Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Biphasic Hormetic-like Effect of Lebecetin, a C-type Lectin of Snake Venom, on Formalin-induced Inflammation in Mice

Author(s): Carmela Belardo, Jed Jebali, Serena Boccella, Rosmara Infantino, Antimo Fusco, Michela Perrone, Roozbe Bonsale, Iolanda Manzo, Monica Iannotta, Damiana Scuteri*, Franca Ferraraccio, Iacopo Panarese, Giovanna Ferrara, Francesca Guida, Livio Luongo, Enza Palazzo, Najet Srairi-Abid, Naziha Marrakchi and Sabatino Maione*

Volume 22, Issue 8, 2024

Published on: 08 December, 2023

Page: [1391 - 1405] Pages: 15

DOI: 10.2174/1570159X22999231207105743

Price: $65

conference banner
Abstract

Background: Integrins, important extracellular matrix (ECM) receptor proteins, are affected by inflammation and can participate in the maintenance of many painful conditions. Although they are ubiquitous and changeable across all cell types, the roles of these cell adhesion molecules in pathological pain have not been fully explored.

Objective: We evaluated the effects of the subcutaneous injection of lebecetin, a C-type lectin isolated from Macrovipera lebetina snake venom, previously reported to inhibit α5β1 and αv integrin activity, on different components of inflammation induced by the formalin administration in the hind paw of mice.

Methods: The formalin-induced nocifensive behavior, edema, and histopathological changes in the hind paw associated with cytokine, iNOS, and COX2 expression, nociceptive-specific neuron activity, and microglial activation analysis in the spinal cord were evaluated in mice receiving vehicle or lebecetin pretreatment.

Results: Lebecetin inhibited the nocifensive responses in the formalin test, related edema, and cell infiltration in the injected paw in a biphasic, hormetic-like, and dose-dependent way. According to that hormetic trend, a reduction in pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha and upregulation of the anti-inflammatory cytokine IL-10 in the spinal cord were found with the lowest doses of lebecetin. Moreover, COX2 and iNOS expression in serum and spinal cord followed the same biphasic pattern of cytokines. Finally, nociceptive neurons sensitization and activated microglia were normalized in the dorsal horn of the spinal cord by lebecetin.

Conclusion: These findings implicate specific roles of integrins in inflammation and tonic pain, as well as in the related central nervous system sequelae.

