Advancements in Non-Addictive Analgesic Diterpenoid Alkaloid Lappaconitine: A Review.

The perennial herb Aconitum sinomontanum Nakai (Ranunculaceae) has been utilized as a traditional oriental medicine in China for numerous years. The principal pharmacological constituent of A. sinomontanum, lappaconitine (LA), exhibits analgesic, anti-inflammatory, anti-tumor, anti-arrhythmic, and anti-epileptic activities. Due to its potent efficacy and non-addictive nature, LA is widely utilized in the management of cancer pain and postoperative analgesia. This review encompasses the research advancements pertaining to LA including extraction methods, separation techniques, pharmacological properties, chemical modifications, and clinical applications. Additionally, it offers insights into the potential applications and current challenges associated with LA to facilitate future research endeavors.

Unlocking renal Restoration: Mesaconine from Aconitum plants restore mitochondrial function to halt cell apoptosis in acute kidney injury.

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor ß1 (TGF-ß1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1ß (interleukin-1ß) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.

[Therapeutic effects of alkaloids in Tibetan medicine Bangna (Aconiti Penduli et Aconiti Flavi Radix) on osteoarthritis rats and mechanisms].

This study aims to investigate the therapeutic effects of alkaloids in Tibetan medicine Bangna(Aconiti Penduli et Aconiti Flavi Radix) on osteoarthritis(OA) rats in vitro and in vivo and the underlying mechanisms. Chondrocytes were isolated from 2-3 week-old male SD rats and lipopolysaccharide(LPS) was used to induce OA in chondrocytes in vitro. Methyl thiazolyl tetrazolium(MTT) assay was used to investigate the toxicity of seven alkaloids(12-epi-napelline, songorine, benzoylaconine, aconitine, 3-acetylaconitine, mesaconitine, and benzoylmesaconine) to chondrocytes. Chondrocytes were classified into the control group, model group(induced by LPS 5 µg·mL~(-1) for 12 h), and administration groups(induced by LPS 5 µg·mL~(-1) for 12 h and incubated for 24 h). The protein expression of inflammatory factors cyclooxygenase-2(COX-2), inducible nitric oxide synthetase(iNOS), tumor necrosis factor-α(TNF-α), and interleukin-1ß(IL-1ß) in each group were detected by Western blot, and the protein expression of matrix metalloprotease-13(MMP-13), aggrecan, collagen Ⅱ, fibroblast growth factor 2(FGF2) by immunofluorescence staining. For the in vivo experiment, sodium iodoacetate was used to induce OA in rats, and the expression of MMP-13, TNF-α, and FGF2 in cartilage tissues of rats in each group was detected by immunohistochemistry. The results showed that the viability of chondrocytes could reach more than 90% under the treatment of the seven alkaloids in a certain dose range. Aconitine, 12-epi-napelline, songorine, 3-acetylaconitine, and mesaconitine could decrease the protein expression of inflammatory factors COX-2, iNOS, TNF-α and IL-1ß compared with the model group. Moreover, 12-epi-napelline, aconitine, and mesaconitine could down-regulate the expression of MMP-13 and up-regulate the expression of aggrecan and collagen Ⅱ. In addition, compared with the model group and other Bangna alkaloids, 12-epi-napelline significantly up-regulated the expression of FGF2. Therefore, 12-epi-napelline was selected for the animal experiment in vivo. Immunohistochemistry results showed that 12-epi-napelline could significantly reduce the expression of MMP-13 and TNF-α in cartilage tissues, and up-regulate the expression of FGF2 compared with the model group. In conclusion, among the seven Bangna alkaloids, 12-epi-napelline can promote the repair of OA in rats by down-regulating the expression of MMP-13 and TNF-α and up-regulating the expression of FGF2.

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

An Effective Phytoconstituent Aconitine: A Realistic Approach for the Treatment of Trigeminal Neuralgia.

