1: J Nat Prod. 2005 Jul;68(7):1031-6.

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Myo-inositol-derived glycolipids with anti-inflammatory activity from Solanum lanceolatum.

Herrera-Salgado Y, Garduno-Ramirez ML, Vazquez L, Rios MY, Alvarez L.

Centro de Investigaciones Quimicas, Universidad Autonoma del Estado de Morelos, Avenida Universidad 1001, Chamilpa, 62210, Cuernavaca, Morelos, Mexico.

Lanceolitols A1-A7 (1-7) and B1-B7 (9-15), two series of new myo-inositol-derived glycolipid analogues, in which a sugar moiety is replaced by a fatty acid esterified myo-inositol moiety, were isolated from the leaves of Solanum lanceolatum. Their structures were elucidated on the basis of spectroscopic analysis (1H NMR, 13C NMR, 1H-1H COSY, HMQC, HMBC, and HRFABMS), as well as chemical analysis. All the compounds showed in vivo anti-inflammatory activity against ear edema in mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA). In vitro enzyme inhibition studies showed that the mixture of lanceolitols A1-A7 inhibited by 58.56% phospholipase A2 from bee venom, while the mixture of lanceolitols B1-B7 was cyclooxygenase-2 (COX-2) inhibitors (IC50 = 237 microM).

PMID: 16038543 [PubMed - indexed for MEDLINE]

2: Brain Res. 2005 May 10;1043(1-2):231-5.

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Evidence for peripherally antinociceptive action of propofol in rats: behavioral and spinal neuronal responses to subcutaneous bee venom.

Sun YY, Li KC, Chen J.

Pain Research Center, Institute of Neuroscience, Fourth Military Medical University, 17 West Chang-le Road, Xi'an 710032, PR China.

In the present study, behavioral and in vivo electrophysiological methods were used to examine the peripheral effects of propofol on tonic ongoing pain-related responses produced by subcutaneous bee venom-induced inflammatory pain state. Local administration of 0.5 microg propofol produced significant suppression of the well-established ongoing pain responses in both conscious rats and dorsal horn nociceptive neurons. The locally antinociceptive action of propofol is not caused by systemic effect, because contralateral administration of the same dose of drug did not produce any effect. This result indicates that besides central actions, propofol has peripherally antinociceptive action as well.

PMID: 15862538 [PubMed - indexed for MEDLINE]

3: Evid Based Complement Alternat Med. 2005 Mar;2(1):79-84.

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An Overview of Bee Venom Acupuncture in the Treatment of Arthritis.

Lee JD, Park HJ, Chae Y, Lim S.

Bee venom acupuncture (BVA), as a kind of herbal acupuncture, exerts not only pharmacological actions from the bioactive compounds isolated from bee venom but also a mechanical function from acupuncture stimulation. BVA is growing in popularity, especially in Korea, and is used primarily for pain relief in many kinds of diseases. We aimed to summarize and evaluate the available evidence of BVA for rheumatoid arthritis and osteoarthritis. Computerized literature searches for experimental studies and clinical trials of BVA for arthritis were performed on the databases from PUBMED, EMBASE and the Cochrane Library. In addition, two leading Korean journals (The Journal of Korean Society for Acupuncture and Moxibustion and The Journal of Korean Oriental Medicine) were searched for relevant studies. The search revealed 67 studies, 15 of which met our criteria. The anti-inflammation and analgesic actions of BVA were proved in various kinds of animal arthritic models. Two randomized controlled trials and three uncontrolled clinical trials showed that BVA was effective in the treatment of arthritis. It is highly likely that the effectiveness of BVA for arthritis is a promising area of future research. However, there is limited evidence demonstrating the efficacy of BVA in arthritis. Rigorous trials with large sample size and adequate design are needed to define the role of BVA for these indications. In addition, studies on the optimal dosage and concentration of BVA are recommended for future trials.

PMID: 15841281 [PubMed - as supplied by publisher]

4: Pharmacol Res. 2005 Feb;51(2):183-8.

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Antinociceptive mechanisms associated with diluted bee venom acupuncture (apipuncture) in the rat formalin test: involvement of descending adrenergic and serotonergic pathways.

Kim HW, Kwon YB, Han HJ, Yang IS, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, San 56-1, Shilim-dong, Kwanak-gu, Seoul 151-742, South Korea.

In a previous report, subcutaneous injection of diluted bee venom (dBV) into a specific acupuncture point (Zusanli, ST36), a procedure termed apipuncture, was shown to produce an antinociceptive effect in the rat formalin pain model. However, the central antinociceptive mechanisms responsible for this effect have not been established. Traditional acupuncture-induced antinociception is considered to be mediated by activation of the descending pain inhibitory system (DPIS) including initiation of its opioidergic, adrenergic and serotonergic components. The purpose of the present study was to investigate whether the antinociceptive effect of apipuncture is also mediated by the DPIS. Behavioral experiments verified that apipuncture significantly reduces licking behavior in the late phase of formalin test in rats. This antinociceptive effect of apipuncture was not modified by intrathecal pretreatment with naltrexone (a non-selective opioid receptor antagonist), prazosin (an alpha1 adrenoceptor antagonist) or propranolol (an beta adrenoceptor antagonist). In contrast, intrathecally injected idazoxan (an alpha2 adrenoceptor antagonist) or intrathecal methysergide (a serotonin receptor antagonist) significantly reversed apipuncture-induced antinociception. These results suggest that apipuncture-induced antinociception is produced by activation of alpha2 adrenergic and serotonergic components of the DPIS.

PMID: 15629266 [PubMed - indexed for MEDLINE]

5: J Vet Sci. 2004 Dec;5(4):309-18.

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General pharmacological profiles of bee venom and its water soluble fractions in rodent models.

Kim HW, Kwon YB, Ham TW, Roh DH, Yoon SY, Kang SY, Yang IS, Han HJ, Lee HJ, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea.

Recently, the antinociceptive and anti-inflammatory efficacy of bee venom (BV, Apis mellifera) has been confirmed in rodent models of inflammation and arthritis. Interestingly, the antinociceptive and anti-inflammatory effect of whole BV can be reproduced by two water-soluble fractions of BV (>20 kDa:BVAF1 and<10 kDa: BVAF3). Based on these scientific findings, BV and its effective water-soluble fractions have been proposed as potential anti-inflammatory and antinociceptive pharmaceuticals. While BV's anti-inflammatory and antinociceptive properties have been well documented, there have been no careful studies of potential, side effects of BV and its fractions when administered in the therapeutic range (BV, 5 microgram/kg; BVAF1, 0.2 microgram/kg: BVAF3, 3 microgram/kg; subcutaneous or intradermal). Such information is critical for future clinical use of BV in humans. Because of this paucity of information, the present study was designed to determine the general pharmacological/physiological effects of BV and its fractions administration on the rodent central nervous, cardiovascular, respiratory and gastrointestinal system. Subcutaneous BV and its fractions treatment did not produce any significant effects on general physiological functions at the highest dose tested (200-fold and 100-fold doses higher than that used clinically, respectively) except writhing test. These results demonstrate that doses of BV or BV subfractions in the therapeutic range or higher can be used as safe antinociceptive and anti-inflammatory agents.

PMID: 15613814 [PubMed - indexed for MEDLINE]

6: Mol Cells. 2004 Apr 30;17(2):329-33.

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Bee venom acupoint stimulation increases Fos expression in catecholaminergic neurons in the rat brain.

Kwon YB, Han HJ, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea.

Fos immunocytochemistry was combined with tyrosine hydroxylase (TH) or dopamine-beta-hydroxylase (DBH) immunolabeling to examine brainstem catecholaminergic neuronal activation resulting from bee venom (BV) stimulation of the Zusanli acupoint (ST36) in Sprague-Dawley rats. BV injection into the Zusanli acupoint caused increased Fos expression in catecholaminergic neurons located in the hypothalamic arcuate nucleus (Arc), the dorsal raphe (DR), the A5 cell group (A5) and the locus coeruleus (LC). BV acupoint stimulation significantly increased Fos-TH double-labeled neurons in the Arc, LC and DR. Fos-DBH positive neurons were also increased by BV acupoint stimulation in the LC and A5. In contrast BV stimulation of a non-acupoint only increased Fos expression and Fos-TH double-labeled neurons in the Arc. These data indicate that BV acupoint stimulation activates brainstem catecholaminergic neurons and that this activation underlies BV acupoint-induced antinociception.