« Previous Next »
Graphical Abstract

[1]
del Río-Portilla, F.; Hernández-Marín, E.; Pimienta, G.; Coronas, F.V.; Zamudio, F.Z.; Rodríguez de la Vega, R.C.; Wanke, E.; Possani, L.D. NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical beta-toxin sequence but with alpha-like physiological activity. Eur. J. Biochem., 2004, 271(12), 2504-2516.
[http://dx.doi.org/10.1111/j.1432-1033.2004.04181.x] [PMID: 15182366]
[2]
Rodríguez de la Vega, R.C.; Possani, L.D. Current views on scorpion toxins specific for K+-channels. Toxicon, 2004, 43(8), 865-875.
[http://dx.doi.org/10.1016/j.toxicon.2004.03.022] [PMID: 15208019]
[3]
Patil, C.G.; Walker, D.G.; Miller, D.M.; Butte, P.; Morrison, B.; Kittle, D.S.; Hansen, S.J.; Nufer, K.L.; Byrnes-Blake, K.A.; Yamada, M.; Lin, L.L.; Pham, K.; Perry, J.; Parrish-Novak, J.; Ishak, L.; Prow, T.; Black, K.; Mamelak, A.N. Phase 1 safety, pharmacokinetics, and fluorescence imaging study of Tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas. Neurosurgery, 2019, 85(4), E641-E649.
[http://dx.doi.org/10.1093/neuros/nyz125] [PMID: 31069381]
[4]
McDermott, A. Venom back in vogue as a wellspring for drug candidates. Proc. Natl. Acad. Sci. USA, 2020, 117(19), 10100-10104.
[http://dx.doi.org/10.1073/pnas.2004486117] [PMID: 32321825]
[5]
Pucca, M.B.; Peigneur, S.; Cologna, C.T.; Cerni, F.A.; Zoccal, K.F.; Bordon, K.C.F.; Faccioli, L.H.; Tytgat, J.; Arantes, E.C. Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages. Biochimie, 2015, 115, 8-16.
[http://dx.doi.org/10.1016/j.biochi.2015.04.010] [PMID: 25906692]
[6]
Jiménez-Vargas, J.M.; Restano-Cassulini, R.; Possani, L.D. Toxin modulators and blockers of hERG K+ channels. Toxicon, 2012, 60(4), 492-501.
[http://dx.doi.org/10.1016/j.toxicon.2012.03.024] [PMID: 22497787]
[7]
Cerni, F.A.; Pucca, M.B.; Amorim, F.G.; de Castro Figueiredo Bordon, K.; Echterbille, J.; Quinton, L.; De Pauw, E.; Peigneur, S.; Tytgat, J.; Arantes, E.C. Isolation and characterization of Ts19 Fragment II, a new long-chain potassium channel toxin from Tityus serrulatus venom. Peptides, 2016, 80, 9-17.
[http://dx.doi.org/10.1016/j.peptides.2015.06.004] [PMID: 26116782]
[8]
Siigur, J.; Aaspõllu, A.; Siigur, E. Biochemistry and pharmacology of proteins and peptides purified from the venoms of the snakes Macrovipera lebetina subspecies. Toxicon, 2019, 158, 16-32.
[http://dx.doi.org/10.1016/j.toxicon.2018.11.294] [PMID: 30472110]
[9]
Bazaa, A.; Luis, J.; Srairi-Abid, N.; Kallech-Ziri, O.; Kessentini-Zouari, R.; Defilles, C.; Lissitzky, J.C.; El Ayeb, M.; Marrakchi, N. MVL-PLA2, a phospholipase A2 from Macrovipera lebetina transmediterranea venom, inhibits tumor cells adhesion and migration. Matrix Biol., 2009, 28(4), 188-193.
[http://dx.doi.org/10.1016/j.matbio.2009.03.007] [PMID: 19351557]
[10]
Zouari-Kessentini, R.; Luis, J.; Karray, A.; Kallech-Ziri, O.; Srairi-Abid, N.; Bazaa, A.; Loret, E.; Bezzine, S.; El Ayeb, M.; Marrakchi, N. Two purified and characterized phospholipases A2 from Cerastes cerastes venom, that inhibit cancerous cell adhesion and migration. Toxicon, 2009, 53(4), 444-453.
[http://dx.doi.org/10.1016/j.toxicon.2009.01.003] [PMID: 19708222]
[11]
