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The neuroprotection induced by Hypericum brasiliense Choisy extract HBE and its main active polyphenol compound quercetin, against Crotalus durissus terrificus Cdt venom and crotoxin and crotamine, was enquired at both central and anin mammal nervous system. These results and a further phytochemical and toxicological investigations could open new perspectives towards therapeutic use of Hypericum brasiliense standardized extract and quercetin, especially to counteract the neurotoxic effect induced by snake neurotoxic venoms.
The problem of human suffering by snake bite is actually so abim that WHO has included it in the list of neglected tropical diseases in April, [ 3 ]. Snake venoms embody a complex mixture of toxic enzymes and proteins, such as myotoxins, neurotoxins, cytotoxins, hemorrhagic metalloproteases, clotting serineproteases, and others [ 4 ]. Among all snake venoms, the crotalic is one of the most neurotoxic, in which systemic effects reside primarily in the peripheral neurotoxicity.
However, when injected directly on CNS of mammals it can induce convulsion and death [ 5 ]. Among other symptoms, abln neurotoxicity induced by Crotalus poisoning in both central and peripheral nervous system is mainly related to the presence in the venom of the toxins crotoxin [ 6 ] and crotamine [ 7 ]. Thus, the search of novel venom inhibitors is therefore relevant, being natural or synthetic, in order to complement the current serum therapy and to neutralize the remaining damages of snake envenomation.
The present work demonstrates the ability of Hypericum brasiliense standardized extract and quercetin to counteract neurodegenerative insults induced by Cdt venom in brain and muscles preparations. In addition, it is shown that the major neurotoxic components of the Crotalus durissus terrificus venom, crotoxin and crotamine, abon had their effects prevented in the neuromuscular paralysis at mouse nerve-muscle preparations.
All chemicals and reagents used were of the highest purity and sbin obtained from Sigma, Aldrich, Merck or BioRad. 0210 durissus terrificus venom, crotamine and crotoxin were donated by Dr. The preparation of H. Immediately after incubation with treatments, slices were assayed for a 3- 4,5-dimethylthiazolyl -2,5-diphenyltetrazolium bromide MTT test 0. The MTT is converted into edita purple formazan product after cleavage of the tetrazolium ring by mitochondrial dehydrogenases.
Whole diaphragms along with the phrenic nerves were removed from mice killed by carbon dioxide CO 2 and exsanguinated. Both hemidiaphragms were mounted essentially as described for dal Belo et al. NaClKCl 2. HBE was shown to be rich in flavonoids derivatives such as kaempferol, edktal, and quercetin glycosides quercitrin, isoquercitrin, guaijaverin, and hyperoside [ 13 ].
Neutralizing activity of H. When HBE was applied alone in the organ-bath no 20100 in the twitch-tension was observed. On both graphs control Tyrode solution lines show no alteration of normal nerve-muscle activity.
On b note that quercetin mimicked the protective effect induced by HBE. Figures 2 a and 2 b. The results in hippocampal slices confirm the HBE and quercetin potential role in the neuroprotection against Cdt poisoning. Therefore, the difference in potency between HBE and quercetin must also be related to the less amount of the flavonoid in the extract.
Effects of Cdt on the viability of hippocampal slices. Cell viability was measured by MTT test. On b note that quercetin mimicked the HBE protective activity. In this work we described for the first time the effectiveness of the H. Also, the effectiveness of HBE and quercetin was validated, to counteract the deleterious effects induced by C. Crotalus venom induces neurotoxicity, coagulation disorders, systemic myotoxicity, and acute renal failure [ 18 ], with possible additional heart and liver damage [ 19 ].
This venom is a mixture of enzymes, toxins crotoxin, crotamine, gyroxin, and convulxinand several other peptides [ 19 ]. The characteristic pathophysiological pictures of neurotoxicity and systemic myotoxicity associated with C. At nerve terminals, crotoxin induces triphasic alterations in the mean quantal content of transmitter release with a slow and progressive decrease of presynaptic release of the neurotransmitter acetylcholine that results in complete neuromuscular blockade [ 2223 ].
At mammal central nervous system, the injection of Cdt venom induces seizures [ 5 ], which is mainly associated with the presence of crotoxin [ 24 ]. At brain synaptosomes, crotoxin has also shown the ability of inhibiting L-glutamate and gamma aminobutyric acid GABA uptake [ 25 ]. Crotamine is the second major toxin in the Cdt venom; it is a basic, low molecular weight myotoxin devoid of PLA 2 activity [ 26 ], with a specific action on voltage-sensitive sodium channels of muscles [ 27 ] and brain cells [ 28 ].