PMID: 15179050 [PubMed - indexed for MEDLINE]

7: Zhong Yao Cai. 2003 Jun;26(6):456-8.

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[Advances in the study of bee venom and its clinical uses]

[Article in Chinese]

Liu H, Tong F.

College of Zoological Sciences, Zhejiang University, Hangzhou 310029, Zhejiang, China.

Publication Types:

·       Review

PMID: 14669739 [PubMed - indexed for MEDLINE]

8: Sheng Li Xue Bao. 2003 Oct 25;55(5):516-24.

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Effects of intravenous Injections Paederiae and Stauntonia on spontaneous pain, hyperalgesia and inflammation induced by cutaneous chemical tissue injury in the rat.

Peng XL, Gao XL, Chen J, Huang X, Chen HS.

Pain Research Center, Institute of Neuroscience, The Fourth Military Medical University, Xi' an 710032.

To study whether commercial traditional Chinese medicinal preparations Injection Paederiae (IP) or Injection Stauntonia (IS) has anti-nociceptive and/or anti-inflammatory effects, we used two persistent pain models (bee venom and formalin test) to evaluate the systemic effects of IP or IS on the chemical tissue injury-induced persistent spontaneous pain-related responses (PSPR), primary thermal/mechanical hyperalgesia and inflammation in conscious rats. Injection of bee venom (BV, 0.1 mg, 50 microl) into the plantar surface of one hind paw resulted in not only a 1-h monophasic PSPR such as flinching reflex in the injected paw and a subsequent period of 3-4 days primary heat and mechanical hyperalgesia, but also a marked sign of inflammation, including redness and swelling of the plantar surface in the injected paw. Intraplantar injection of formalin produced two phases of PSPR as reported previously. Systemic pre-treatment with three doses of IP (0.32, 1.6 and 9.0 ml/kg, 500%) or IS (0.32, 1.6 and 9.0 ml/kg, 250%) produced a dose-dependent suppression of the BV- or formalin-induced flinching reflex of 1 h time course as compared with the saline control group. Post-treatment with IP or IS 5 min after BV injection also produced a significant suppression of the flinching reflex in both BV test and formalin test respectively, as compared with the control group. However, neither pre- nor post-treatment with IP or IS produced any significantly suppressive effect on the BV-induced primary heat and mechanical hyperalgesia and inflammation. The analgesia produced by IP or IS was not mediated by the endogenous opioid receptors since naloxone, a non-selective opioid receptor antagonist, had no reversal effect on the IP and IS-produced analgesia in the BV-induced PSPR. Our present results suggest that IP or IS might prevent and relieve clinical persistent spontaneous pain, but without any anti-nociceptive and anti-inflammatory effects on the primary heat hyperalgesia, mechanical hyperalgesia, as well as inflammatory responses. The BV test might be a useful model of pain to evaluate and screen anti-nociceptive and anti-inflammatory effects of certain compounds of the Chinese medicinal herbs on the pathological origins of pain.

PMID: 14566397 [PubMed - indexed for MEDLINE]

9: Neuroscience. 2003;121(2):459-72.

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Differential antinociceptive effects induced by a selective cyclooxygenase-2 inhibitor (SC-236) on dorsal horn neurons and spinal withdrawal reflexes in anesthetized spinal rats.

You HJ, Morch CD, Chen J, Arendt-Nielsen L.

Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Fredrik Bajers Vej 7D-3, DK-9220, Aalborg, Denmark. lan@smi.auc.dk

The aim of present study was to examine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold (1.5xT, the intensity threshold) electrical stimuli with different frequencies (3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced inflammation and central sensitization. During normal conditions, the responses of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli (3 Hz, wind-up) were depressed by systemic administration of SC-236 as well as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both the WDR neurons and the simultaneously recorded SMUs after electrical stimuli with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms underlying the generation of the C-fiber mediated late responses and the after-discharges may be different. The enhanced responsiveness of both WDR neurons and SMUs to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia) in the BV experiments was apparently depressed by SC-236, but not its vehicle. For electrical stimulation, the enhanced late responses and after-discharges, but not early responses, of both the WDR neurons and the simultaneously recorded SMUs were markedly depressed only by SC-236. This indicates that different central pharmacological mechanisms underlie the generation of these enhanced early, late responses, and after-discharges during BV-induced inflammation. The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities of both spinal cord dorsal horn neuron and spinal withdrawal reflex during BV-induced sensitization, indicating that COX-2 plays an important role in the maintenance of central sensitization.

PMID: 14522004 [PubMed - indexed for MEDLINE]

10: Inflamm Res. 2003 Mar;52(3):132-9.

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Analysis of the inflammatory response in the rat paw caused by the venom of Apis melifera bee.

Calixto MC, Triches KM, Calixto JB.

Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82, Florianopolis, SC, 88015-420, Brazil.

OBJECTIVE: This study examines the pro-inflammatory action caused by subcutaneous (s.c.) injection of the bee venom (BV) Apis melifera in the rat paw. METHODS: Male Wistar rats were used. The venom of Apis melifera was injected s.c. into the rat paw and the oedema formation and the activity of myeleperoxidase (MPO) were measured. RESULTS: Subcutaneous injection of BV caused dose-and time-dependent paw oedema (ED50 of 1.5 microg/paw) with peak at 30 min. The MPO activity increased about 1.6, 4.2 and 8.9 folds at 0.5, 4 and 6 h after s.c. injection of BV. The mast cell degranulating drug 48/80, pyrilamine or metysergide, inhibited BV-mediated oedema formation (88, 62 and 96%, respectively). Likewise, L-NAME, the NK1 antagonist FK 888, the B1 des-Arg9-[Leu8]-BK or B2 kinin antagonist Hoe 140 also antagonised the paw oedema induced by BV (60, 59, 49, and 49%, respectively). SR48968 and SR14280, respectively NK2 and NK3 antagonists and also indomethacin, inhibited by 31, 29 and 22%, respectively BV-induced oedema formation. In contrast, the PAF antagonist WEB 2086 or valeryl salycilate, did not affect the BV-induced paw oedema. The levels of MPO were inhibited by compound 48/80, cyproheptadine, Hoe 140, or by des-Arg9[Leu8]-BK (85, 61, 59, and 53%, respectively) measured 6 h after. CONCLUSION: These results indicate that the BV from Apis melifera causes a marked dose-and time-dependent oedema formation in the rat paw, an effect that is accompanied by intense leukocyte migration. The pro-inflammatory response induced by BV is mediated by several mechanisms, namely the release of histamine and/or serotonin from mast cells, activation of H1 histamine receptor, production of nitric oxide, the involvement of kinins through the activation of B1 and B2 receptors, and also tachykinins acting at NK1 receptor or and to a lesser extent at NK2 and NK3 receptors.

PMID: 12755378 [PubMed - indexed for MEDLINE]

11: J Pharmacol Sci. 2003 Feb;91(2):95-104.

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Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299.

Jang MH, Shin MC, Lim S, Han SM, Park HJ, Shin I, Lee JS, Kim KA, Kim EH, Kim CJ.

Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea.

To investigate whether bee venom (BV) induces apoptosis, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, terminal deoxynucleotidyl transferase- mediated dUTP nick end-labeling assay, 4,6-diamidino-2-phenylindole staining, flow cytometric analysis, and DNA fragmentation assay were performed on NCI-H1299 lung cancer cells treated with BV. Through morphological and biochemical analyses, it was demonstrated that NCI-H1299 cells treated with BV exhibit several features of apoptosis. In addition, reverse transcription-polymerase chain reaction and prostaglandin E(2) (PGE(2)) immunoassay were performed to verify whether BV possesses an inhibitory effect on the expression of cyclooxygenase (COX) and PGE(2 )synthesis. Expression of COX-2 mRNA and synthesis of PGE(2) were inhibited by BV. These results suggest the possibility that BV may exert an anti-tumor effect on human lung cancer.