Baîram, D.; Aissa, I.; Louati, H.; Othman, H.; Abdelkafi-Koubaa, Z.; Krayem, N.; El Ayeb, M.; Srairi-Abid, N.; Marrakchi, N.; Gargouri, Y. Biochemical and monolayer characterization of Tunisian snake venom phospholipases. Int. J. Biol. Macromol., 2016, 89, 640-646.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.05.020] [PMID: 27164498]
[12]
Morjen, M.; Othman, H.; Abdelkafi-Koubaa, Z.; Messadi, E.; Jebali, J.; El Ayeb, M.; Abid, N.S.; Luis, J.; Marrakchi, N. Targeting α1 inserted domain (I) of α1β1 integrin by Lebetin 2 from M. lebetina transmediterranea venom decreased tumorigenesis and angiogenesis. Int. J. Biol. Macromol., 2018, 117, 790-799.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.05.230] [PMID: 29870815]
[13]
Gasmi, A.; Srairi, N.; Guermazi, S.; Dkhil, H.; Karoui, H.; El Ayeb, M. Amino acid structure and characterization of a heterodimeric disintegrin from Vipera lebetina venom. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol., 2001, 1547(1), 51-56.
[http://dx.doi.org/10.1016/S0167-4838(01)00168-6] [PMID: 11343790]
[14]
Jebali, J.; Bazaa, A.; Sarray, S.; Benhaj, K.; Karboul, A.; El Ayeb, M.; Marrakchi, N.; Gargouri, A. C-type lectin protein isoforms of Macrovipera lebetina: cDNA cloning and genetic diversity. Toxicon, 2009, 53(2), 228-237.
[http://dx.doi.org/10.1016/j.toxicon.2008.11.006] [PMID: 19059426]
[15]
Sarray, S.; Berthet, V.; Calvete, J.J.; Secchi, J.; Marvaldi, J.; Ayeb, M.E.; Marrakchi, N.; Luis, J. Lebectin, a novel C-type lectin from Macrovipera lebetina venom, inhibits integrin-mediated adhesion, migration and invasion of human tumour cells. Lab. Invest., 2004, 84(5), 573-581.
[http://dx.doi.org/10.1038/labinvest.3700088] [PMID: 15048137]
[16]
Jebali, J.; Fakhfekh, E.; Morgen, M.; Srairi-Abid, N.; Majdoub, H.; Gargouri, A.; El Ayeb, M.; Luis, J.; Marrakchi, N.; Sarray, S. Lebecin, a new C-type lectin like protein from Macrovipera lebetina venom with anti-tumor activity against the breast cancer cell line MDA-MB231. Toxicon, 2014, 86, 16-27.
[http://dx.doi.org/10.1016/j.toxicon.2014.04.010] [PMID: 24814013]
[17]
Sarray, S.; Delamarre, E.; Marvaldi, J.; Ayeb, M.E.; Marrakchi, N.; Luis, J. Lebectin and lebecetin, two C-type lectins from snake venom, inhibit α5β1 and αv-containing integrins. Matrix Biol., 2007, 26(4), 306-313.
[http://dx.doi.org/10.1016/j.matbio.2007.01.001] [PMID: 17300927]
[18]
Sarray, S.; Srairi, N.; Hatmi, M.; Luis, J.; Louzir, H.; Regaya, I.; Slema, H.; Marvaldi, J.; El Ayeb, M.; Marrakchi, N. Lebecetin, a potent antiplatelet C-type lectin from Macrovipera lebetina venom. Biochim. Biophys. Acta. Proteins Proteomics, 2003, 1651(1-2), 30-40.
[http://dx.doi.org/10.1016/S1570-9639(03)00232-2] [PMID: 14499586]
[19]
Sarray, S.; Srairi, N.; Luis, J.; Marvaldi, J.; El Ayeb, M.; Marrakchi, N. Lebecetin, a C-lectin protein from the venom of Macrovipera lebetina that inhibits platelet aggregation and adhesion of cancerous cells. Haemostasis, 2001, 31(3-6), 173-176.
[PMID: 11910182]
[20]
Montassar, F.; Darche, M.; Blaizot, A.; Augustin, S.; Conart, J.B.; Millet, A.; Elayeb, M.; Sahel, J.A.; Goazigo, A.R-L.; Sennlaub, F.; Marrakchi, N.; Messadi, E.; Guillonneau, X. Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization. FASEB J., 2017, 31(3), 1107-1119.
[http://dx.doi.org/10.1096/fj.201600351R] [PMID: 27974593]