Trigeminal neuralgia pain remains a challenge to treat. Natural compounds may be promising options for relieving pain. This study was aimed at investigating the effects of aconitine in a rat model of trigeminal neuralgia pain. Infraorbital nerve chronic constriction injury was performed in adult Wistar Albino rats. After the neuropathic pain developed, the rats were assigned to one of the treatment groups: carbamazepine 40 or 80 mg/kg; aconitine 0.25, 0.50, or 0.75 mg/kg; or saline injection (control group). Behavioral testing with von Frey filaments and the rotarod test were carried out before the surgical procedure and on the 24th to 29th postoperative days. Following the completion of tests, ipsilateral and contralateral spinal cords were harvested for Western blot analyses to assess NR-1 protein expression. ANOVA followed by Mann-Whitney U test was performed for the statistical analyses. P values of <0.05 were considered significant. Aconitine significantly reduced mechanical sensitivity in a dose-dependent manner. A significant reduction in motor coordination was noted for the higher doses of aconitine which was similar with the 40 and 80 mg/kg doses of carbamazepine. NR-1 expression was reduced in the ipsilateral spinal cord, whereas no significant difference was noted between the groups in the expression of NR-1 in the contralateral spinal cord. Aconitine had a significant pain relieving effect, which was similar to carbamazepine, in a dose-dependent manner. Aconitine may be an alternative pharmacological agent for the control of trigeminal neuralgia pain.

Comparison of analgesic activities of aconitine in different mice pain models.

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.

Lappaconitine Sulfate Inhibits Proliferation and Induces Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells through the Reactive Oxygen Species-Dependent Mitochondrial Pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of tumor-related deaths in the word. Lappaconitine (LA), a diterpenoid alkaloid, exerts antitumor activities. However, the effects and mechanisms of LA sulfate (LS) on HCC remain unclear. This study evaluated the activities and explored the underlying mechanisms of LS in HCC cell line HepG2 cells. MATERIALS AND METHODS: The cell viability and proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assay, respectively. The cell cycle distribution was detected by propidium iodide (PI) staining assay. The apoptosis was detected by Annexin -V-fluorescein isothiocyanate (FITC)/PI double staining assay. The cell cycle arrest and apoptosis-related proteins were estimated by western blot analysis. The mitochondrial membrane potential (MMP) was -determined through the 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimi-dazolyl carbocyanine iodide (JC-1) staining assay. The reactive oxygen species (ROS) was monitored by 20-70-dichlorofluorescein diacetate (DCFH-DA) staining assay. In vivo antitumor activities were investigated by HepG2 xenograft model. RESULTS: Our results showed that LS significantly -inhibited the viability and proliferation of HepG2 cells. LS triggered G0/G1 cell cycle arrest, apoptosis and caspase activation. Furthermore, LS induced MMP loss and ROS accumulation. Additionally, LS suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3ß (GSK3ß) signaling pathway. An in vivo assay showed that LS exhibited a pronounced antitumor effect in nude mice bearing HepG2 xenografts. CONCLUSIONS: Our results demonstrated that LS is a promising therapeutic agent for HCC directed -toward the proliferation inhibition and the induction of apoptosis.

Neoline is the active ingredient of processed aconite root against murine peripheral neuropathic pain model, and its pharmacokinetics in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed aconite root (PA), the root of Aconitum carmichaeli (Ranunculaceae), is a crude drug used in traditional Chinese or Japanese kampo medicine to treat pain associated with coldness. In our previous study, PA and its active ingredient, neoline, alleviated oxaliplatin-induced peripheral neuropathy in mice. AIM OF THE STUDY: The present study investigated the effects of PA on a murine peripheral neuropathy model induced by intraperitoneal injection of paclitaxel and partial ligation of the sciatic nerve (Seltzer model), and identified its active ingredients. MATERIALS AND METHODS: PA powder (1 g/kg/day) was orally administered, and either neoline or benzoylmesaconine (10 mg/kg/day) was subcutaneously injected into the murine model. Mechanical hyperalgesia was evaluated via the von Frey filament method. PA extract was orally administered to rats; blood samples were chronologically collected, and the plasma concentrations of Aconitum alkaloids were measured. The contents of Aconitum alkaloids in commercial PA products were also measured. RESULTS: PA extract and neoline significantly attenuated the mechanical hyperalgesia induced by either paclitaxel or partial ligation of the sciatic nerve in mice. In the plasma samples of rats treated with PA extract, higher concentrations of benzoylmesaconine and neoline were apparent among Aconitum alkaloids. The contents of benzoylmesaconine and neoline varied among PA products with different processing procedures. Subcutaneous injection of benzoylmesaconine did not attenuate the hyperalgesia induced by each paclitaxel, partial ligation of the sciatic nerve, or oxaliplatin in mice. CONCLUSIONS: The present results indicate that PA and its active ingredient, neoline, are promising agents for the alleviation of neuropathic pain. Neoline can be used as a marker compound to determine the quality of the PA products for the treatment of neuropathic pain.

Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain.

Bulleyaconitine A, a diterpenoid alkaloid isolated from Aconitum bulleyanum plants, has been used for the treatment of chronic pain in China since 1985. Clinical studies show that the oral administration of bulleyaconitine A is effective for treating different kinds of chronic pain, including back pain, joint pain, and neuropathic pain with minimal side effect in human patients. The experimental studies have revealed that bulleyaconitine A at therapeutic doses potently inhibits the peripheral sensitization and central sensitization that underlie chronic pain and has no effect on acute pain. Bulleyaconitine A preferably blocks tetrodotoxin-sensitive voltage-gated sodium channels in dorsal root ganglion neurons by inhibition of protein kinase C, and the effect is around 600 times more potent in neuropathic animals than in naïve ones. Bulleyaconitine A at 5 nM inhibits the hypersensitivity of dorsal root ganglion neurons in neuropathic rats but has no effect on excitability of dorsal root ganglion neurons in sham group. Bulleyaconitine A inhibits long-term potentiation at C-fiber synapses in spinal dorsal horn, a synaptic model of pathological pain, preferably in neuropathic pain rats over naïve rats. The following mechanisms may underlie the selective effect of bulleyaconitine A on chronic pain. (1) In neuropathic conditions, protein kinase C and voltage-gated sodium channels in dorsal root ganglion neurons are upregulated, which enhances bulleyaconitine A's effect. (2) Bulleyaconitine A use-dependently blocks voltage-gated sodium channels and therefore inhibits the ectopic discharges that are important for neuropathic pain. (3) Bulleyaconitine A is shown to inhibit neuropathic pain by the modulation of spinal microglia, which are involved in the chronic pain but not in acute (nociceptive) pain. Moreover, bulleyaconitine A facilitates the anesthetic effect of morphine and inhibits morphine tolerance in rats. Together, bulleyaconitine A is able to inhibit chronic pain by targeting at multiple molecules. Further clinical and experimental studies are needed for evaluating the efficacy of bulleyaconitine A in different forms of chronic pain in patients and for exploring the underlying mechanisms.

Varenicline is a smoking cessation drug that blocks alveolar expansion in mice intratracheally administrated porcine pancreatic elastase.

Smoking cessation is the most effective treatment in patients with emphysema and lung inflammation. The aim of the present study was to examine the effect of varenicline, a smoking cessation drug, on emphysema in porcine pancreatic elastase (PPE)-inhaled mice. PPE-inhaled mice were treated with varenicline and an α7 nicotinic acetylcholine receptor (nAChR) antagonist, methyllycaconitine (MLA) for 5 and 21 days. Varenicline markedly ameliorated alveolar expansion and inflammatory response in bronchoalveolar lavage fluid in PPE-inhaled mice. These blocking effects were inhibited by MLA. Our findings demonstrate that varenicline likely has an anti-inflammatory property including reduced inflammatory cell recruitment in lung tissue to protect PPE-induced alveolar expansion via α7 nAChR.

[Effects of lappaconitine on intraoperative administration of remifentanil induced postoperative hyperalgesia in general anaesthesia patients].