PMID: 12686753 [PubMed - indexed for MEDLINE]

12: Chembiochem. 2002 Jul 2;3(7):664-71.

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Erratum in:

·       Chembiochem. 2002 Aug 29;3(8):687.

Molecular basis of phospholipase A2 inhibition by petrosaspongiolide M.

Dal Piaz F, Casapullo A, Randazzo A, Riccio R, Pucci P, Marino G, Gomez-Paloma L.

Dipartimento di Chimica Organica e Biochimica Universita di Napoli Federico II via Cinthia 6, 80126 Napoli, Italy.

Petrosaspongiolide M (PM) is an anti-inflammatory marine metabolite that displays a potent inhibitory activity toward group II and III secretory phospholipase A(2) (PLA(2)) enzymes. The details of the mechanism, which leads to a covalent adduct between PLA(2) and gamma-hydroxybutenolide-containing molecules such as PM, are still a matter of debate. In this paper the covalent binding of PM to bee venom PLA(2) has been investigated by mass spectrometry and molecular modeling. The mass increment observed for the PM-PLA(2) adduct is consistent with the formation of a Schiff base by reaction of a PLA(2) amino group with the hemiacetal function (masked aldehyde) at the C-25 atom of the PM gamma-hydroxybutenolide ring. Proteolysis of the modified PLA(2) by the endoprotease LysC followed by HPLC MS analysis allowed us to establish that the PLA(2) alpha-amino terminal group of the Ile-1 residue was the only covalent binding site for PM. The stoichiometry of the reaction between PM and PLA(2) was also monitored and results showed that even with excess inhibitor, the prevalent product is a 1:1 (inhibitor:enzyme) adduct, although a 2:1 adduct is present as a minor component. The 2:1 adduct was also characterized, which showed that the second site of reaction is located at the epsilon -amino group of the Lys-85 residue. Similar results in terms of the reaction profile, mass increments, and location of the PLA(2) binding site were obtained for manoalide, a paradigm for irreversible PLA(2) inhibitors, which suggests that the present results may be considered of more general interest within the field of anti-inflammatory sesterterpenes that contain the gamma-hydroxybutenolide pharmacophore. Finally, a 3D model, constrained by the above experimental results, was obtained by docking the inhibitor molecule into the PLA(2) binding site through AFFINITY calculations. The model provides an interesting insight into the PM-PLA(2) inhibition process and may prove useful in the design of new anti-inflammatory agents that target PLA(2) secretory enzymes.

PMID: 12325001 [PubMed - indexed for MEDLINE]

13: Biol Pharm Bull. 2002 Jun;25(6):710-7.

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Participation of the arachidonic acid cascade pathway in macrophage binding/uptake of oxidized low density lipoprotein.

Beppu M, Watanabe M, Sunohara M, Ohishi K, Mishima E, Kawachi H, Fujii M, Kikugawa K.

School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.

Arachidonic acid cascade inhibitors, including phospholipase A2 inhibitors, dexamethasone and quinacrine (mepacrine), cyclooxygenase inhibitors, indomethacin and aspirin, and lipoxygenase inhibitor AA861, prevented foam cell formation and cholesterol accumulation in the incubation of thioglycollate-induced mouse peritoneal macrophages with oxidized low density lipoprotein (LDL) at 37 degrees C for 24 h. These inhibitors similarly prevented foam cell formation of fibronectin- and Ca ionophore A23187-stimulated macrophages. Binding and/or uptake of Dil (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine)-acetyl LDL by macrophages at 37 degrees C for 3h and arachidonic acid release from macrophages at 37 degrees C for 4h were inhibited by dexamethasone. Exogenously added phospholipase A2 of bee venom and Crotalus adamanteous venom increased arachidonic acid release during incubation for 2 h, and increased macrophage binding and/or uptake of Dil-acetyl LDL at 37 degrees C for 3 h, and foam cell formation at 37 degrees C for 24 h. Protein kinase inhibitors, ML-9 and staurosporine, that inhibited macrophage binding and/or uptake of Dil-acetyl LDL did not inhibit arachidonic acid release, indicating that protein phosphorylation was not involved in the arachidonic acid pathway in the macrophage scavenger receptor activation. Nordihydroguaiaretic acid that inhibited arachidonic acid release prevented binding and/or uptake of Dil-acetyl LDL. The release of arachidonic acid was not enhanced by fibronectin-stimulation, indicating that Ca influx-dependent stimulation of macrophage activity was not through the activation of phospholipase A2. These results indicate that, as well as the fibronectin-stimulated Ca influx pathway and protein phosphorylation pathway, the arachidonic acid pathway participated in the activation of macrophages to bind and take up oxidized LDL.

PMID: 12081134 [PubMed - indexed for MEDLINE]

14: Life Sci. 2002 May 31;71(2):191-204.

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The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats.

Kwon YB, Lee HJ, Han HJ, Mar WC, Kang SK, Yoon OB, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Suwon, South Korea.

We recently demonstrated that bee venom (BV) injection into the Zusanli acupoint produced a significantly more potent anti-inflammatory and antinociceptive effect than injection into a non-acupoint in a Freund's adjuvant induced rheumatoid arthritis (RA) model. However, the precise BV constituents responsible for these antinociceptive and/or anti-inflammatory effects are not fully understood. In order to investigate the possible role of the soluble fraction of BV in producing the anti-arthritic actions of BV acupuncture, whole BV was extracted into two fractions according to solubility (a water soluble fraction, BVA and an ethylacetate soluble fraction, BVE) and the BVA fraction was further tested.Subcutaneous BVA injection (0.9 mg/kg/day) into the Zusanli acupoint was found to dramatically inhibit paw edema and radiological change (i.e. new bone proliferation and soft tissue swelling) caused by Freund's adjuvant injection. BVA treatment also reduced the increase in serum interleukin-6 caused by RA induction to levels observed in non-arthritic animals. In addition, BVA therapy significantly reduced arthritis-induced nociceptive behaviors (i.e. nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia). Finally, BVA treatment significantly suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3 weeks post-adjuvant injection. In contrast, BVE treatment (0.05 mg/kg/day) failed to show any anti-inflammatory or antinociceptive effects on RA.The results of the present study demonstrate that BVA is the effective fraction of whole BV responsible for the antinociception and anti-inflammatory effects of BV acupuncture treatment. Thus it is recommended that this fraction of BV be used for long-term treatment of RA-induced pain and inflammation. However, further study is necessary to clarify which constituents of the BVA fraction are directly responsible for these anti-arthritis effects.

PMID: 12031688 [PubMed - indexed for MEDLINE]

15: Am J Chin Med. 2001;29(2):187-99.

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The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture.

Kwon YB, Kim JH, Yoon JH, Lee JD, Han HJ, Mar WC, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Suwon, Korea.

The aim of this investigation was to determine whether bee venom (BV) administered directly into an acupoint was a clinically effective and safe method for relieving the pain of patients with knee osteoarthritis (OA) as compared to traditional needle acupuncture. We evaluated the efficacy of BV acupuncture using both pain relief scores and computerized infrared thermography (IRT) following 4 weeks of BV acupuncture treatment. We observed that a significantly higher proportion of subjects receiving BV acupuncture reported substantial pain relief as compared with those receiving traditional needle acupuncture therapy. Furthermore, the IRT score was significantly improved and paralleled the level of pain relief.

Publication Types:

·       Clinical Trial

·       Randomized Controlled Trial

PMID: 11527062 [PubMed - indexed for MEDLINE]

16: Neurosci Lett. 2001 Aug 3;308(2):133-7.

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Visceral antinociception produced by bee venom stimulation of the Zhongwan acupuncture point in mice: role of alpha(2) adrenoceptors.

Kwon YB, Kang MS, Han HJ, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Suwon 441-744, South Korea.