[21]
Jebali, J.; Zakraoui, O.; Aissaoui, D.; Abdelkafi-Koubaa, Z.; Srairi-Abid, N.; Marrakchi, N.; Essafi-Benkhadir, K. Lebecetin, a snake venom C-type lectin protein, modulates LPS-induced inflammatory cytokine production in human THP-1-derived macrophages. Toxicon, 2020, 187, 144-150.
[http://dx.doi.org/10.1016/j.toxicon.2020.09.001] [PMID: 32918926]
[22]
Dina, O.A.; Parada, C.A.; Yeh, J.; Chen, X.; McCarter, G.C.; Levine, J.D. Integrin signaling in inflammatory and neuropathic pain in the rat. Eur. J. Neurosci., 2004, 19(3), 634-642.
[http://dx.doi.org/10.1111/j.1460-9568.2004.03169.x] [PMID: 14984413]
[23]
Hunskaar, S.; Hole, K. The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain. Pain, 1987, 30(1), 103-114.
[http://dx.doi.org/10.1016/0304-3959(87)90088-1] [PMID: 3614974]
[24]
Tjølsen, A.; Berge, O.G.; Hunskaar, S.; Rosland, J.H.; Hole, K. The formalin test: An evaluation of the method. Pain, 1992, 51(1), 5-17.
[http://dx.doi.org/10.1016/0304-3959(92)90003-T] [PMID: 1454405]
[25]
Tjolsen, A.; Hole, K. Animal models of analgesia. In: The Pharmacology of Pain; Dickenson, A.; Besson, J., Eds.; Springer Verlag: Berlin, 1997; 30, pp. 1-20.
[http://dx.doi.org/10.1007/978-3-642-60777-6_1]
[26]
Coderre, T.J.; Melzack, R. The role of NMDA receptor-operated calcium channels in persistent nociception after formalin-induced tissue injury. J. Neurosci., 1992, 12(9), 3671-3675.
[http://dx.doi.org/10.1523/JNEUROSCI.12-09-03671.1992] [PMID: 1326611]
[27]
Gu, N.; Yi, M.H.; Murugan, M.; Xie, M.; Parusel, S.; Peng, J.; Eyo, U.B.; Hunt, C.L.; Dong, H.; Wu, L.J. Spinal microglia contribute to sustained inflammatory pain via amplifying neuronal activity. Mol. Brain, 2022, 15(1), 86.
[http://dx.doi.org/10.1186/s13041-022-00970-3] [PMID: 36289499]
[28]
Schaible, H.G.; Richter, F. Pathophysiology of pain. Langenbecks Arch. Surg., 2004, 389(4), 237-243.
[http://dx.doi.org/10.1007/s00423-004-0468-9] [PMID: 15034717]
[29]
Demirovic, D.; Rattan, S.I.S. Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. Exp. Gerontol., 2013, 48(1), 94-98.
[http://dx.doi.org/10.1016/j.exger.2012.02.005] [PMID: 22525591]
[30]
Schirrmacher, V. Less can be more: The hormesis theory of stress adaptation in the global biosphere and its implications. Biomedicines, 2021, 9(3), 293.
[http://dx.doi.org/10.3390/biomedicines9030293] [PMID: 33805626]
[31]
Reynolds, A.R.; Hart, I.R.; Watson, A.R.; Welti, J.C.; Silva, R.G.; Robinson, S.D.; Da Violante, G.; Gourlaouen, M.; Salih, M.; Jones, M.C.; Jones, D.T.; Saunders, G.; Kostourou, V.; Perron-Sierra, F.; Norman, J.C.; Tucker, G.C.; Hodivala-Dilke, K.M. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med., 2009, 15(4), 392-400.
[http://dx.doi.org/10.1038/nm.1941] [PMID: 19305413]
[32]
Monteiro, D.A.; Kalinin, A.L.; Selistre-de-Araujo, H.S.; Rantin, F.T. Hormetic-like dose-response induced by alternagin-C, a protein isolated from urutu snake (Rhinocerophis alternatus) venom, in fish (Hoplias malabaricus) cardiac contractility. Toxicon, 2022, 205, 67-70.
[http://dx.doi.org/10.1016/j.toxicon.2021.11.123] [PMID: 34838810]
[33]
Miranti, C.K.; Brugge, J.S. Sensing the environment: A historical perspective on integrin signal transduction. Nat. Cell Biol., 2002, 4(4), E83-E90.