Flavonoids are plant secondary metabolites that embrace a wealth of possibilities of hydrogen bonding arranged around a relatively small carbon skeleton, capable of interacting with molecular targets [ 29 ]. Quercetin and several of its glycosides are the most often encountered flavonoids in anti-snake venom plants where Albizia lebbeckAchillea millefoliumEuphorbia hirtaCamellia sinensisand Casearia sylvestris are some examples.
Flavonoids have been reported as snake venom phospholipase A 2 inhibitors [ 30 ]. Recent studies revealed that the treatment of the snake venom PLA 2 isoform from Crotalus durissus cascavella snake venom with rdital flavonoid quercetin produced a decrease in the pharmacological activity of the neurotoxin by inducing alterations in the secondary but not in tertiary structure composition of the molecule [ 31 ].
As discussed above, flavonoids have the ability of binding to biological polymers e. Therefore, snake PLA 2 catalyzed the production of lysophospholipids and fatty acids that are involved in membrane damage [ 21 ].
We suggest that, in the case where biological activity is enzyme-dependent, the HBE antineurotoxic activity would involve the inactivation of PLA 2 activity by quercetin. However, the possibility that the HBE acts through a mechanistic intervention rather than an in vitro direct physical interaction with the venom is also a reasonable idea.
Flavonoids derived from plants or tea extracts also affect acetylcholine release, muscle contraction, or neuromuscular junction activity [ 34 ]. Crotoxin also stabilizes the postsynaptic membrane of Torpedo marmorata by binding in non-ACh biding sites [ 37 ]. Hence, these similarities in terms of binding sites would strengthen the hypothesis of a site-direct antagonism between quercetin and crotoxin at nerve terminals.
In addition, quercetin actively participates in intracellular signaling, inhibiting phosphatidylinositol-3 kinase, protein kinase C, xanthine oxidase, and NADPH diaphorase [ 34 ]. Current explanation for the neuroprotective effect of quercetin is its antioxidant capacity and its ability to scavenge free radicals [ 34 ].
At moment there is no evidence that snake venoms induce cellular insults to increase free radicals in nerve terminals. However, the actions of Cdt venom on cell viability of brain slices is likely to be devoid to the presence of crotoxin and crotamine that ultimately account for the increase of excitatory neurotransmitters [ 22 ], resulting in excitotoxicity [ 38 ].
The decrease in neurotransmitter uptake by crotoxin is calcium independent [ 25 ], and quercetin potentiates neuronal excitability by increasing neuronal firing rates [ 39 ]. Ultimately, excitotoxicity is a result of synaptic dysfunction processes, which involves the excessive glutamate receptor activation and neuronal degeneration [ 38 ].
Based on the above considerations we suggest that the mechanism of the benefit of quercetin on snake venom-induced neuronal cellular death is complex and beyond the inhibition of presynaptic activity of snake PLA 2and structural modifications, which may affect neurotransmitter uptake, involve the maintenance of neuronal mitochondrial transmembrane electric potential which would decrease the overstimulation of glutamate receptors [ 34 ].
However, in the case of crotamine, a direct inhibition of voltage-gated sodium channels by quercetin seems to be a coherent explanation [ 40 ].
Further investigation on Hypericum brasiliense isolated compounds will strengthen the understanding of its antiophidian activity. Preclinical assays, including safety assessment protocols, could also open the way towards therapeutic use of Hypericum brasiliense especially when neurotoxic venoms are involved. The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Gildo Bernardo Leite for the excellence in technical assistance with mouse phrenic nerve-diaphragm preparations. Thais Posser for kind loan of MTT. National Center for Biotechnology InformationU. Journal List Biomed Res Int v.
Published online Dec Author information Article notes Copyright and License information Disclaimer. Received Sep 20; Accepted Dec 4. This is an open aibn 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.
This article has been cited by other articles in PMC. Abstract The neuroprotection induced by Hypericum brasiliense Choisy extract HBE and its main active polyphenol compound quercetin, against Crotalus durissus terrificus Cdt venom and crotoxin abi crotamine, was enquired at both central and peripheral mammal nervous system.
Introduction An estimated 5. Chemical Analysis The preparation of H. Hippocampal Slices Viability Immediately after incubation with treatments, slices were assayed for a 3- 4,5-dimethylthiazolyl -2,5-diphenyltetrazolium bromide MTT test 0.
Phrenic Nerve-Diaphragm Preparation Whole diaphragms along with the phrenic nerves were removed from mice killed by carbon dioxide CO 2 and exsanguinated.
Results HBE was shown to be rich in flavonoids derivatives such as kaempferol, quercetin, and quercetin glycosides quercitrin, isoquercitrin, guaijaverin, and hyperoside [ 13 ].
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Open in a separate window. Discussion In this work we described for the first time the effectiveness of the H. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Acknowledgments The authors thank Gildo Bernardo Leite for the excellence in technical assistance with mouse phrenic nerve-diaphragm preparations.
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