The goal of the present study was to determine whether bee venom (BV) injection into the Zhongwan acupoint (CV12), compared to injection into a non-acupoint, produced antinociception in an acetic acid-induced visceral pain model. This was accomplished by injecting BV subcutaneously into the Zhongwan acupoint or into a non-acupoint 30 min before intraperitoneal injection of acetic acid in ICR mice. BV injection into the acupoint produced a dose dependent suppression of acetic acid-induced abdominal stretches and of acetic acid-induced Fos expression in the spinal cord and the nucleus tractus solitarii. In contrast BV injection into the non-acupoint only produced antinociception at the highest dose of BV tested. Naloxone pretreatment did not alter the antinociceptive effect of BV acupoint injection on the abdominal stretch reflex. On the other hand, pretreatment with the alpha 2-adrenoceptor antagonist, yohimbine completely blocked the antinociceptive effect of BV acupoint injection. These results imply that BV acupoint stimulation can produce visceral antinociception that is associated with activation of alpha 2-adrenoceptors, but not with naloxone-sensitive opioid receptors.

PMID: 11457577 [PubMed - indexed for MEDLINE]

17: Acupunct Electrother Res. 2001;26(1-2):59-68.

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Antinociceptive effects of bee venom acupuncture (apipuncture) in rodent animal models: a comparative study of acupoint versus non-acupoint stimulation.

Kwon YB, Kang MS, Kim HW, Ham TW, Yim YK, Jeong SH, Park DS, Choi DY, Han HJ, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Suwon, South Korea.

From a clinical perspective, the alternative forms of acupoint stimulation including electroacupuncture, moxibustion and acupressure appear to have more potent analgesic effects than manual needle acupuncture. Bee venom (BV) injection has also been reported to produce persistent nociceptive stimulation and to cause neuronal activation in the spinal cord. In previous study, we observed that BV stimulation into acupoint, namely BV acupuncture or Apipuncture, produced more potent anti-inflammatory and antinociceptive potency in rodent arthritis model as comparing with that of non-acupoint injection. Based on previous report, we decided to further investigate that BV injection into an acupoint produces antinociception as a result of its potent chemical stimulatory effect in both abdominal stretch assay and formalin test. Different doses of BV were injected into an acupoint or a non-acupoint 30 min prior to intraplantar formalin injection or intraperitoneal acetic acid injection. Using the abdominal stretch assay, we found that the high dose of BV (1:100 diluted in 20microl saline) produced a potent antinociceptive effect irrespective of the site of BV injection. In contrast the antinociceptive effect observed in both the writhing and formalin tests following administration of a low dose of BV (1:1000 diluted in 20microl saline) was significantly different between acupoint and non-acupoint sites. BV injection into an acupoint (Zhongwan, Cv. 12) was found to produce significantly greater antinociception than non-acupoint injection (10 mm from Zhongwan, Cv. 12) in the abdominal stretch assay. Similarly, in the formalin test, acupoint (Zusanli, St. 36) injection of BV produced more potent antinociception than non-acupoint injection (gluteal muscle). In contrast, BV injection into an arbitrary non-acupoint site on the back did not produce antinociception in either the writhing or formalin test. These results indicate that BV injection directly into an acupoint can produce a potent antinociceptive effect and suggest that this alternative form of acupoint stimulation (Apipuncture) may be a promising method for the relief of pain.

PMID: 11394494 [PubMed - indexed for MEDLINE]

18: Neuropeptides. 2001 Feb;35(1):32-44.

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Differential roles of spinal neurokinin 1/2 receptors in development of persistent spontaneous nociception and hyperalgesia induced by subcutaneous bee venom injection in the conscious rat.

Zheng JH, Chen J.

Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, P.R. China.

To evaluate the roles of spinal neurokinin receptors in the development of persistent nociception and hyperalgesia to thermal and mechanical stimuli induced by subcutaneous (s.c.) bee venom injection, effects of intrathecal (i.t.) pre- or post-treatment with a non-selective antagonist of (NK1/2) receptors, [D-Arg1,D-Trp7,9,Leu11] substance P (spantide), and a selective NK3 receptor antagonist, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl acetamide (SR142801) were assessed in conscious rat. Injection of bee venom s.c. into the plantar surface of one hind paw resulted in a pathological pain phenomenon characterized by a 1-2 h single phase of persistent spontaneous nociceptive behaviors (continuously flinching the injected paw) and a 72-96 h profound primary thermal and mechanical hyperalgesia in the injection site and a secondary thermal hyperalgesia in the non-injected hindpaw. Pre-treatment with spantide i.t. at 0.05 microg, 0.5 microg and 5 microg produced a dose-related suppression of the bee venom-induced flinching reflex during the whole time course and the inhibitory rate was 24 +/- 12.60% (35.38 +/- 4.12 flinches/5 min, n=5), 48 +/- 6.75% (24.53 +/- 2.90 flinches/5 min, n=5) and 60 +/- 7.69% (18.88 +/- 3.58 flinches/5 min, n=5) respectively when compared with the saline control group (46.80 +/- 2.60 flinches/5 min, n=5). Post-treatment of spantide i.t. at the highest dose (5 microg) used in the present study 5 min after bee venom injection also produced a 49% suppression of the flinching reflex in the control group [post-spantide vs saline: 19.42 +/- 3.15 (n=5) vs 38.42 +/- 3.25 flinches/5 min (n=5)]. Moreover, i.t. pre-treatment with 5 microg spantide partially prevented the primary and secondary thermal hyperalgesia from occurring, while it did not show any influence on the development of primary mechanical hyperalgesia. Neither the established thermal nor mechanical hyperalgesia identified in the above sites was affected by i.t. post-treatment with the same dose of spantide 3 h after bee venom injection. Pre and post-treatment of SR142801 did not produce any significant effect on the bee venom-induced spontaneous pain and thermal and mechanical hyperalgesia. Our present result suggests that activation of spinal NK1/2 receptors is involved in both induction and maintenance of the persistent spontaneous nociception, while it is only involved in induction of the primary and secondary thermal, but not primary mechanical hyperalgesia induced by s.c. bee venom injection. The spinal NK3 receptor seems not likely to be involved in the bee venom-induced behavioral response characterized by spontaneous pain and thermal and mechanical hyperalgesia.
Copyright 2001 Harcourt Publishers Ltd.

PMID: 11346308 [PubMed - indexed for MEDLINE]

19: J Vet Med Sci. 2001 Mar;63(3):251-9.

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Bee venom pretreatment has both an antinociceptive and anti-inflammatory effect on carrageenan-induced inflammation.

Lee JH, Kwon YB, Han HJ, Mar WC, Lee HJ, Yang IS, Beitz AJ, Kang SK.

Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Suwon, South Korea.

Although the injection of bee venom (BV) has been reported to evoke tonic pain and hyperalgesia, there is conflicting evidence in the literature indicating that BV can also exert an anti-inflammatory and antinociceptive effects on inflammation. In this regard, BV has been traditionally used in Oriental medicine to relieve pain and to treat chronic inflammatory diseases such as rheumatoid arthritis. The present study was designed to test the hypothesis that BV induces acute nociception under normal conditions, but that it can serve as a potent anti-inflammatory and antinociceptive agent in a localized inflammatory state. The experiments were designed to evaluate the effect of BV pretreatment on carrageenan (CR)-induced acute paw edema and thermal hyperalgesia. In addition, spinal cord Fos expression induced by peripheral inflammation was quantitatively analyzed. In normal animals subcutaneous BV injection into the hindlimb was found to slightly increase Fos expression in the spinal cord without producing detectable nociceptive behaviors or hyperalgesia. In contrast pretreatment with BV (0.8 mg/kg) 30 min prior to CR injection suppressed both the paw edema and thermal hyperalgesia evoked by CR. In addition, there was a positive correlation between the percent change in paw volume and the expression of Fos positive neurons in the spinal cord. These results indicate that BV pretreatment has both antinociceptive and anti-inflammatory effects in CR-induced inflammatory pain. These data also suggest that BV administration may be useful in the treatment of the pain and edema associated with chronic inflammatory diseases.

