Epilepsy is a common chronic central nervous system disorder characterized by repeated malicious seizures. Current medications acceptable by medical practitioners till date mostly suppresses the seizures and has symptomatic relief, but no effect on epileptogenesis. In the present work, we have attempted to provide the scientific base to use the bee venom therapy (Apitherapy) which was practiced throughout ancient Egyptian, Greek and Chinese civilization to treat epilepsy. Our computational studies and molecular dynamics simulation results indicate that interaction between S100B (calcium binding protein) and melittin (a venom peptide from bee), resulted in the structural distortion and inaccessibility of calcium binding domain of S100B protein, which is required to maintain ionic imbalance due to over expressed S100B in disease conditions.

1. Blume, WT. , Lüders, HO. , Mizrahi, E. , Tassinari, C. , van Emde Boas, W. , Engel J, Jr. , 2001. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia. 42, 1212–1218.
2. Carpio, A. , and Hauser, WA. , 2009. Epilepsy in the developing world. Curr. Neurol. Neurosci. Rep. 9, 319-326.
3. Spinella, M. 2001. Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects. Epilepsy Behav. 2, 524-532.
4. Perucca, E. 2009. What is the promise of new antiepileptic drugs in status epilepticus? Focus on brivaracetam, carisbamate, lacosa-mide, NS-1209, and topiramate. Epilepsia. 50, 49-50.
5. McCabe, PH. 2000. New anti-epileptic drugs for the 21st century. Expert. Opin. Pharmacother. 1, 633-674.
6. Johannessen Landmark, C. , and Patsalos, PN. , 2010. Drug interactions in-volving the new second- and third-generation antiepileptic drugs. Expert. Rev. Neurother. 10, 119-140.
7. Temkin, NR. 2001. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia. 42, 515-524.
8. Schachter, SC. 2002. Current evidence indicates that antiepileptic drugs are anti-ictal, not antiepileptic. Epilepsy Res. 50, 67-70.
9. Macleod, S. , and Appleton, RE. , 2007. The new antiepileptic drugs. Arch. Dis. Child Educ. Pract. Ed. 92, 182-188.
10. Mirshafiey. 2007. A Venom therapy in multiple sclerosis. Neuro-pharmacology. 53, 353-361.
11. Maulet, Y. , Mathey-Prevot, B. , Kaiser, G. , Rüegg, UT. , Fulpius, BW. , 1980. Purification and Chemical Characterization of Melittin and Acetylated Derivatives. Biochim. Biophys. Acta. 625, 274-80.
12. Habermann, E. , 1972. Bee and Wasp Venom. Science, 177, 314-322.
13. Miller, RJ. , 2001. Rocking and rolling with Ca2+ channels. Trends Neurosci. 24, 445-449.
14. Van Eldik, LJ. , Griffin, WS. , 1994. S100 beta expression in Alzheimer's disease: relati on to neuropathology in brain regions. Biochim Biophys Acta. 29, 3398-3403.
15. Donato, R. , 2001. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 33, 637-668.
16. Liu, CH. , Lin, YW. , Tang, NY. , Liu, HJ. , Hsieh, CL. , 2012. Neuroprotective Effect of Uncaria rhyncho-phylla in Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression. Evid. Based. Complement. Alternat. Med. 2012, 194790.
17. Gauldie, J. , Hanson, JM. , Rumjanek, FD. , Shipolini, RA. , Vernon, CA. 1976. The peptide components of bee venom. Eur. J. Biochem. 61, 369-376.
18. Baudier, J. , Mochly-Rosen, D. , Newton, A. , Lee, SH. , Koshland, DE Jr. , Cole, RD. , 1987. Comparison of S100b protein with calmodulin: interactions with melittin and microtubule-associated tau proteins and inhibition of phosphorylation of tau proteins by protein kinase C. Biochemistry. 26, 2886-2893.
