TY - JOUR T1 - Investigation of antiepileptic potentials of usnic acid and some lichen species on the behavioral and biochemical levels in pentylenetetrazole-induced kindling model of epilepsy AU - Berköz, Mehmet AU - Yunusoğlu, Oruç AU - Aslan, Ali AU - Bozkurt, Ayşe PY - 2025 DA - July JF - Journal of Research in Pharmacy JO - J. Res. Pharm. PB - Marmara University WT - DergiPark SN - 2630-6344 SP - 1378 EP - 1390 VL - 28 IS - 5 LA - en AB - In this study, the effects of various lichen and usnic acid applications on seizure scores and biochemical parameters in brain tissue in rats with epilepsy model was investigated. For this aim, 91 rats were divided into 13 groups, each containing 7 rats, which were: control, pentylenetetrazole (PTZ) (35 mg/kg), PTZ + Valproic acid (100 mg/kg), PTZ + Dolichousnea longissima (200 mg/kg), PTZ + Dolichousnea longissima (400 mg/kg), PTZ + Xanthoparmelia somloensis ( 50 mg/kg), PTZ + Xanthoparmelia somloensis (200 mg/kg), PTZ + Cetraria islandica (250 mg/kg), PTZ + Cetraria islandica (500 mg/kg), PTZ + Pseudevernia furfuracea (250 mg/kg), PTZ + Pseudevernia furfuracea (500 mg/kg), PTZ + usnic acid (50 mg/kg), and PTZ + usnic acid (200 mg/kg). All items were applied with an interval of 120 minutes for a period of one week. Seizure detection, seizure scores and total seizure duration of each group was recorded. After the applications, oxidative stress parameters and acetylcholinesterase enzyme activity in the brain tissue of rats were measured. There was no difference between the groups in the 1st, 2nd, and 3rd injections (p>0.05). Starting from the 4th injection, the seizure score was significantly higher in the PTZ group compared to the control group (p0.05). In PTZ applied groups, an increase in lipid and protein oxidation as well as a decrease in antioxidant and acetylcholine esterase levels were observed (p KW - Epilepsy KW - lichen KW - pentylenetetrazole KW - oxidative stress KW - seizure scores KW - brain CR - [1] Fisher RS. Redefining epilepsy. Curr Opin Neurol. 2015; 28(2): 130-135. https://doi.org/10.1097/wco.0000000000000174 CR - [2] Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N, Bueno-Junior LS, Leite JP. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 2014; 10: 1693-1705. https://doi.org/10.2147/ndt.s50371 CR - [3] Dhir A, Naidu PS, Kulkarni SK. Effect of naproxen, a non-selective cyclo-oxygenase inhibitor, on pentylenetetrazol-induced kindling in mice. Clin Exp Pharmacol Physiol. 2005; 32(7): 574-584. https://doi.org/10.1111/j.1440-1681.2005.04233.x CR - [4] Ilhan A, Iraz M, Kamisli S, Yigitoglu R. Pentylenetetrazol-induced kindling seizure attenuated by Ginkgo biloba extract (EGb 761) in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(8): 1504-1510. https://doi.org/10.1016/j.pnpbp.2006.05.013 CR - [5] Arhan E, Serdaroglu A, Ozturk B, Ozturk HS, Ozcelik A, Kurt N, Kutsal E, Sevinc N. Effects of epilepsy and antiepileptic drugs on nitric oxide, lipid peroxidation and xanthine oxidase system in children with idiopathic epilepsy. Seizure. 2011; 20(2): 138-142. https://doi.org/10.1016/j.seizure.2010.11.003 CR - [6] Essawy AE, El-Sayed SA, Tousson E, Abd El-Gawad HS, Alhasani RH, Abd Elkader HAE. Anti-kindling effect of Ginkgo biloba leaf extract and L-carnitine in the pentylenetetrazol model of epilepsy. Environ Sci Pollut Res Int. 2022; 29(32): 48573-48587. https://doi.org/10.1007/s11356-022-19251-6 CR - [7] Adenubi OT, Famuyide IM, McGaw LJ, Eloff JN. Lichens: An update on their ethnopharmacological uses and potential as sources of drug leads. J Ethnopharmacol. 2022; 298: 115657. https://doi.org/10.1016/j.jep.2022.115657 CR - [8] Xu M, Heidmarsson S, Olafsdottir ES, Buonfiglio R, Kogej T, Omarsdottir S. Secondary metabolites from cetrarioid lichens: Chemotaxonomy, biological activities and pharmaceutical potential. Phytomedicine. 2016; 23(5): 441-459. https://doi.org/10.1016/j.phymed.2016.02.012 CR - [9] Reddy RG, Veeraval L, Maitra S, Chollet-Krugler M, Tomasi S, Dévéhat FL, Boustie J, Chakravarty S. Lichen-derived compounds show potential for central nervous system therapeutics. Phytomedicine. 2016; 23(12): 1527-1534. https://doi.org/10.1016/j.phymed.2016.08.010 CR - [10] Fernández-Moriano C, Divakar PK, Crespo A, Gómez-Serranillos MP. Protective effects of lichen metabolites evernic and usnic acids against redox impairment-mediated cytotoxicity in central nervous system-like cells. Food Chem Toxicol. 2017; 105: 262-277. https://doi.org/10.1016/j.fct.2017.04.030 CR - [11] Dobson FS, Lichens. An illustrated guide to the British and Irish species. first ed., Richmond Publishing, Slough, 2000. CR - [12] Brodo IM, Sharnoff SD, Sharnoff S, Lichens of North America, first ed., Yale Univ Press, New Haven, London, 2001. CR - [13] Aslan A, Güllüce M, Sökmen M, Adıgüzel A, Şahin F, Özkan, H. Antioxidant and antimicrabial properties of the lichens Cladonia foliacea, Dermatocarpon miniatum, Evernia divaricata, Evernia prunastri and Neofuscella pulla. Pharm Biol. 2006; 44(4): 247-252. https://doi.org/10.1080/13880200600713808 CR - [14] Golmohammadi R, Pejhan A, Azhdari-Zarmehri H, Mohammad-Zadeh M. The role of ethanol on the anticonvulsant effect of valproic acid and cortical microvascular changes after epileptogenesis in mice. Neurol Sci. 2013; 34(7): 1125-1131. https://doi.org/10.1007/s10072-012-1190-y CR - [15] Racine RJ, Gartner JG, Burnham WM. Epileptiform activity and neural plasticity in limbic structures. Brain Res. 1972; 47(1): 262-268. https://doi.org/10.1016/0006-8993(72)90268-5 CR - [16] Verma P, Paswan SK, Raj A, Nath V, Gupta RK, Verma S, Srivastava S, Rao CV. Hematological, antioxidant and protective performance of Usnea longissima on chemical induced hepatotoxicity in experimental animals. J Coast Life Med. 2017; 5(5): 224-232. http://dx.doi.org/10.12980/jclm.5.2017J6-250 CR - [17] Halıcı MB. PhD Thesis. Investigation of the antiulcer mechanisms of substances isolated from some lichens in the indomethacin-induced ulcer model in rats. Department of Chemistry, Institute of Natural and Applied Sciences, Ataturk University, Erzurum, Turkiye, 2008. CR - [18] Gülçin I, Oktay M, Küfrevioğlu OI, Aslan A. Determination of antioxidant activity of lichen Cetraria islandica (L) Ach. J Ethnopharmacol. 2002; 79(3): 325-329. https://doi.org/10.1016/s0378-8741(01)00396-8 CR - [19] Bakır TÖ, Geyikoglu F, Çolak S, Türkez H, Aslan A, Bakır M. The effects of Cetraria islandica and Pseudevernia furfuracea extracts in normal and diabetic rats. Toxicol Ind Health. 2015; 31(12): 1304-1317. https://doi.org/10.1177/0748233713475521 CR - [20] Odabasoglu F, Cakir A, Suleyman H, Aslan A, Bayir Y, Halici M, Kazaz C. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006; 103(1): 59-65. https://doi.org/10.1016/j.jep.2005.06.043 CR - [21] Yagi K. Simple assay for the level of total lipid peroxides in serum or plasma. Methods Mol Biol. 1998; 108: 101-106. https://doi.org/10.1385/0-89603-472-0:101 CR - [22] Aebi H. Catalase in vitro. Methods Enzymol. 