PMID: 11307924 [PubMed - indexed for MEDLINE]

20: Pain. 2001 Feb 15;90(3):271-80.

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Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses.

Kwon YB, Lee JD, Lee HJ, Han HJ, Mar WC, Kang SK, Beitz AJ, Lee JH.

Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Suwon 441-744, South Korea.

Bee venom (BV) has traditionally been used in Oriental medicine to relieve pain and to treat inflammatory diseases such as rheumatoid arthritis (RA). While several investigators have evaluated the anti-inflammatory effect of BV treatment, the anti-nociceptive effect of BV treatment on inflammatory pain has not been examined. Previous studies in experimental animals suggest that the therapeutic effect of BV on arthritis is dependent on the site of administration. Because of this potential site specificity, the present study was designed to evaluate the anti-nociceptive effect of BV injections into a specific acupoint (Zusanli) compared to a non-acupoint in an animal model of chronic arthritis. Subcutaneous BV treatment (1 mg/kg per day) was found to dramatically inhibit paw edema caused by Freund's adjuvant injection. Furthermore, BV therapy significantly reduced arthritis-induced nociceptive behaviors (i.e. the nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia). These anti-nociceptive/anti-inflammatory effects of BV were observed from 12 days through 21 days post-BV treatment. In addition, BV treatment significantly suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3 weeks post-adjuvant injection. Finally, injection of BV into the Zusanli acupoint resulted in a significantly greater analgesic effect on arthritic pain as compared to BV injection in to a more distant non-acupoint. The present study demonstrates that BV injection into the Zusanli acupoint has both anti-inflammatory and anti-nociceptive effects on Freund's adjuvant-induced arthritis in rats. These findings raise the possibility that BV acupuncture may be a promising alternative medicine therapy for the long-term treatment of rheumatoid arthritis.

PMID: 11207399 [PubMed - indexed for MEDLINE]

21: Am J Emerg Med. 2000 Jan;18(1):22-7.

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Phospholipase A2-induced coagulation abnormalities after bee sting.

Petroianu G, Liu J, Helfrich U, Maleck W, Rufer R.

University of Heidelberg at Mannheim, Department of Pharmacology and Toxicology, Germany. petroia@rumms.uni-mannheim.de

We will examine the correlation between various bee venom phospholipase A2 (PLA2) concentrations and several parameters of coagulation in human plasma in order to offer a rationale for requesting a particular laboratory coagulation test after bee sting(s). We will also evaluate in vitro the influence of clinically available drugs with a noncompetitive inhibitory effect on PLA2 on the anticoagulant effect of bee venom PLA2. Prothrombin index (PTi), partial thromboplastin time (PTT), antithrombin III (AT III), soluble fibrin monomers (SFM), the activity of coagulation factors I, II, V, and VIII, and thrombelastography (TEG) parameters (split point [Sp], reaction time [R], kinetic time [K], coagulation time [R + K], maximal amplitude [MA], and the growth angle [alpha]) were determined before and after addition of 1.4, 2.7, and 4.1 units (1, 2, and 3 microg protein respectively) of bee venom PLA2. Linear regression was used to determine the significance of the relationship between these coagulation parameters and bee venom PLA2 concentrations used. To study the influence of ketamine, lidocaine, magnesium, furosemide, and cromolyn on the anticoagulant effect of bee venom PLA2, PTi and factor II- and V-activities were measured before and after addition of 2.7 units of PLA2 and PLA2 plus one of the tested substances. Determinations of F II, PTi, F V, and F VIII showed a negative correlation to bee venom PLA2 concentration (r = -0.88, -0.86, -0.81, and -0.79 respectively). A positive correlation was found for PTT (r = 0.69). FII- activity and PTi correlated better with bee venom PLA2 concentration than other parameters. F I, AT III, and SFM showed no changes. Whereas Sp, R, and K were prolonged by bee venom PLA2 and a was reduced, there was no correlation to the PLA2 concentration. Addition of none of the 5 substances could correct the effects of bee venom PLA2 on the coagulation. In a patient with toxic reaction or a severe anaphylactic reaction after bee sting(s) we suggest determinations of FII and/or PTi. This will allow a quick and economical assessment of coagulation abnormalities after bee sting(s). Noncompetitive PLA2-inhibitors (ketamine, lidocaine, magnesium, furosemide, and cromolyn) are unable to correct in vitro the anticoagulant effect of bee venom PLA2. They cannot be recommended at this stage for this purpose. Further investigations with competitive PLA2-inhibitors are warranted.

PMID: 10674526 [PubMed - indexed for MEDLINE]

22: Neurosci Lett. 2000 Jan 7;278(1-2):41-4.

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Modulatory roles of the adenosine triphosphate P2x-purinoceptor in generation of the persistent nociception induced by subcutaneous bee venom injection in the conscious rat.

Zheng JH, Chen J.

Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, People's Republic of China.

To study the role of adenosine triphosphate (ATP) P2x-purinoceptor in the persistent nociceptive response induced by subcutaneous (s.c.) bee venom injection, we used a selective P2x receptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), to evaluate whether spinal P2x receptor play a role in development of spontaneous persistent pain. Injection s.c. of bee venom into the plantar surface of one hindpaw in the conscious rat produces a monophasic, prolonged persistent nociception characterized by continuously flinching reflex of the injected paw for 1-2 h. Intrathecal (i.t.) pretreatment with PPADS at two lower doses of 5 and 10 microg resulted in suppression of the flinching reflex in a dose dependent manner with the inhibitory rate 37 and 44%, respectively, when compared with the control group; whereas i.t. PPADS at a higher dose of 30 microg failed to produce any inhibitory effect. This result suggests that activation of P2x-purinoceptor in the spinal cord contributes to the induction of bee venom-induced prolonged persistent pain. However, the antinociceptive effect of ATP P2x-purinoceptor antagonist such as PPADS on clinical pathological pain seems to be limited due to its lack of effectiveness at higher dose.

PMID: 10643796 [PubMed - indexed for MEDLINE]

23: J Pharmacol Exp Ther. 1999 Apr;289(1):166-72.

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Effects of petrosaspongiolide M, a novel phospholipase A2 inhibitor, on acute and chronic inflammation.

Garcia-Pastor P, Randazzo A, Gomez-Paloma L, Alcaraz MJ, Paya M.

Departamento de Farmacologia, Universidad de Valencia, Facultad de Farmacia, Valencia, Spain.

The marine product petrosaspongiolide M is a novel inhibitor of phospholipase A2 (PLA2), showing selectivity for secretory PLA2 versus cytosolic PLA2, with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA2 (group III) and had no effect on group I enzymes (Naja naja and porcine pancreatic PLA2). Inhibition of PLA2 was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This marine metabolite (0.01-1.0 micromol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E2, leukotriene B4, and tumor necrosis factor-alpha in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B4 levels in serum and PGE2 levels in paw homogenates. In contrast with indomethacin, this marine compound did not reduce PGE2 levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation.

PMID: 10087000 [PubMed - indexed for MEDLINE]

24: Brain Res. 1998 Sep 28;806(2):175-85.

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Spatial and temporal expression of c-Fos protein in the spinal cord of anesthetized rat induced by subcutaneous bee venom injection.

Luo C, Chen J, Li HL, Li JS.

Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.