Objective: To explore the effects of lappaconitine on intraoperative administration of remifentanil induced postoperative hyperalgesia in general anaesthesia patients. Methods: One hundred and twenty patients from March to October 2016 undergoing elective thyroid operation under general anaesthesia at Ningbo NO.2 hospital, American Society of Anesthesiologists(ASA) Ⅰ or Ⅱ grade, aged 20-60, were enrolled in this study and randomly assigned to 3 groups (n=40). Remifentanil was intraoperatively infused at 0.1 µg·kg(-1)·min(-1) (Group S) or 0.3 µg·kg(-1)·min(-1) (Groups L and G), and patients in group G received lappaconitine 8 mg 30 minutes before the ending of surgery. Mechanical pain thresholds, visual analogue scale (VAS) and additional analgesics were recorded at 2, 6 and 24 hours after the operation. Results: There was no significant difference among the VAS and additional analgesics in three groups at 2, 6 and 24 h after operation (all P>0.05). There was no significant difference among the mechanical pain thresholds in three groups before and 2 h after operation (all P>0.05). The mechanical pain thresholds of group S, L and G was (45.7±15.6), (35.8±15.0), (47.6±16.4)g at 6 h and (50.7±17.0), (33.7±14.0), (49.7±13.9 )g at 24 h after operation. There was significant difference among the mechanical pain thresholds in group S, L and G at 6 h and 24 h after operation (F=6.586, 16.089, all P<0.01). Compared to group S, the mechanical pain thresholds significantly decreased in group L at 6 h and 24 h after operation (q=2.837, 5.045, all P<0.01). While there was a significantly increase in pain thresholds at 6 h and 24 h postoperatively in group G, as compared with the group L (q=3.384, 4.770, all P<0.01). Conclusion: Lappaconitine significantly alleviated intraoperative administration of remifentanil induced postoperative hyperalgesia in general anaesthesia patients.

Bulleyaconitine A preferably reduces tetrodotoxin-sensitive sodium current in uninjured dorsal root ganglion neurons of neuropathic rats probably via inhibition of protein kinase C.

Oral Bulleyaconitine A (BLA) is effective for treating neuropathic pain in human patients, but the underlying mechanism is poorly understood. Here, we tested whether BLA blocked voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons. Compelling evidence shows that voltage-gated sodium channels are upregulated in uninjured DRG neurons but downregulated in injured ones following peripheral nerve injury. We found that BLA preferably inhibited Na currents in uninjured DRG neurons in neuropathic rats. Compared to sham rats, IC50 values for resting and inactivated Na currents were 113 and 74 times lower in injured and uninjured neurons of L4-6 DRGs in spared nerve injury (SNI) rats (4.55 and 0.56 nM) and were 688 and 518 times lower in the uninjured L4 and L6 DRG neurons of L5 spinal nerve ligation (L5-SNL) rats. The use-dependent blockage of BLA on Na currents was more potent in neuropathic rats compared to sham rats. Bulleyaconitine A facilitated the inactivation of Na channels in each group. IC50 values for resting and inactivated tetrodotoxin-sensitive (TTX-S) channels were 1855 and 1843 times lower than those for TTX-resistant channels in the uninjured neurons of L5 spinal nerve ligation rats. The upregulation of protein kinase C was associated with the preferable effect of BLA on TTX-S Na channels in the uninjured DRG neurons. Local application of BLA onto L4-6 DRGs at 0.1 to 10 nM dose-dependently alleviated the mechanical allodynia and thermal hyperalgesia in L5 spinal nerve ligation model. Thus, preferable blockage of TTX-S Na channels in uninjured DRG neurons may contribute to BLA's antineuropathic pain effect.

Aconitine: A potential novel treatment for systemic lupus erythematosus.

BACKGROUND: Aconitum plants have been widely used in China for thousands of years. Recent evidences indicate that aconitine, the main active ingredient of Aconitum, has immunomodulatory properties that might be useful for treating autoimmune diseases, such as rheumatoid arthritis. In this study, we conducted a pilot study to explore the effect and mechanisms of aconitine on the treatment of systemic lupus erythematosus. METHODS: A pristane-induced murine model was used. The pristane-induced mice were treated with aconitine (25, 75 µg kg-1 d-1, po) for 9 weeks. Every three weeks, proteinuria was detected to monitor the kidney damage and blood was collected to measure serum levels of autoantibodies, besides the kidney pathological examination. The major B cell activating factor and major pro-inflammatory mediators, PGE2, IL-17a and IL-6, were also detected. RESULTS: We found that aconitine significantly improved the mouse health, decreased the elevated blood leukocyte counts, reduced the serum level of anti-double-stranded DNA (anti-dsDNA) antibody, greatly ameliorated renal histopathologic damage and reduced IgG deposit in glomerular. Furtherly, the levels of PGE2, IL-17a and IL-6, were found to have decreased in aconitine treated mice. CONCLUSION: We have demonstrated that aconitine can inhibit the progression of disease and ameliorate the pathologic lesion of systemic lupus erythematosus.

Diurnal Variation of the Peripheral Cholinergic Antiinflammatory Function in Mice.