1984; 105: 121-126. https://doi.org/10.1016/s0076-6879(84)05016-3 CR - [23] Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34(3): 497-500. https://doi.org/10.1093/clinchem/34.3.497 CR - [24] Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. 1963; 61: 882-888. CR - [25] Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7(2): 88-90. https://doi.org/10.1016/0006-2952(61)90145-9 CR - [26] Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001; 5(1): 62-71. https://doi.org/10.1006/niox.2000.0319 CR - [27] Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990; 186: 464-478. https://doi.org/10.1016/0076-6879(90)86141-h CR - [28] Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-275. CR - [29] Allahverdiyev O, Dzhafar S, Berköz M, Yıldırım M. Advances in current medication and new therapeutic approaches in epilepsy. East J Med. 2018;23(1): 48-59. http://dx.doi.org/10.5505/ejm.2018.62534 CR - [30] Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005; 46(4): 470-472. https://doi.org/10.1111/j.0013-9580.2005.66104.x CR - [31] Wu XH, Ding MP, Zhu-Ge ZB, Zhu YY, Jin CL, Chen Z. Carnosine, a precursor of histidine, ameliorates pentylenetetrazole-induced kindled seizures in rat. Neurosci Lett. 2006; 400(1-2): 146-149. https://doi.org/10.1016/j.neulet.2006.02.031 CR - [32] Seher Y, Filiz O, Melike B. Gamma-amino butyric acid, glutamate dehydrogenase and glutamate decarboxylase levels in phylogenetically divergent plants. Plant Syst Evol. 2013; 299(2): 403-412. https://doi.org/10.1007/s00606-012-0730-5 CR - [33] Ergul Erkec O, Arihan O, Kara M, Karatas E, Erten R, Demir H, Meral I, Mukemre M, Ozgokce F. Effects of Leontice leontopetalum and Bongardia chrysogonum on oxidative stress and neuroprotection in PTZ kindling epilepsy in rats. Cell Mol Biol (Noisy-le-grand). 2018; 64(15): 71-77. http://dx.doi.org/10.14715/cmb/2017.64.15.12 CR - [34] Calcott MJ, Ackerley DF, Knight A, Keyzers RA, Owen JG. Secondary metabolism in the lichen symbiosis. Chem Soc Rev. 2018; 47(5): 1730-1760. https://doi.org/10.1039/C7CS00431A CR - [35] Munguía-Martínez MF, Nava-Ruíz C, Ruíz-Díaz A, Díaz-Ruíz A, Yescas-Gómez P, Méndez-Armenta M. Immunohistochemical study of antioxidant enzymes regulated by Nrf2 in the models of epileptic seizures (KA and PTZ). Oxid Med Cell Longev. 2019; 2019: 1327986. https://doi.org/10.1155/2019/1327986 CR - [36] Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA. Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse. 1989; 3(2): 154-171. https://doi.org/10.1002/syn.890030207 CR - [37] Sales IM, Freitas RL, Saldanha GB, Souza GF, Freitas RM. Choline acetyltransferase and acetylcholinesterase activities are reduced in rat striatum and frontal cortex after pilocarpine-induced seizures. Neurosci Lett. 2010; 469(1): 81-83. https://doi.org/10.1016/j.neulet.2009.11.048 CR - [38] Giacobini E. Cholinesterase inhibitors stabilize Alzheimer disease. Neurochem Res. 2000; 25(9-10): 1185-1190. https://doi.org/10.1023/a:1007679709322 CR - [39] Visweswari G, Prasad KS, Chetan PS, Lokanatha V, Rajendra W. Evaluation of the anticonvulsant effect of Centella asiatica (gotu kola) in pentylenetetrazol-induced seizures with respect to cholinergic neurotransmission. Epilepsy Behav. 2010; 17(3): 332-335. https://doi.org/10.1016/j.yebeh.2010.01.002 CR - [40] Pahuja M, Mehla J, Reeta KH, Joshi S, Gupta YK. Hydroalcoholic extract of Zizyphus jujuba ameliorates seizures, oxidative stress, and cognitive impairment in experimental models of epilepsy in rats. Epilepsy Behav. 2011; 21(4): 356-363. https://doi.org/10.1016/j.yebeh.2011.05.013 CR - [41] Obay BD, Taşdemir E, Tümer C, Bilgin HM, Atmaca M. Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model. Peptides. 2008; 29(3): 448-455. https://doi.org/10.1016/j.peptides.2007.11.020 CR - [42] Agarwal NB, Jain S, Agarwal NK, Mediratta PK, Sharma KK. Modulation of pentylenetetrazole-induced kindling and oxidative stress by curcumin in mice. Phytomedicine. 2011; 18(8-9): 756-759. https://doi.org/10.1016/j.phymed.2010.11.007 CR - [43] Ilhan A, Aladag MA, Kocer A, Boluk A, Gurel A, Armutcu F. Erdosteine ameliorates PTZ-induced oxidative stress in mice seizure model. Brain Res Bull. 2005; 65(6): 495-499. https://doi.org/10.1016/j.brainresbull.2005.02.027 CR - [44] Eraković V, Zupan G, Varljen J, Simonić A. Pentylenetetrazol-induced seizures and kindling: changes in free fatty acids, superoxide dismutase, and glutathione peroxidase activity. Neurochem Int. 2003; 42(2): 173-178. https://doi.org/10.1016/s0197-0186(02)00070-0 CR - [45] Akbas SH, Yegin A, Ozben T. Effect of pentylenetetrazol-induced epileptic seizure on the antioxidant enzyme activities, glutathione and lipid peroxidation levels in rat erythrocytes and liver tissues. Clin Biochem. 2005; 38(11): 1009-1014. https://doi.org/10.1016/j.clinbiochem.2005.07.012 CR - [46] De Luca G, Di Giorgio RM, Macaione S, Calpona PR, Di Paola ED, Costa N, Cuzzocrea S, Citraro R, Russo E, De Sarro G. Amino acid levels in some brain areas of inducible nitric oxide synthase knock out mouse (iNOS-/-) before and after pentylenetetrazole kindling. Pharmacol Biochem Behav. 2006; 85(4): 804-812. https://doi.org/10.1016/j.pbb.2006.11.016 CR - [47] Hamed SA, Abdellah MM, El-Melegy N. Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. J Pharmacol Sci. 2004; 96(4): 465-473. https://doi.org/10.1254/jphs.fpj04032x CR - [48] Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta. 2001; 303(1-2): 19-24. https://doi.org/10.1016/s0009-8981(00)00337-5 CR - [49] Naseer MI, Shupeng L, Kim MO. Maternal epileptic seizure induced by pentylenetetrazol: apoptotic neurodegeneration and decreased GABAB1 receptor expression in prenatal rat brain. Mol Brain. 2009; 2: 20. https://doi.org/10.1186/1756-6606-2-20 CR - [50] Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol. 2002; 1(3): 173-181. https://doi.org/10.1016/s1474-4422(02)00073-x CR - [51] Fernández-Moriano C, Gómez-Serranillos MP, Crespo A. Antioxidant potential of lichen species and their secondary metabolites. A systematic review. Pharm Biol. 2016; 54(1): 1-17. https://doi.org/10.3109/13880209.2014.1003354 CR - [52] Paluszczak J, Kleszcz R, Studzińska-Sroka E, Krajka-Kuźniak V. Lichen-derived caperatic acid and physodic acid inhibit Wnt signaling in colorectal cancer cells. Mol Cell Biochem. 2018; 441(1-2): 109-124. https://doi.org/10.1007/s11010-017-3178-7 CR - [53] Schinkovitz A, Le Pogam P, Derbré S, Roy-Vessieres E, Blanchard P, Thirumaran SL, Breard D, Aumond MC, Zehl M, Urban E, Kaur A, Jäger N, Hofer S, Kopp B, Stuppner H, Baglin I, Seraphin D, Tomasi S, Henrion D, Boustie J, Richomme P. Secondary metabolites from lichen as potent inhibitors of advanced glycation end products and vasodilative agents. Fitoterapia. 2018; 131: 182-188. https://doi.org/10.1016/j.fitote.2018.10.015 CR - [54] Martinc B, Grabnar I, Vovk T. Antioxidants as a preventive treatment for epileptic process: a review of the current status. Curr Neuropharmacol. 2014; 12(6): 527-550. https://doi.org/10.2174/1570159x12666140923205715 UR - https://dergipark.org.tr/en/pub/jrespharm/issue//1688832 L1 - https://dergipark.org.tr/en/download/article-file/4826653 ER -