In order to study central neuronal components involved in subcutaneous (s.c.) bee venom-induced persistent pain (a new tonic pain model), we use Fos immunostaining technique to study the spatial and temporal patterns of neuronal activity in the spinal cord of anesthetized rats. Following intraplantar bee venom injection, Fos-like immunoreactive (ir) neurons were only seen from L1 to S3 rostrocaudally with distinct distribution at L4-5 segments. At segments of L1-2 and S1-3, Fos-ir labelings were diffusely and symmetrically distributed on both sides of the gray matter; however, at L4-5 segments, Fos-ir neurons were densely localized in medial portion of laminae I-II, less densely in laminae V-VI and a few in laminae VII and X ipsilateral to the injection side. No Fos labeling was seen in ventral horn of the spinal cord at L4-5 segments. Fos protein began to express only within lamina I at 0.5 h, but increased over the whole dorsal horn at 1 h and reached peak labeling at 2 h after bee venom. Expression of c-Fos in laminae I-II decreased at 4 h, and completely disappeared at 24 h, however, labeling in laminae V-VI disappeared much slowly and existed even at 96 h after bee venom. Within laminae III-IV, Fos-ir neurons could not be seen at 0.5 h, but began to be seen at 1 h and appeared to exist even at 24 h after bee venom. Systemic morphine suppressed c-Fos expression dose-dependently in both superficial and deep layers of dorsal horn and the latter region was much more sensitive to morphine than the former one. The present results demonstrated that prolonged neuronal activities in superficial and deep layers of dorsal horn were essential to mediation of bee venom induced tonic pain and may have different roles in generation and/or modulation of spontaneous pain and hyperalgesia and allodynia. Copyright 1998 Elsevier Science B.V.

PMID: 9739136 [PubMed - indexed for MEDLINE]

25: Pain. 1996 Aug;66(2-3):271-7.

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Comment in:

·       Pain. 1997 May;71(1):113-4.

·       Pain. 2000 Jan;84(1):111-2.

The bee venom test: a new tonic-pain test.

Lariviere WR, Melzack R.

Department of Psychology, McGill University, Montreal, Quebec, Canada.

The present study describes a new test of tonic pain to be used as an animal model of persistent pain. First, pain responses and edema produced by subcutaneous injection of increasing doses of honey bee venom into the hind paw of the rat were quantified. Second, the effect of morphine and aspirin on the pain responses was investigated. Finally, the response to concurrent injections of bee venom and formalin was examined. Subcutaneous injection of bee venom produced local inflammation, tonic-pain responses lasting from 10 min to more than 1 h, and marked edema lasting from 3 h to more than 48 h. Increasing doses of bee venom produced higher mean pain scores and increased durations of responding. The time course of the edema did not follow the time course of the pain responses. Analgesia was produced by morphine and aspirin, indicating that the bee venom test can be used to test analgesic drugs. Concurrent administration of bee venom and formalin produced pain responses similar to formalin alone, with a less profound interphase depression and a longer duration. The data suggest that the bee venom test is a valid animal model of experimental tonic pain.

PMID: 8880850 [PubMed - indexed for MEDLINE]

26: Eur J Pharmacol. 1995 Oct 24;285(3):281-8.

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Effects of marine 2-polyprenyl-1,4-hydroquinones on phospholipase A2 activity and some inflammatory responses.

Gil B, Sanz MJ, Terencio MC, De Giulio A, De Rosa S, Alcaraz MJ, Paya M.

Department of Pharmacology, University of Valencia, Faculty of Pharmacy, Spain.

Three 2-polyprenyl-1,4-hydroquinone derivatives (2-heptaprenyl-1,4-hydroquinone: IS1, 2-octaprenyl-1,4-hydroquinone: IS2 and 2-[24-hydroxy]-octaprenyl-1,4-hydroquinone: IS3) isolated from the Mediterranean sponge Ircinia spinosula, were evaluated for effects on phospholipase A2 activity of different origin (Naja naja venom, human recombinant synovial fluid and bee venom), as well as on human neutrophil function and mouse ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). IS1 interacted minimally with these responses. In contrast, IS2 and IS3 inhibited human recombinant synovial phospholipase A2 in a concentration-dependent manner, with minor effects on the rest of the enzymes. Both compounds slightly affected superoxide generation and degranulation in human neutrophils, whereas they decreased thromboxane B2 and leukotriene B4 synthesis and release in a mixed suspension of human platelets and neutrophils stimulated by ionophore A23187, with IC50 values in the microM range. IS3 was the most effective inhibitor of the synthesis of thromboxane B2 by human platelet microsomes and of leukotriene B4 by high speed supernatants from human neutrophils. IS2 and IS3 showed topical anti-inflammatory activity against the TPA-induced ear inflammation in mice, with similar effects on oedema and a higher inhibition of IS3 on leukocyte migration, estimated as myeloperoxidase activity in supernatants of ear homogenates. Some structure-activity relationships were established since differences in the prenylated chain attached to the hydroquinone moiety result in important modifications of these inflammatory responses.

PMID: 8575515 [PubMed - indexed for MEDLINE]

27: Brain Res. 1995 Feb 13;671(2):195-200.

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Melittin increases AMPA receptor affinity in rat brain synaptoneurosomes.

Bernard J, Chabot C, Gagne J, Baudry M, Massicotte G.

Universite du Quebec a Trois-Rivieres, Departement de Chimie-Biologie, Canada.

Recent experimental evidence suggests that phospholipase-induced changes in binding properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors account for the increase in synaptic response observed in long-term potentiation (LTP). In the present study, we report that treatment of rat telencephalic synaptoneurosomes with the bee venom peptide melittin, a potent activator of endogenous phospholipases, increased [3H]AMPA binding to the AMPA receptor. The action of melittin was concentration-dependent (EC50 value = 10 micrograms/ml) and did not require the presence of extracellular calcium. Saturation kinetic experiments revealed that the increase in [3H]AMPA binding produced by melittin was due to an enhancement in the affinity of the AMPA receptor, an effect markedly reduced by the phospholipase A2 (PLA2) inhibitor bromophenacyl bromide (BPB). In contrast to BPB, inhibitors of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism did not interfere with the melittin-induced increase in [3H]AMPA binding. In neonatal synaptoneurosomes, the effect of melittin on [3H]AMPA binding was significantly reduced when compared to adult synaptoneurosomes, an effect which is consistent with the observation that LTP is not present in very young animals. The results indicate that activation of endogenous phospholipases may be an important mechanism in the regulation of AMPA receptor properties in LTP.

PMID: 7743208 [PubMed - indexed for MEDLINE]

28: Agents Actions. 1994 Mar;41(1-2):111-3.

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Groups I, II and III extracellular phospholipases A2: selective inhibition of group II enzymes by indomethacin but not other NSAIDs.

Lobo IB, Hoult JR.

Pharmacology Group, King's College, London, U.K.

The three types (groups I, II and III) of stable extracellular 14 kDa phospholipase A2 enzymes differ in their primary amino acid sequences and their properties. It may thus be possible to design low-molecular weight inhibitors targeted to the secretory form of mammalian PLA2. This enzyme has been implicated in inflammatory disorders. We have studied the inhibition of four distinct PLA2 enzymes by a range of NSAIDs, using 3H-oleate release from prelabelled membranes of E. coli for assay. The enzymes used were cobra venom PLA2 (Naja naja, a group I enzyme), bee venom PLA2 (Apis mellifera, group III), recombinant human synovial PLA2 (group II) and rat peritoneal PLA2 (group II). Under the conditions of the 3H-oleate E. coli assay, 1 mM concentrations of aspirin, sodium salicylate, paracetamol (acetaminophen), oxphenbutazone, ibuprofen, flurbiprofen and nabumetone failed to inhibit significantly any of the four enzymes. However, indomethacin inhibited all four enzymes, although effects were greatest on the two group II enzymes (rat peritoneal and human synovial PLA2). Approximate IC50 values were 28 and 35 microM, respectively. Inhibition by indomethacin was not time dependent and was greater at micromolar rather than millimolar levels of calcium. We conclude that indomethacin but not the other tested classes of NSAID inhibits the group II PLA2 enzyme in a selective manner and suggest that this may be relevant both to its clinical spectrum and to the design of novel pharmaceutical leads.

PMID: 8079814 [PubMed - indexed for MEDLINE]

29: Inflammation. 1993 Jun;17(3):245-61.

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Effect of a series of 1-alkyl ether lipids on inhibition of phospholipase A2 activity and PAF responses.

Kohler C, Carroll M, Tarrant E, Torley L, Wissner A.

Oncology and Inflammation Section, Lederle Labs American Cyanamid Co., Pearl River, New York 10965.

