The effects of TGN-020 on penicillin induced epileptiform activity in rats

Öz

Objective: Aquaporin-4 (AQP-4) is a water channel protein which is the most abundant aquaporin isoform in the brain. Recent studies indicate the relationship between AQP-4 with epileptogenesis. Therefore, we examined the potential effect of the AQP-4 inhibitor TGN-020 on penicillin-induced epileptiform activity in rats.

Material and Method: Epileptiform activity was induced by intracortical (i.c.) administration of penicillin (200 IU, 1 μl). TGN-020, at doses of 25 µg, 50 µg, 100 µg and 200 µg, was administered by intracerebroventricular (i.c.v.) 30 minutes after penicillin injection. The epileptiform activity was verified by electrocorticographic (ECoG) recordings. Twenty four hours later, animals are decapitated for the collection of blood samples and brain tissue.

Results: The dose of 100 µg TGN-020 decreased the mean spike frequency of epileptiform activity in the 30 min after the injection without changing the amplitude (p < 0.05). Serum neuropeptide Y level was up-regulated by 25 µg TGN-020 in comparison with the other groups (p<0.001). Plasma levels of calcineurin in the 50 µg dose of TGN-020 were lower than 25 µg and 200 µg doses of TGN-020 (p<0.01). Enzymatic ativity of glutathione peroxidase (GP_x-1) in brain tissue was higher in the penicillin and 25 µg TGN-020 group compared with the sham group (p < 0.05).

Conclusion: Given all these data, the anticonvulsant effect of TGN-020 which is aquaporin-4 water channel inhibitor in the brain has been studied extensively for the first time in an experimental model of epilepsy. Inhibition of AQP-4 might be useful in the treatment of epilepsy in future.

Anahtar Kelimeler

• TGN-020,Aquaporin 4,Epilepsy,EcoG,DMSO,Neuropeptide Y

Kaynakça

1. 1. Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiological reviews. 2013;93(4):1543-62.
2. 2. Papadopoulos MC, Verkman AS. Aquaporin-4 and brain edema. Pediatric nephrology. 2007;22(6):778-84.
3. 3. Benga O, Huber VJ. Brain water channel proteins in health and disease. Molecular aspects of medicine. 2012;33(5-6):562-78.
4. 4. Chu H, Tang Y, Dong Q. Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4. PloS one. 2013;8(6):e66051.
5. 5. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA. Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1990;10(5):1583-91.
6. 6. Rutledge EM, Aschner M, Kimelberg HK. Pharmacological characterization of swelling-induced D-[3H]aspartate release from primary astrocyte cultures. The American journal of physiology. 1998;274(6 Pt 1):C1511-20.
7. 7. Binder DK, Oshio K, Ma T, Verkman AS, Manley GT. Increased seizure threshold in mice lacking aquaporin-4 water channels. Neuroreport. 2004;15(2):259-62.
8. 8. Huber VJ, Tsujita M, Yamazaki M, Sakimura K, Nakada T. Identification of arylsulfonamides as Aquaporin 4 inhibitors. Bioorganic & medicinal chemistry letters. 2007;17(5):1270-3.

