Jararaca (Bothrops jararaca)

Bothrops jararaca
Jararaca - Bothrops jararaca

The snakes from genus Bothrops are divided into 21 species that have a large distribution in Brazil. They are responsible for 90% of accidents caused by snakes bites and their venoms have a large variety of complex toxins that act on the hemostatic system. In a general way, these toxins can be separated in groups based on their activity in the hemostatic system. Therefore, there are toxins that act in the coagulation process; there are those that act in the plaquetes and cause lesions in the vascular system resulting in a hemorrhagic effect (ROSENFELD, 1971). Based on these facts, the Bothrops venom is largely studied, especially the toxins that can have therapeutic applications for various snake bites. 

Local pain, edema, local and systemic hemorrhages, and blood coagulation disturbances are usual symptoms observed in accidents inflicted by Bothrops snakes (ROSENFELD, 1971). In fact, edema is one of the local effects of Bothrops envenomation less efficiently neutralized by serum therapy (CARDOSO et al., 1993). The rapid manifestation of edema and its modulation by endogenous mediators decrease the efficacy of serum therapy (FRANCA et al, 2003). Once serum therapy has a low efficacy to treat the local edema of patients bitten by Bothrops snakes, other therapies have been investigated.

Damage due to a jararaca bitten
Damage of Jararaca bitten

Myotoxins and metalloproteinases present in Bothrops venoms can induce liberation of endogenous inflammatory mediators from affected tissues (TEIXEIRA et al., 2003; BJARNASON and FOX, 1994). Thus, associating anti-inflammatory drugs, such as dexamethasone or indomethacin, with antivenom should be a rational alternative to treat the local reaction provoked by Bothrops venoms. Studying this idea, many tests were made to get into the conclusion that the efficiency of serum therapy was improved when antivenom was administered in combination with dexamethasone or indomethacin (ARAUJO et al., 2007). Preliminary results point out to the efficacy of treatment of patients accidentally envenomed by Bothrops snakes with an association of dexamethasone and serum, especially for reducing edema in the first day after envenomation (SUSAKI et al., 2005).

Oral bleeding due to the toxic effect of Jararaca venom
Below are some important substances contained in the Bothrops venom that act in the coagulation system:
Trombin-like: serinoproteases that convert fibrinogen into fibrin non-stable. This makes with the clots be not stable.
Pro-coagulant: serinoproteases that activate the coagulate cascade. The most important are: Factor X activator, that convert factor X into Xa; Protrombim activator, that converts protrombin into trombones independently of phospholipids and factor Va and Trombocitin, activate factors V, VIII and XIII.
Anticoagulants: the most important are: Protein C activator, the protein C activation leads to the inhibition of factors Va and VIIIa; Botrojaracin, trombone inhibitor; Botrocetins, inhibitors of factor Xa, IX and X and Jararafibrases, fibrin and fibrinogen degradation.
Pro-aggregating platelets: proteases that activate platelets due to the secretion of ADP.
Anti-aggregating platelets: prevents that the platelets binds in the surface of the damaged tissue, blocking the integrins.
Metaloproteases: enzymes that degrade many kinds of protein and can cause hemorrhage.
Myotoxic Phospholipases: activites the phospholipase A.

Damage after 24 hours of the bitten
Tissue damage after 24h from the bit 

Studies indicating how Bothrops venom affects the offspring were developed in mice. As a result of envenomation the researchers observed that the offspring presented a high incidence of skeletal anomalies such as vertebrae anomalies, sternebrae anomalies and incomplete skull ossification (BERNARDI et al., 2011).

Bothrops jarara

Other kinds of studies that have being developed utilizing the Bothrops venom are those that use the toxins for medical treatments, such the drug Captopril first developed from the jararaca venoms to treat hypertension. Pyroglutamyl proline-rich oligopeptides, present in the venom of the pit viper Bothrops jararaca (Bj-PROs), are the first described naturally occurring inhibitors of the angio- tensin I-converting enzyme (ACE), which is a new class of therapeutic agents for the treatment of hypertension (SMITH and VANE, 2003). Studies about the Bj-PRO-10c, a oligopeptide from Bothrops jararaca, has shown that this oligopeptide evoked changes in arterial blood pressure that were followed by a significant reduction of heart rate (FERREIRA et al, 1970a and 1970b). Taking the results presented in the literature, the mechanism of action of Bj-PRO-10c  appears to provide evidence that Bj-PRO-10c induces transient increases of free intracellular calcium concentration in neuronal cells through a mechanism by activation of a yet unknown Gi/o-protein coupled receptor and promotes release of neurotransmitters in neuronal cells, namely GABA and glutamate, which may contribute to central cardiovascular effects exerted by Bj-PRO-10c (IANZER et al., 2007; LAMEU et al., 2010).

Botrhops jararaca attack 

Araujo, S. D., Souza A., Nunes, F.P.B. and Goncalves, L.R.C. Effect of dexamethasone associated with serum theraphy on treatment of Bothrops jararaca venom-induced paw edema in mice. Inflamm. Res. 56, 2007.

Bernardi, M. M., Kirsten, T. B., Manetta, P. R., Harb, S.F., Macrini D.J. And Cury, Y. Maternal exposure to Bothrops jararaca snake venom: effects in mice offsprings. J Health Sci Inst. 2011.

Bjarnason JB, Fox JW. Hemorrhagic metalloproteinases from snake venoms. Pharmacol. Ther. 1994.  

Cardoso JL, Fan HW, França FO, Jorge MT, Leite RP, Nishioka SA et al. Rando- mized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops Jararaca) in São Paulo. Q J Med., 86, 1993.

Ferreira SH, Greene LH, Alabaster VA, Bakhle YS, Vane JR. Activity of various fractions of bradykinin potentiating factor against angiotensin I converting enzyme. Nature, 1970.

Ferreira SH, Bartelt DC, Greene LJ. Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. Biochemistry, 1970.

França FOS, Málaque CMS. Acidente botrópico. In: Cardoso JLC, França FO, Fan HW, Málaque CMS, Haddad Jr V (eds.), Animais Peçonhentos no Brasil: Biologia, clínica e terapêutica dos aciden- tes. São Paulo: Sarvier, 2003.

Ianzer D, Santos RA, Etelvino GM, Xavier CH, de Almeida Santos J, Mendes EP, Machado LT, Prezoto BC, Dive V, de Camargo AC. Do the cardiovascular effects of angiotensin-converting enzyme (ACE) I involve ACE-independent mechanisms? New insights from proline-rich peptides of Bothrops jararaca. J Pharmacol Exp Ther, 2007.  

Lameu, C., Hayashi, M. A., Guerreiro, J. R., Oliveira, E. F., Lebrun, I., Pontieri, V., Morais, K. L. P., Camargo, A. C. M. and Ulrich H. The Central Nervous System as Target for Antihypertensive Actions of a Proline-rich Peptide from Bothrops jararaca Venom. Cytrometry Part A, 2010.

Rosenfeld G. Symptomathology, pathology and treatment of snakes bites in South America. In: Bucherl W, Buckley E,Editors. Venomous animals and their venoms. New York: Academic Press; 1971.

Smith CG, Vane JR. The discovery of captopril. FASEB J, 2003.

Susaki TT, Fan HW, Málaque CMS, Medeiros CR, Cardoso JLC, Ferrari RA et al. Effect of dexamethasone therapy on local edema after Bothrops accidents. Mem. Instituto Butantan 2005.

Teixeira CFP, Landucci ECT, Antunes E, Chacur M, Cury Y. In- flammatory effects of snake venom myotoxic phospholipase A2. Toxicon, 2003.