Several 1-alkyl ether lipids were studied for their ability to inhibit PLA2 and antagonize PAF responses. Studies with synthetic micellar substrate (1-stearyl-2-arachidonyl phosphocholine), at concentrations ranging from 0.02 to 1000 microM, demonstrate that CL 118326 inhibits porcine pancreatic PLA2 in vitro. As the substrate concentration increases, there is a dose-dependent increase in the IC50 value (IC50 ranges: 1.6-84.6 micrograms/ml or 2.6-137 microM). CL 118326 inhibits mammalian pancreatic PLA2, but not snake or bee venom PLA2. CL 118326 inhibits thrombin (IC50 = 7.9 microM), but not Na arachidonate- (IC50 > 100 microM) induced platelet aggregation, indicative of inhibition of cellular PLA2. CL 118326 inhibits other PLA2-dependent processes such as antigen-induced leukotriene (LTC4) release (IC50 = 2.3 micrograms/ml or 3.8 microM) and histamine release (IC50 = 1.4 micrograms/ml or 2.2 microM) in basophil-enriched WBCs. Intradermal coinjection of CL 118326 (10 micrograms) with PLA2 into guinea pig skin inhibits pancreatic PLA2-induced increase in vascular permeability and leakage, but not snake or bee venom PLA2-induced leakage. CL 118326 shows no PAF-like agonist activity in stimulating rabbit platelet-rich plasma. It inhibits PAF-induced aggregation (IC50 = 5.8 microM), but not ADP-induced aggregation. CL 118326 has greater efficacy as a PLA2 inhibitor than as a PAF antagonist since the IC50-substrate concentration ratio for PLA2 inhibition is < or = 1.0 at substrate concentrations of 10-1000 microM while the IC50-agonist ratio for PAF antagonism is > 100. Results for four other compounds related to CL 118326 are also presented.

PMID: 8330926 [PubMed - indexed for MEDLINE]

30: Zhongguo Zhong Xi Yi Jie He Za Zhi. 1993 Apr;13(4):226-7, 198.

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[Comparison of anti-inflammatory, analgesic activities, anaphylactogenicity and acute toxicity between bee venom and its peptides]

[Article in Chinese]

Chen CY, Chen WX, Sun X.

Nanjing Institute of Biochemical Pharmacy.

Bee venom 1.0-2.0 mg/kg and bee venom peptides 1.0-2.0 mg/kg inhibited several inflammatory processes, such as ear swelling induced by xylene in mice, edema produced by injecting 1% carrageenin 0.1 ml beneath the plantar surface of hind paw in rats and showed a marked analgesic action induced by the hot plate and potassium antimony tartrate. Bee venom peptides had a markedly more effective action as compared with bee venom itself. The anaphylactogenicity of bee venom peptides was apparently milder than that of bee venom. The LD50 of bee venom ip in mice and bee venom peptides was 7.4 mg/kg and 7.9 mg/kg respectively.

PMID: 8400773 [PubMed - indexed for MEDLINE]

31: Planta Med. 1992 Dec;58(6):549-51.

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Cajucarinolide and isocajucarinolide: anti-inflammatory diterpenes from Croton cajucara.

Ichihara Y, Takeya K, Hitotsuyanagi Y, Morita H, Okuyama S, Suganuma M, Fujiki H, Motidome M, Itokawa H.

Department of Pharmacognosy, Tokyo College of Pharmacy, Japan.

Cajucarinolide and isocajucarinolide, two new clerodane diterpenes, have been isolated from the cortices of Croton cajucara (Euphorbiaceae). These compounds possess anti-inflammatory activity and inhibit bee venom phospholipase A2 in vitro.

PMID: 1484896 [PubMed - indexed for MEDLINE]

32: J Pharmacol Exp Ther. 1992 Aug;262(2):866-73.

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Fuscoside: an anti-inflammatory marine natural product which selectively inhibits 5-lipoxygenase. Part I: Physiological and biochemical studies in murine inflammatory models.

Jacobson PB, Jacobs RS.

Department of Biological Sciences, University of California, Santa Barbara.

The biological and biochemical pharmacology of fuscoside, a novel anti-inflammatory marine natural product isolated from the Caribbean gorgonian Eunicea fusca, has recently been characterized using murine (part I) and human (part II) models of inflammation. Topically applied fuscoside (FSD) effectively inhibits phorbol myristate acetate (PMA)-induced edema in mouse ears at levels comparable with indomethacin over a 3.3-hr exposure period, and is significantly more efficacious than indomethacin over 24 hr in the PMA model. Histological preparations and quantification of the neutrophil-specific marker, myeloperoxidase, demonstrate that FSD inhibits neutrophil infiltration into PMA-induced regions of edema and inflammation. In systemic studies, where FSD is injected i.p. before the topical application of PMA, negligible effects on ear inflammation are observed. FSD does not inhibit bee venom or human synovial fluid phospholipase A2 up to concentrations of 500 microM. In calcium ionophore-activated cultures of mouse peritoneal macrophages, FSD selectively and irreversibly inhibits leukotriene C4 biosynthesis (IC50 = 8 microM), yet has negligible effects on prostaglandin E2 production. FSD is also without effect on the conversion of arachidonic acid to prostaglandin E2 by ram seminal vesicle cyclooxygenase. Chromatographic and spectroscopic studies suggest that FSD is not metabolized, and that drug uptake/binding by macrophages is time dependent, saturable and independent of active transport mechanisms. These studies represent the first report of an anti-inflammatory marine natural product that selectively inhibits leukotriene biosynthesis.

PMID: 1501127 [PubMed - indexed for MEDLINE]

33: Eur J Pharmacol. 1991 Jun 18;199(1):93-8.

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Anti-inflammatory effect of gangliosides in the rat hindpaw edema test.

Correa SG, Bianco ID, Riera CM, Fidelio GD.

Departamento de Bioquimica Clinica, CIOUIBIC, Facultad de Ciencias Quimicas, Cordoba, Argentina.

The influence of total brain gangliosides on acute inflammation was investigated using the rat hind paw edema test. Total gangliosides (10 micrograms/paw) inhibited the edema produced by the injection of bee venom phospholipase A2 (5 micrograms/paw) when the lipids were co-injected or injected 15 min before the phospholipase A2. Sulphatide (10 micrograms/paw) did not inhibit the edema but potentiated it. Gangliosides (40 micrograms/paw) inhibited the edema induced by carrageenin 1% when they were injected 1 h before the agent. However, gangliosides (up to 200 micrograms/paw) failed to inhibit the dextran-induced edema. The edema test was also used to investigate the effect of gangliosides on the production of mediators of inflammation by peritoneal adherent macrophages. Gangliosides inhibited the production of mediators of inflammation only when they were incubated with these cells before the stimulation with phospholipase A2 or carrageenin. Gangliosides did not inhibit the production of mediators of inflammation when arachidonic acid was added to the cells. These results suggest that the anti-inflammatory effect observed with gangliosides is mediated by inhibition at or before endogenous phospholipase activity.

PMID: 1716576 [PubMed - indexed for MEDLINE]

34: Br J Pharmacol. 1990 Feb;99(2):350-4.

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Anti-inflammatory activity of bee venom peptide 401 (mast cell degranulating peptide) and compound 48/80 results from mast cell degranulation in vivo.

Banks BE, Dempsey CE, Vernon CA, Warner JA, Yamey J.

Department of Physiology, University College London.

1. The relationship between the anti-inflammatory activity of the bee venom peptide 401 in the carrageenin-induced oedema of the rat hind paw and its mast cell degranulating activity has been reinvestigated. 2. Mast cell degranulation caused by compound 48/80 (10 mg kg-1) or by allergen challenge in rats sensitized to Nippostrongylus brasiliensis also suppressed rat hind paw oedema in the same test. 3. The anti-inflammatory activities of peptide 401 and compound 48/80 were partially suppressed by pretreatment of rats with mepyramine and methysergide, at doses (2.5 mg kg-1) that completely suppressed skin reactions to these mast cell-derived amines. Pretreatment of rats with compound 48/80 also suppressed the apparent anti-inflammatory actions of peptide 401 and of compound 48/80. 4. Injection of peptide 401 together with carrageenin increased the inflammatory response in the rat hind paw. 5. The anti-inflammatory activity of peptide 401 and of compound 48/80 in the carrageenin-induced swelling of the rat hind paw arises from mast cell degranulation in vivo.