AIMS: Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock. METHODS: Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine. RESULTS: Both levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA. CONCLUSION: Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

[The Study of Evidence Base for the Use of Lappaconitine Hydrobromide in Patients With Atrial Fibrillation].

Lappaconitine Hydrobromide (LH, allapinin) has been included by authors of National Guidelines on Diagnosis and Treatment of Atrial Fibrillation (AF), 2012 in the number of medications recommended for use in patients with AF for rhythm control. Moreover, LH is also included into the List of Vital and Essential Medicinal Drugs (VEMD) 2015. However, LH is not mentioned in corresponding guidelines of the European Society of Cardiology (ESC). Aim of the present review was to explore evidence base underlining use of LH in the context of AF and to understand reason for LH-related discrepancy between European and domestic guidelines. RESULTS: Literature search has indicated that efficacy of LH was assessed only in small open studies. None of prospective trials included more than 100 patients. For more than 25 years of presence on the market slightly more than 400 patients were administered LH in clinical studies. In the only trial, designated as randomized number of participants (only men younger than 60 years) was small and the comparator was quinidine that presently is not used for maintenance of sinus rhythm in AF. Another study referenced in domestic guidelines on management of AF was observational and not intended for comparison of antiarrhythmic activity of drugs. CONCLUSION: Design of studies reviewed as well as their results provide insufficient evidence supporting the use of LH for maintenance of sinus rhythm in routine management of AF. At present inclusion of LH in guidelines on AF management and in the List of VEMD appears unjustified.

Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats.

Paclitaxel, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and at present no effective drug is available for treatment of the serious side effect. Here, we tested if intragastrical application of bulleyaconitine A (BLA), which has been approved for clinical treatment of chronic pain in China since 1985, could relieve the paclitaxel-induced neuropathic pain. A single dose of BLA attenuated the mechanical allodynia, thermal hyperalgesia induced by paclitaxel dose-dependently. Repetitive administration of the drug (0.4 and 0.8 mg/kg, t.i.d. for 7 d) during or after paclitaxel treatment produced a long-lasting inhibitory effect on thermal hyperalgesia, but not on mechanical allodynia. In consistency with the behavioral results, in vivo electrophysiological experiments revealed that spinal synaptic transmission mediated by C-fiber but not A fiber was potentiated, and the magnitude of long-term potentiation (LTP) at C-fiber synapses induced by the same high frequency stimulation was ~50% higher in paclitaxel-treated rats, compared to the naïve rats. Spinal or intravenous application of BLA depressed the spinal LTP, dose-dependently. Furthermore, patch clamp recordings in spinal cord slices revealed that the frequency but not amplitude of both spontaneous excitatory postsynaptic current (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in lamina II neurons was increased in paclitaxel-treated rats, and the superfusion of BLA reduced the frequency of sEPSCs and mEPSCs in paclitaxel-treated rats but not in naïve ones. Taken together, we provide novel evidence that BLA attenuates paclitaxel-induced neuropathic pain and that depression of spinal LTP at C-fiber synapses via inhibiting presynaptic transmitter release may contribute to the effect.

[Effect of Lappaconitine on Postoperative Pain and Serum Complement 3 and 4 Levels of Cancer Patients Undergoing Rectum Surgery].

