; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Disease Models, Animal; Drugs, Chinese Herbal; Indole Alkaloids; Inflammation; Male; Rats; Rats, Wistar

Postoperative pain (POP) of various durations is a common complication of surgical procedures. POP is caused by nerve damage and inflammatory responses that are difficult to treat. The neuroinflammation-glia-steroid network is known to be important in POP. It has been reported that the Gelsemium alkaloid koumine possesses analgesic, anti-inflammatory and neurosteroid modulating activities. This study was undertaken to test the analgesic effects of koumine against POP and explore the underlying pharmacologic mechanisms. Our results showed that microglia and astroglia were activated in the spinal dorsal horn post-incision, along with an increase of proinflammatory cytokines (interleukin 1β, interleukin 6, and tumor necrosis factor α). Both subcutaneous and intrathecal (i.t.) koumine treatment after incision significantly prevented mechanical allodynia and thermal hyperalgesia, inhibited microglial and astroglial activation, and suppressed expression of proinflammatory cytokines. Moreover, the analgesic effects of koumine were antagonized by i.t. administration of translocator protein (18 kDa) (TSPO) antagonist PK11195 and GABA

Topics: Analgesics; Animals; Cytokines; Disease Models, Animal; Disease Progression; Down-Regulation; Gelsemium; Indole Alkaloids; Neuroglia; Pain, Postoperative; Rats; Receptors, GABA-A; Spinal Cord Dorsal Horn

To examine the effect of koumine, a Gelsemium alkaloid, on two experimental models of rheumatoid arthritis (RA), rats with adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) were administered koumine (0.6, 3, or 15 mg/kg/day) or vehicle through gastric gavage (i.g.). Clinical evaluation was performed via measurements of hind paw volume, arthritis index (AI) score, mechanical withdrawal threshold, organ weight, and by radiographic and histological examinations. Levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and antitype II collagen (CII) antibody were also examined. In rats with AIA, koumine reduced the AI score and mechanical allodynia of the injected hind paw in a dose-dependent manner and significantly inhibited increase in thymus and liver weights. In rats with CIA, koumine inhibited increase in hind paw volume, AI score, and mechanical allodynia in a dose-dependent manner and reduced joint space narrowing. Furthermore, koumine also attenuated the increase in the expression of IL-1β and TNF-α, as well as the robust increase of serum anti-CII antibodies in response to immunization. These results suggested that koumine effectively attenuated arthritis progression in two rat models of RA and that this therapeutic effect may be associated with its immunoregulatory action.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Gelsemium; Indole Alkaloids; Interleukin-1beta; Male; Methotrexate; Molecular Structure; Rats; Rats, Inbred Lew; Rats, Wistar; Tumor Necrosis Factor-alpha

Koumine is an alkaloid monomer found abundantly in Gelsemium plants. It has been shown to reverse thermal hyperalgesia and mechanical allodynia induced by sciatic nerve chronic constriction injury (CCI) in rats in a dose-dependent manner. Interestingly, this effect is mediated by elevated allopregnanolone levels in the spinal cord (SC). Since 3α-hydroxysteroid oxidoreductase (3α-HSOR), the key synthetase of allopregnanolone, is responsible for allopregnanolone upregulation in the SC, the objective of the present study was to investigate the role of its expression in the SC in koumine-induced analgesia using a rat model of neuropathic pain following peripheral nerve injury.. Time-course investigations of immunohistochemistry and real-time polymerase chain reaction revealed that the immunoreactivity and mRNA expression of 3α-HSOR markedly increased in a time-dependent manner in the SC of koumine-treated CCI rats. Furthermore, 3α-HSOR activity in the SC of koumine-treated CCI rats increased by 15.8% compared to the activity in untreated CCI rats. Intrathecal injection of medroxyprogesterone acetate, a selective 3α-HSOR inhibitor, reversed the analgesic effect of koumine on CCI-induced mechanical pain perception. Our results confirm that koumine alleviates neuropathic pain in rats with CCI by enhancing 3α-HSOR mRNA expression and bioactivity in the SC.. This study demonstrates that 3α-HSOR is an important molecular target of koumine for alleviating neuropathic pain. Koumine may prove a promising compound for the development of novel analgesic agents effective against intractable neuropathic pain.

Topics: 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); Analgesics; Animals; Biocatalysis; Chronic Disease; Constriction; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Hyperalgesia; Immunohistochemistry; Indole Alkaloids; Injections, Subcutaneous; Male; Medroxyprogesterone Acetate; Neuralgia; Rats, Sprague-Dawley; RNA, Messenger; Sciatic Nerve; Spinal Cord; Spinal Cord Dorsal Horn

Crude alkaloidal extraction from Gelsemium elegans Benth. produces analgesic property. However, its clinical utility has been obstructed by its narrow therapeutic index. Here, we investigated the potential of koumine, a monomer of Gelsemium alkaloids, to reduce both inflammatory and neuropathic pain. Interestingly, allopregnanolone, a neurosteroid, appeared to mediate the reduction of neuropathic pain. The potential anti-inflammatory pain effects of koumine were evaluated by acetic acid-, formalin- and complete Freund's adjuvant (CFA) -induced nociceptive behaviors in mice. Chronic constriction injury (CCI) and L5 spinal nerve ligation (L5 SNL), inducing thermal hyperalgesia and mechanical allodynia in rats, were used to test whether repeated treatment of koumine ameliorated neuropathic pain. Finally, we explored if koumine altered the level of neurosteroids in rat spinal cord of CCI neuropathy using liquid chromatography-tandem mass spectrometry. Koumine dose-dependently reduced the acetic acid-induced writhes and formalin-induced licking/biting time of Phase II in mice. Repeated administrations of koumine also dose-dependently reversed the CFA-, CCI- and L5 SNL-induced thermal hyperalgesia, as well as, CCI- and L5 SNL-induced mechanical allodynia in rats. The level of allopregnanolone, but not pregnenolone, in the L5-6 spinal cord was elevated by repeated treatment of koumine in CCI-induced neuropathic rats. These results demonstrate that koumine has a significant analgesic effect in rodent behavioral models of inflammatory and neuropathic pain, and that the reduction in neuropathic pain may be associated with the upregulation of allopregnanolone in the spinal cord.

Topics: Analgesics; Animals; Disease Models, Animal; Gelsemium; Hyperalgesia; Indole Alkaloids; Inflammation; Male; Mice; Mice, Inbred ICR; Neuralgia; Pain; Pain Measurement; Pregnanolone; Rats; Rats, Sprague-Dawley; Spinal Cord; Up-Regulation