9. 9. Huber VJ, Tsujita M, Nakada T. Identification of aquaporin 4 inhibitors using in vitro and in silico methods. Bioorganic & medicinal chemistry. 2009;17(1):411-7.
10. 10. Igarashi H, Huber VJ, Tsujita M, Nakada T. Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2011;32(1):113-6.
11. 11. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet neurology. 2007;6(3):258-68.
12. 12. Andrew RD. Seizure and acute osmotic change: clinical and neurophysiological aspects. Journal of the neurological sciences. 1991;101(1):7-18.
13. 13. Pan E, Stringer JL. Influence of osmolality on seizure amplitude and propagation in the rat dentate gyrus. Neuroscience letters. 1996;207(1):9-12.
14. 14. Traynelis SF, Dingledine R. Role of extracellular space in hyperosmotic suppression of potassium-induced electrographic seizures. Journal of neurophysiology. 1989;61(5):927-38.
15. 15. Andrew RD, Fagan M, Ballyk BA, Rosen AS. Seizure susceptibility and the osmotic state. Brain research. 1989;498(1):175-80.
16. 16. Kozan R, Sefil F, Bagirici F. Anticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats. Brain research. 2008;1239:249-55.
17. 17. Walden J, Straub H, Speckmann EJ. Epileptogenesis: contributions of calcium ions and antiepileptic calcium antagonists. Acta neurologica Scandinavica Supplementum. 1992;140:41-6.
18. 18. Fisher RS. Animal models of the epilepsies. Brain research Brain research reviews. 1989;14(3):245-78.
19. 19. Rauca C, Wiswedel I, Zerbe R, Keilhoff G, Krug M. The role of superoxide dismutase and alpha-tocopherol in the development of seizures and kindling induced by pentylenetetrazol - influence of the radical scavenger alpha-phenyl-N-tert-butyl nitrone. Brain research. 2004;1009(1-2):203-12.
20. 20. Kato K, Ishiguro Y, Suzuki F, Ito A, Semba R. Distribution of nervous system-specific forms of enolase in peripheral tissues. Brain research. 1982;237(2):441-8.
21. 21. Kacinski M, Budziszewska B, Lason W, Zajac A, Skowronek-Bala B, Leskiewicz M, et al. Level of S100B protein, neuron specific enolase, orexin A, adiponectin and insulin-like growth factor in serum of pediatric patients suffering from sleep disorders with or without epilepsy. Pharmacological reports : PR. 2012;64(6):1427-33.
22. 22. Rothermundt M, Peters M, Prehn JH, Arolt V. S100B in brain damage and neurodegeneration. Microscopy research and technique. 2003;60(6):614-32.
23. 23. Villarreal A, Aviles Reyes RX, Angelo MF, Reines AG, Ramos AJ. S100B alters neuronal survival and dendrite extension via RAGE-mediated NF-kappaB signaling. Journal of neurochemistry. 2011;117(2):321-32.
24. 24. Tumani H, Otto M, Gefeller O, Wiltfang J, Herrendorf G, Mogge S, et al. Kinetics of serum neuron-specific enolase and prolactin in patients after single epileptic seizures. Epilepsia. 1999;40(6):713-8.
25. 25. Calik M, Abuhandan M, Sonmezler A, Kandemir H, Oz I, Taskin A, et al. Elevated serum S-100B levels in children with temporal lobe epilepsy. Seizure : the journal of the British Epilepsy Association. 2013;22(2):99-102.
26. 26. Kozan R, Ayyildiz M, Agar E. The effects of intracerebroventricular AM-251, a CB1-receptor antagonist, and ACEA, a CB1-receptor agonist, on penicillin-induced epileptiform activity in rats. Epilepsia. 2009;50(7):1760-7.
27. 27. Paxinos G WC. The rat brain in stereotaxic coordinates. Sydney: Academic Press; 1986.
28. 28. Igarashi H, Tsujita M, Suzuki Y, Kwee IL, Nakada T. Inhibition of aquaporin-4 significantly increases regional cerebral blood flow. Neuroreport. 2013;24(6):324-8.
29. 29. Wasterlain CG, Mazarati AM, Naylor D, Niquet J, Liu H, Suchomelova L, et al. Short-term plasticity of hippocampal neuropeptides and neuronal circuitry in experimental status epilepticus. Epilepsia. 2002;43 Suppl 5:20-9.
30. 30. Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nature reviews Neuroscience. 2003;4(12):991-1001.
31. 31. Binder DK, Nagelhus EA, Ottersen OP. Aquaporin-4 and epilepsy. Glia. 2012;60(8):1203-14.
32. 32. Eid T, Lee TS, Thomas MJ, Amiry-Moghaddam M, Bjornsen LP, Spencer DD, et al. Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(4):1193-8.
33. 33. Dudek FE, Rogawski MA. Regulation of brain water: is there a role for aquaporins in epilepsy? Epilepsy currents / American Epilepsy Society. 2005;5(3):104-6.
34. 34. Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia. 2006;53(6):631-6.
35. 35. Malheiros JM, Persike DS, Castro LU, Sanches TR, Andrade Lda C, Tannus A, et al. Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: edema or apoptosis? Epilepsy research. 2014;108(4):644-52.
36. 36. Song YC, Li WJ, Li LZ. Regulatory effect of miRNA 320a on expression of aquaporin 4 in brain tissue of epileptic rats. Asian Pacific journal of tropical medicine. 2015;8(10):807-12.
37. 37. Cardoso A, Freitas-da-Costa P, Carvalho LS, Lukoyanov NV. Seizure-induced changes in neuropeptide Y-containing cortical neurons: Potential role for seizure threshold and epileptogenesis. Epilepsy & behavior : E&B. 2010;19(4):559-67.
38. 38. Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM. Neuropeptides as Targets for the Development of Anticonvulsant Drugs. Molecular neurobiology. 2014.
39. 39. Poulsen FR, Jahnsen H, Blaabjerg M, Zimmer J. Pilocarpine-induced seizure-like activity with increased BNDF and neuropeptide Y expression in organotypic hippocampal slice cultures. Brain research. 2002;950(1-2):103-18.
40. 40. Vazquez-Lopez A, Sierra-Paredes G, Sierra-Marcuno G. Anticonvulsant effect of the calcineurin inhibitor ascomycin on seizures induced by picrotoxin microperfusion in the rat hippocampus. Pharmacology, biochemistry, and behavior. 2006;84(3):511-6.
41. 41. Bacci A, Huguenard JR, Prince DA. Differential modulation of synaptic transmission by neuropeptide Y in rat neocortical neurons. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(26):17125-30.
42. 42. Baraban SC. Neuropeptide Y and epilepsy: recent progress, prospects and controversies. Neuropeptides. 2004;38(4):261-5.
43. 43. Schwarzer C, Sperk G. Glutamate-stimulated neuropeptide Y mRNA expression in the rat dentate gyrus: a prominent role of metabotropic glutamate receptors. Hippocampus. 1998;8(3):274-88.
44. 44. Duan H, Hao C, Fan Y, Wang H, Liu Y, Hao J, et al. The role of neuropeptide Y and aquaporin 4 in the pathogenesis of intestinal dysfunction caused by traumatic brain injury. The Journal of surgical research. 2013;184(2):1006-12.
45. 45. Jiang H, Xiong F, Kong S, Ogawa T, Kobayashi M, Liu JO. Distinct tissue and cellular distribution of two major isoforms of calcineurin. Molecular immunology. 1997;34(8-9):663-9.
46. 46. Klee CB, Ren H, Wang X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. The Journal of biological chemistry. 1998;273(22):13367-70.
47. 47. Kurz JE, Sheets D, Parsons JT, Rana A, Delorenzo RJ, Churn SB. A significant increase in both basal and maximal calcineurin activity in the rat pilocarpine model of status epilepticus. Journal of neurochemistry. 2001;78(2):304-15.
48. 48. Dubey D, Porter BE. CRTC1 nuclear localization in the hippocampus of the pilocarpine-induced status epilepticus model of temporal lobe epilepsy. Neuroscience. 2016;320:57-68.
49. 49. Balasubramanian L, Sham JS, Yip KP. Calcium signaling in vasopressin-induced aquaporin-2 trafficking. Pflugers Archiv : European journal of physiology. 2008;456(4):747-54.
50. 50. Ilhan A, Gurel A, Armutcu F, Kamisli S, Iraz M. Antiepileptogenic and antioxidant effects of Nigella sativa oil against pentylenetetrazol-induced kindling in mice. Neuropharmacology. 2005;49(4):456-64.
51. 51. Songur A, Sarsilmaz M, Sogut S, Ozyurt B, Ozyurt H, Zararsiz I, et al. Hypothalamic superoxide dismutase, xanthine oxidase, nitric oxide, and malondialdehyde in rats fed with fish omega-3 fatty acids. Progress in neuro-psychopharmacology & biological psychiatry. 2004;28(4):693-8.
52. 52. Peker E, Oktar S, Ari M, Kozan R, Dogan M, Cagan E, et al. Nitric oxide, lipid peroxidation, and antioxidant enzyme levels in epileptic children using valproic acid. Brain research. 2009;1297:194-7.
53. 53. Bortolatto CF, Jesse CR, Wilhelm EA, Ribeiro LR, Rambo LM, Royes LF, et al. Protective effect of 2,2'-dithienyl diselenide on kainic acid-induced neurotoxicity in rat hippocampus. Neuroscience. 2011;193:300-9.