OBJECTIVE: To explore the effect of lappaconitine on patient-controlled intravenous analgesia (PCIA) and serum complement 3 and 4 (C3 and C4) levels of cancer patients undergoing rectum surgery. METHODS: Totally 60 patients, who were scheduled for rectum carcinoma surgery, were recruited to the study and assigned in 3 groups, the blank control group, the tramadol group, and the lappaconitine group, 20 in each group. Lappaconitine (8 mg) was intravenously dripped to patients in the lappaconitine group 30 min before ending the operation. PCIA started as soon as the end of the surgery and the total dose of lappaconitine was 36 mg. Patients of the tramadol group were treated with tramadol (100 mg) intravenously within 30 min before ending the operation. The dripping was completed within 30 min. PCIA was started as soon as the end of the surgery and the total dose of lappaconitine was 36 mg. Tramadol (100 mg) was intravenously dripped to patients in the tramadol group 30 min before ending the operation. PICA was started as soon as the end of the surgery and the total dose of tramadol was 900 mg. Pethidine (50 mg) and droperidol (2. 5 mg) was intramuscularly injected to patients in the blank control group for pain relief according to their complaints. Pain degrees were assessed by visual analog scale (VAS) 12 h before surgery, 12, 24, 48, and 72 h after surgery. Blood samples were withdrawn at the same time point. Contents of serum C3 and C4 were determined by immunoturbidimetry. RESULTS: VAS scores of the blank control group were significantly higher after surgery than before surgery (P <0. 01). There was no statistical difference in VAS scores between before surgery and after surgery in the tramadol group and the lappaconitine group (P >0. 05). VAS scores were significantly lower at each post-surgery time point in the tramadol group and the lappaconitine group than in the blank control group with statistical difference (P < 0.01). There was no statistical difference in VAS scores at each post-surgery time point between the tramadol group and the lappaconitine group (P >0. 05). Compared with before surgery, contents of serum C3 and C4 significantly decreased in all of the three groups at 12, 24, and 48 h after surgery (P < 0.05, P < 0.01). They recovered to the pre-surgery level till 72 h after surgery (P > 0.05). Serum C3 and C4 contents at 48 h after surgery were higher in the tramadol group than in the blank control group (P < 0.05). Serum C3 and C4 contents at 24 and 48 h after surgery were higher in the lappaconitine group than in the blank control group (P < 0.05). There was no statistical difference in serum C3 and C4 contents at each time point between the tramadol group and the lappaconitine group (P > 0.05). VAS scores were obviously negatively correlated with serum contents of C3 and C4 (r = -0.622, r = -0.649, P < 0.01). CONCLUSIONS: Lappaconitine (used at the dose in this study) showed better pain relief effect after surgery. Besides, it could inhibit the surgic wound and pain, and elevate serum contents of C3 and C4.

Clinical Aspects of Aconitum Preparations.

Aconite species have played an important role in human history. Aconitum species have been used worldwide as poisons as well as remedies. Their potential in targeting several ailments such as pain, rheumatism, and lethargy has been recognized by Western, Chinese, and Indian health care practitioners. Aconite use in herbal preparations has declined, especially in Europe and the United States, in the first half of the twentieth century due to several reported toxicity cases. The situation has changed with the application of new technologies for the accurate analysis of its toxic components and the development of efficient detoxification protocols. Some Asian countries started small clinical trials to evaluate the potency and safety of different marketed aconite preparations. The current review summarizes therapeutic uses of aconite preparations in China, Taiwan, India, and Japan. It also highlights clinical trial results with special emphasis on their limitations. Modern drugs and pharmacopoeial preparations derived from aconite are also discussed.

Selective activation of α7 nicotinic acetylcholine receptor by PHA-543613 improves Aß25-35-mediated cognitive deficits in mice.

Agonists of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as therapeutic approaches for managing cognitive deficits in Alzheimer's disease (AD). Present study was designed to evaluate the effect of α7 nAChR selective activation by PHA-543613 (PHA) on beta-amyloid (Aß)25-35-mediated cognitive deficits in mice. For this purpose, PHA (1mg/kg, i.p.), a selective α7 nAChR agonist, and galantamine (Gal) (3mg/kg, s.c.), an acetylcholine-esterase inhibitor (AChEI) effects on α7 nAChR were tested in Aß25-35-received (intracerebroventricular, 10 nmol) mice model of AD. Methyllycaconitine (MLA) (1mg/kg, i.p.), a α7 nAChR antagonist, was used for receptor blockage effects evaluation. Working and reference memory in animals was assessed by the Morris water maze (MWM) task. The mRNA and protein levels of α7 subunit were analyzed by real-time PCR and Western blotting, respectively. PHA and Gal, ameliorate Aß-impaired working and reference memory. However, Gal had less effect than PHA in this regard. Pretreatment with MLA reverses both Gal and PHA effects in MWM. PHA and Gal treatment prevent Aß-induced α7 subunit protein reduction, but Gal has lesser effect than PHA. This effect blocked by pretreatment with MLA. In neither the pretreatment nor treatment group, the mRNA levels of nAChR α7 subunit were significantly changed. Therefore, α7 nAChR activation, reduces Aß-induced cognitive deficits and increases the α7 protein level and subsequent neuron survival. However, blockage of receptor, increases Aß toxicity and cognitive impairment and reduces the α7 nAChR protein level and flowing neuroprotection.