19. Billeter, SR. , Alexander, J. , Turner. , Walterm, Thiel. , 2000. Linear scaling geometry optimization and transition state search in hybrid delocalized internal coordinates. Phys. Chem. 2, 2177-2186.
20. Chen, R. , Weng, ZP. , 2002. Docking unbound proteins using shape complementarity, desolvation, and electrostatics. Proteins. 47, 281-294.
21. Chen, R. , Li, L. , Weng, Z. , 2003. ZDOCK: An Initial-Stage Protein-Docking Algorithm. Proteins. 52, 80–87
22. Li, L. , Chen, R. , Weng, Z. , 2003. RDOCK: Refinement of rigid-body protein docking predictions. Proteins. 53, 693-707.
23. Brooks, BR. , Bruccoleri, RE. , Olafson, BD. , States, DJ. , Swaminathan, S. , Karplus, M. , 1983. CHARMm: A program for macromolecular energy, minimization and dynamics calculations. J. Comput. Chem. 4, 187-217.
24. Momany, FA. , and Rone, R. ,1992. Validation of the general purpose QUANTA ®3. 2/ CHARMm® force field. J comp chem. 13, 888-900.
25. Heizmann, CW. , Günter, Fritz. , Beat, W. , Schäfer. , 2002. S100 Proteins: Structure, Functions and Pathology Frontiers in Bioscience. 7, 1356-1368.
26. Baudier, J. , Cole, RD. , 1988. Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 263, 5876-5883.
27. Sheng, JG. , Mrak, RE. , Bales, KR. , Cordell, B. , Paul, SM. , Jones, RA. , Woodward, S. , Zhou, XQ. , McGinness, JM. , Griffin, WS. , 2000. Overexpression of the neuritotrophic cytokine S100beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice. J. Neurochem. 74, 295-301.
28. Sorci, G. , Agneletti, AL. , Donato, R. , 2000. Effects of S100A1 and S100B on microtubule stability. An in vitro study using triton-cytoskeletons from astrocyte and myoblast cell lines. Neuroscience. 99, 773-83.
29. Winocur, G. , Roder, J. , Lobaugh, N. , 2001. Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function. Neurobiol. Learn. Mem. 75, 230-243.
30. Ostendorp, T. , Leclerc, E. , Galichet, A. , Koch, M. , Demling, N. , Weigle, B. , Heizmann, CW. , Kroneck, PM. , Fritz, G. , 2007. Structural and functional insights into RAGE activation by multimeric S100B. EMBO J. 26, 3868-3878.
31. Grigorian, M. , Andresen, S. , Tulchinsky, E. , Kriajevska, M. , Carlberg, C. , Kruse, C. , Cohn, M. , Ambartsumian, N. , Christensen, A. , Selivanova, G. , Lukanidin, E. , 2001. Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J. Biol. Chem. 276, 22699-22708.
32. Lin, J. , Blake, M. , Tang, C. , Zimmer, D. , Rustandi, RR. , Weber, DJ. , Carrier, F. , 2001. Inhibition of p53 transcriptional activity by the S100B calcium-binding protein. J. Biol. Chem. 14, 35037-35041.
33. Carrier, F. , M, Blake. , D, Zimmer. , Rustandi, RR. , Weber, DJ. , 1999. Abrogation of p53 transcriptional activity by the S100 calcium binding proteins: Possible implication in angiogenesis. Proc. AACR. 40, 102.
34. Wilder, PT. , Lin, J. , Bair, CL. , Charpentier, TH. , Yang, D. , Liriano, M. , Varney, KM. , Lee, A. , Oppenheim, AB. , Adhya, S. , Carrier, F. , Weber, DJ. , 2006. Recognition of the tumor suppressor pro-tein p53 and other protein targets by the calcium-binding protein S100B. Biochim. Biophys. Acta. 1763, 1284-1297.

Epilepsy Melittin S100b Protein-protein Interaction Ca2+ -binding Domains