[http://dx.doi.org/10.1038/ncb0402-e83] [PMID: 11944041]
[34]
Andrew, S.M.; Edwards, B.D.; Chalmers, R.J.G.; O’Driscoll, J.B. A quantitative immunohistochemical study of the expression of integrins by nerves in psoriatic and normal skin. Br. J. Dermatol., 1992, 127(4), 359-364.
[http://dx.doi.org/10.1111/j.1365-2133.1992.tb00454.x] [PMID: 1419755]
[35]
Tomaselli, K.J.; Doherty, P.; Emmett, C.J.; Damsky, C.H.; Walsh, F.S.; Reichardt, L.F. Expression of beta 1 integrins in sensory neurons of the dorsal root ganglion and their functions in neurite outgrowth on two laminin isoforms. J. Neurosci., 1993, 13(11), 4880-4888.
[http://dx.doi.org/10.1523/JNEUROSCI.13-11-04880.1993] [PMID: 7693896]
[36]
Catalina, M.D.; Estess, P.; Siegelman, M.H. Selective requirements for leukocyte adhesion molecules in models of acute and chronic cutaneous inflammation: participation of E and P but not L-selectin. Blood, 1999, 93(2), 580-589.
[http://dx.doi.org/10.1182/blood.V93.2.580] [PMID: 9885219]
[37]
Giancotti, F.G.; Ruoslahti, E. Integrin Signaling. Science, 1999, 285(5430), 1028-1033.
[http://dx.doi.org/10.1126/science.285.5430.1028] [PMID: 10446041]
[38]
Berrier, A.L.; Mastrangelo, A.M.; Downward, J.; Ginsberg, M.; LaFlamme, S.E. Activated R-ras, Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin beta1 cytoplasmic domains. J. Cell Biol., 2000, 151(7), 1549-1560.
[http://dx.doi.org/10.1083/jcb.151.7.1549] [PMID: 11134082]
[39]
Sachs, D.; Villarreal, C.F.; Cunha, F.Q.; Parada, C.A.; Ferreira, S.H. The role of PKA and PKCε pathways in prostaglandin E2-mediated hypernociception. Br. J. Pharmacol., 2009, 156(5), 826-834.
[http://dx.doi.org/10.1111/j.1476-5381.2008.00093.x] [PMID: 19220288]
[40]
Suzuki, K.; Grinnell, A.D.; Kidokoro, Y. Hypertonicity-induced transmitter release at Drosophila neuromuscular junctions is partly mediated by integrins and cAMP/protein kinase A. J. Physiol., 2002, 538(1), 103-119.
[http://dx.doi.org/10.1113/jphysiol.2001.012901] [PMID: 11773320]
[41]
Dormond, O.; Bezzi, M.; Mariotti, A.; Rüegg, C. Prostaglandin E2 promotes integrin alpha Vbeta 3-dependent endothelial cell adhesion, rac-activation, and spreading through cAMP/PKA-dependent signaling. J. Biol. Chem., 2002, 277(48), 45838-45846.
[http://dx.doi.org/10.1074/jbc.M209213200] [PMID: 12237321]
[42]
Geiger, B.; Bershadsky, A.; Pankov, R.; Yamada, K.M. Transmembrane crosstalk between the extracellular matrix and the cytoskeleton. Nat. Rev. Mol. Cell Biol., 2001, 2(11), 793-805.
[http://dx.doi.org/10.1038/35099066] [PMID: 11715046]
[43]
Marchand, F.; Perretti, M.; McMahon, S.B. Role of the Immune system in chronic pain. Nat. Rev. Neurosci., 2005, 6(7), 521-532.
[http://dx.doi.org/10.1038/nrn1700] [PMID: 15995723]
[44]
Baral, P.; Udit, S.; Chiu, I.M. Pain and immunity: Implications for host defence. Nat. Rev. Immunol., 2019, 19(7), 433-447.
[http://dx.doi.org/10.1038/s41577-019-0147-2] [PMID: 30874629]
[45]
Bauer, M.; Brakebusch, C.; Coisne, C.; Sixt, M.; Wekerle, H.; Engelhardt, B.; Fässler, R. β 1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc. Natl. Acad. Sci. USA, 2009, 106(6), 1920-1925.
[http://dx.doi.org/10.1073/pnas.0808909106] [PMID: 19179279]
[46]