PMID: 2328399 [PubMed - indexed for MEDLINE]

35: Biochem Pharmacol. 1988 Oct 1;37(19):3639-46.

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Inactivation of phospholipase A2 by manoalide. Localization of the manoalide binding site on bee venom phospholipase A2.

Glaser KB, Vedvick TS, Jacobs RS.

Department of Biological Sciences, University of California, Santa Barbara 93106.

The marine natural product manoalide (MLD), a potent inhibitor of phospholipases, completely inactivates bee venom phospholipase A2 (PLA2) by an irreversible mechanism. It has been proposed [K. B. Glaser and R. S. Jacobs, Biochem. Pharmac. 36, 2079 (1987)] that the reaction of MLD with PLA2 may involve the selective reactivity of MLD to a peptide sequence, possibly a Lys-X-X-Lys peptide. Localization of the MLD binding site on bee venom PLA2 demonstrated that upon MLD modification of bee venom PLA2 the only change in amino acid content was an apparent loss of Lys, corresponding to approximately three of the eleven Lys residues present. Selective chemical modification of Lys residues with [14C]maleic anhydride demonstrated that all eleven Lys residues on bee venom PLA2 were accessible to this reagent (11.6 mol maleyl group incorporated/mol of PLA2). Pretreatment of PLA2 with MLD (less than 0.7% residual activity) resulted in a molar ratio of 8.7, also consistent with the loss of three Lys residues upon modification by MLD. Reverse phase high performance liquid chromatography (RP-HPLC) of the cyanogen bromide (CNBr) digestion product of MLD-treated PLA2 produced three peaks (A280). The second peak showed the most intense absorbance at 434 nm. This material corresponded to residues 81-128, as determined by gas-phase microsequence analysis. Sequencing failure was observed at Lys-88 in the MLD-treated fragment. The control carboxymethylated-PLA2 fragment corresponding to residues 81-128 sequenced beyond Lys-88 without significant change in the expected yield. These data suggest that Lys-88 may correspond to one of the three MLD-modified Lys residues. The minor absorbance at 434 nm of the CNBr fragments containing residues 42-80 and 1-36 as compared to the fragment of residues 81-128 suggests that the major MLD binding fragment residues in residues 81-128.

PMID: 3178877 [PubMed - indexed for MEDLINE]

36: Biochem Pharmacol. 1987 Mar 1;36(5):733-40.

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Differential effects of manoalide on secreted and intracellular phospholipases.

Bennett CF, Mong S, Clarke MA, Kruse LI, Crooke ST.

Manoalide, a novel nonsteroidal sesterterpenoid, is a potent inhibitor of phospholipase A2 isolated from bee and cobra venoms. This report compares the inhibition by manoalide of phospholipase A2 in crude cytosol fractions from four mammalian tissues with that of four purified extracellular phospholipase A2's. Phospholipase A2 isolated from bee venom (Apis mellifera) was the most sensitive to inactivation by manoalide (IC50 approximately equal to 0.12 microM). Extracellular phospholipase A2 from rattlesnake and cobra venom was intermediate in sensitivity to manoalide (IC50 values of 0.7 and 1.9 microM respectively). Porcine pancreatic phospholipase A2 was relatively resistant to inactivation by manoalide (IC50 approximately equal to 30 microM). The phospholipase A2 assayed in crude cytosol fractions from four mammalian tissues exhibited IC50 values of 30 microM or greater. Cytosolic proteins as well as bovine serum albumin and poly-L-lysine (Mr = 57,000) protected purified bee venom phospholipase A2 from inactivation by manoalide. In contrast, amino acids such as lysine and alanine failed to protect the purified enzyme from inactivation. Proteins and certain amino acids, such as lysine, formed a chromogenic product when incubated with manoalide. These data suggest that lysine is capable of reacting with manoalide, but only when it is present in macromolecules is it capable of protecting phospholipase A2 from inactivation by manoalide. Because cellular proteins protect PLA2 from inactivation by manoalide, high concentrations of manoalide must be applied topically to produce statistically significant inactivation of intracellular phospholipase A2. Finally, a chemical model is presented which explains the formation of a chromogenic product when manoalide is incubated with proteins and amino acids.

PMID: 3103628 [PubMed - indexed for MEDLINE]

37: Acta Physiol Pharmacol Bulg. 1985;11(2):50-5.

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Further investigation on the antiinflammatory properties of adolapin--bee venom polypeptide.

Koburova KL, Michailova SG, Shkenderov SV.

Adolapin is a basic polypeptide (M. W. 11500) isolated from bee venom. It showed marked antiinflammatory and analgetic properties and inhibited cyclooxygenase. It was found that adolapin inhibited also the activity of bee venom phospholipase A2 (7 nmole/ml producing about 80% inhibition of 2.5 nmole/ml phospholipase). In addition it inhibited the lipoxygenase from human platelets (4.5 nmole/ml inhibited about 80% of the activity of 0.8 mg protein/ml). Adolapin (20 micrograms/kg) caused an elevation of c-GMP level in rat spleen and brain as well as a decrease of c-AMP in rat spleen. Adolapin was tested by the "tail flick" method which allowed the demonstration of its analgetic action. The partial inhibition of the analgetic effect of adolapin induced by naloxon, proved the participation of a central mechanism of action. Similar to other nonsteroid analgetics, adolapin displayed antipyretic effect (40 micrograms/kg caused an inhibition of the mean temperature rise about 62%.

PMID: 2996298 [PubMed - indexed for MEDLINE]

38: Eksp Med Morfol. 1984;23(3):143-8.

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[Antipyretic effect of a polypeptide from bee venom--adolapin]

[Article in Bulgarian]

Koburova K, Mikhailova S, Shkenderov S.

PMID: 6440766 [PubMed - indexed for MEDLINE]

39: Toxicon. 1982;20(1):317-21.

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Adolapin--a newly isolated analgetic and anti-inflammatory polypeptide from bee venom.

Shkenderov S, Koburova K.

Adolapin was isolated by a two-step procedure: gel filtration and chromatography on CM cellulose. The molecular mass of the polypeptide as determined by SDS electrophoresis and amino acid composition proved to be 11500 and 11092 respectively. Adolapin exhibited a potent analgesic effect demonstrated by the "writhing" test (ED50-0,016mg/kg) and by the Randall-Sellito's test (ED50-0,013 mg/kg). The anti-inflammatory activity of adolapin was most marked with regard to carrageenin, prostaglandin and adjuvant rat hind paw edemas and adjuvant polyarthritis. The adolapin effects are presumably due to its capacity to inhibit the prostaglandin synthase system, following a biphasic dose-response relationship. It is likely that central mechanisms are also involved in the analgetic action of adolapin.

PMID: 7080045 [PubMed - indexed for MEDLINE]

40: Naunyn Schmiedebergs Arch Pharmacol. 1980 Feb;311(1):105-7.

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Apamin, a nonspecific antagonist of smooth muscle relaxants.

Muller MJ, Baer HP.

Apamin, a peptide of bee venom, was shown to inhibit the relaxant responses of guinea-pig taenia caeci to ATP, noradrenaline, adenosine and, less effectively, to stimulation of noradrenergic inhibitory nerves. Thus apamin acts nonspecifically and, contrary to the suggestion of Vladimirova and Shuba (1978), the fact that inhibitory responses due to nerve stimulation and ATP are blocked by the toxin does not allow conclusions as to the possible transmitter role of ATP in these nerves.

PMID: 7366739 [PubMed - indexed for MEDLINE]

41: Klin Med (Mosk). 1954 Aug;32(8):20-5.

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[Therapeutic application of bee venom KF.]

[Article in Russian]


PMID: 13202305 [PubMed - OLDMEDLINE for Pre1966]