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Molecules 2014, 19(5), 5790-5805; doi:10.3390/molecules19055790
Article

An Isoflavone from Dipteryx alata Vogel is Active against the in Vitro Neuromuscular Paralysis of Bothrops jararacussu Snake Venom and Bothropstoxin I, and Prevents Venom-Induced Myonecrosis

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1 Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Rodovia Raposo Tavares, Km 92.5, 18023-000 Sorocaba, SP, Brazil 2 Post-Graduate Program in Technological and Environmental Processes, University of Sorocaba (UNISO), Rodovia Raposo Tavares, Km 92.5, 18023-000 Sorocaba, SP, Brazil 3 Serpentarium of the Vale do Paraíba University (CEN—UNIVAP), Av Shishima Hifumi 2911, 12244-000 São José dos Campos, SP, Brazil 4 Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences, São Paulo University (USP), Via do Café S/N, 14040-903 Ribeirão Preto, SP, Brazil 5 LANETOX, Federal University of Pampa (UNIPAMPA), Avenida Antonio Trilha 1847, 97300-000 São Gabriel, RS, Brazil 6 Methodist University of Piracicaba, Rodovia do Açucar, Km 156, 13423-170 Piracicaba, SP, Brazil 7 Post-Graduate Course in Environmental Sciences, Federal University of Tocantins (UFT), Av NS 15 ALC NO 14, 109 Norte, 77001-090 Palmas, TO, Brazil 8 Faculty of Pharmaceutical Sciences, São Paulo State University (UNESP), Rodovia Araraquara-Jau, Km 1, 14801-902 Araraquara, SP, Brazil 9 Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, 13083-887 Campinas, SP, Brazil 10 Department of Pharmaceutical Chemistry, Salamanca University, CIETUS, IBSAL, Salamanca 37007, Spain
* Author to whom correspondence should be addressed.
Received: 10 March 2014 / Revised: 22 April 2014 / Accepted: 24 April 2014 / Published: 6 May 2014
(This article belongs to the Section Metabolites)
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Abstract

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 μg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 μg/mL) caused irreversible paralysis. Preincubation of TM (200 μg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% ± 5% (mean ± SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA2 of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% ± 1.7% were damaged; n = 4) compared to venom alone (50.3% ± 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% ± 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (−S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom.
Keywords: ames test; bothropstoxin-I; 7,8,3'-trihydroxy-4'-methoxyisoflavone; neuromuscular junction; Salmonella mutagenicity; snake venoms ames test; bothropstoxin-I; 7,8,3'-trihydroxy-4'-methoxyisoflavone; neuromuscular junction; Salmonella mutagenicity; snake venoms
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Ferraz, M.C.; Yoshida, E.H.; Tavares, R.V.; Cogo, J.C.; Cintra, A.C.; Dal Belo, C.A.; Franco, L.M.; dos Santos, M.G.; Resende, F.A.; Varanda, E.A.; Hyslop, S.; Puebla, P.; San Feliciano, A.; Oshima-Franco, Y. An Isoflavone from Dipteryx alata Vogel is Active against the in Vitro Neuromuscular Paralysis of Bothrops jararacussu Snake Venom and Bothropstoxin I, and Prevents Venom-Induced Myonecrosis. Molecules 2014, 19, 5790-5805.

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