He, Y.; Gao, Y.; Zhang, Q.; Zhou, G.; Cao, F.; Yao, S. IL-4 switches microglia/macrophage M1/M2 polarization and alleviates neurological damage by modulating the JAK1/STAT6 pathway following ICH. Neuroscience, 2020, 437, 161-171.
[http://dx.doi.org/10.1016/j.neuroscience.2020.03.008] [PMID: 32224230]
[47]
Cam, A.; de Mejia, E.G. RGD-peptide lunasin inhibits Akt-mediated NF-κB activation in human macrophages through interaction with the αVβ3 integrin. Mol. Nutr. Food Res., 2012, 56(10), 1569-1581.
[http://dx.doi.org/10.1002/mnfr.201200301] [PMID: 22945510]
[48]
Peng, S.; Jia, J.; Sun, J.; Xie, Q.; Zhang, X.; Deng, Y.; Yi, L. LXW7 attenuates inflammation via suppressing Akt/nuclear factor kappa B and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated BV2 microglial cells. Int. Immunopharmacol., 2019, 77, 105963.
[http://dx.doi.org/10.1016/j.intimp.2019.105963] [PMID: 31732449]
[49]
Geijtenbeek, T.B.H.; Gringhuis, S.I. Signalling through C-type lectin receptors: Shaping immune responses. Nat. Rev. Immunol., 2009, 9(7), 465-479.
[http://dx.doi.org/10.1038/nri2569] [PMID: 19521399]
[50]
Gringhuis, S.I.; den Dunnen, J.; Litjens, M.; van der Vlist, M.; Wevers, B.; Bruijns, S.C.M.; Geijtenbeek, T.B.H. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat. Immunol., 2009, 10(2), 203-213.
[http://dx.doi.org/10.1038/ni.1692] [PMID: 19122653]
[51]
Sancho, D.; Reis e Sousa, C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu. Rev. Immunol., 2012, 30(1), 491-529.
[http://dx.doi.org/10.1146/annurev-immunol-031210-101352] [PMID: 22224766]
[52]
Mata-Martínez, P.; Bergón-Gutiérrez, M.; del Fresno, C. Dectin-1 signaling update: New perspectives for trained immunity. Front. Immunol., 2022, 13, 812148.
[http://dx.doi.org/10.3389/fimmu.2022.812148] [PMID: 35237264]
[53]
Geijtenbeek, T.B.H.; Gringhuis, S.I. C-type lectin receptors in the control of T helper cell differentiation. Nat. Rev. Immunol., 2016, 16(7), 433-448.
[http://dx.doi.org/10.1038/nri.2016.55] [PMID: 27291962]
[54]
Bliss, T.V.P.; Collingridge, G.L. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature, 1993, 361(6407), 31-39.
[http://dx.doi.org/10.1038/361031a0] [PMID: 8421494]
[55]
Dickenson, A.H.; Sullivan, A.F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: Differential response to an intrathecal opiate administered pre or post formalin. Pain, 1987, 30(3), 349-360.
[http://dx.doi.org/10.1016/0304-3959(87)90023-6] [PMID: 3670880]
[56]
Haley, J.E.; Dickenson, A.H.; Schachter, M. Electrophysiological evidence for a role of bradykinin in chemical nociception in the rat. Neurosci. Lett., 1989, 97(1-2), 198-202.
[http://dx.doi.org/10.1016/0304-3940(89)90163-8] [PMID: 2537479]
[57]
Haley, J.; Ketchum, S.; Dickenson, A. Peripheral κ-opioid modulation of the formalin response: An electrophysiological study in the rat. Eur. J. Pharmacol., 1990, 191(3), 437-446.
[http://dx.doi.org/10.1016/0014-2999(90)94178-Z] [PMID: 1964910]
[58]
Sullivan, A.F.; Dickenson, A.H.; Roques, B.P. δ-Opioid mediated inhibitions of acute and prolonged noxious-evoked responses in rat dorsal horn neurones. Br. J. Pharmacol., 1989, 98(3), 1039-1049.
[http://dx.doi.org/10.1111/j.1476-5381.1989.tb14636.x] [PMID: 2556199]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy