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01-08-2019 | Statins | Original Article

Neuroprotective effects of lovastatin in the pilocarpine rat model of epilepsy according to the expression of neurotrophic factors

Authors: Pooyan Moradi, Mahin Ganjkhani, Iraj Jafari Anarkooli, Alireza Abdanipour

Published in: Metabolic Brain Disease | Issue 4/2019

Abstract

Studies have suggested that neurotrophic factors (NTFs) are involved in the status epilepticus development. This indicates their essential role in mediating acquired epileptic conditions. Therefore, modulating the expression of NTFs may inhibit seizure-induced cell loss in the epileptic lesions. In this study, we examined the anti-apoptotic, anti-necrotic and regulatory effects of lovastatin on the expression of NTFs in the pilocarpine rat model of temporal lobe epilepsy (TLE). A total of 32 male Wistar rats were divided into 4 groups (n = 8 per group): i) normal; ii) non-treated epileptic group [intraperitoneal (i.p.) administration of 350–400 mg/kg pilocarpine]; iii) treatment group (pilocarpine-treated rats treated followed by 5 mg/kg lovastatin); and iv) vehicle epileptic rats treated with Carboxymethyl cellulose (CMC). Animals that had a behavioral score of 4–5 according to the Racine scale were selected for study participation. Three days after the first seizure, pilocarpine-treated rats received i.p. injections of lovastatin for 14 days. The rats were killed and prepared for histopathologic analysis as well as real-time RT-PCR 17 days after the first seizure. The results of this study showed increased mRNA expression of glial cell line–derived neurotrophic factor (GDNF) and Ciliary neurotrophic factor (CNTF) and decreased expressions of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4) mRNA in the epileptic rats treated with lovastatin. Histological analysis of neurodegeneration in the brain sections showed that the number of hippocampal apoptotic and necrotic cells significantly decreased in the treatment groups. Furthermore, numerical density of neurons per area was significantly higher in the treated groups compared with the untreated groups. Collectively, the results of this study have shown that lovastatin could attenuate seizure-induced expression of neurotrophic factors and consequently reduce hippocampal cell death in the pilocarpine rat model of TLE.

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Abdanipour A, Tiraihi T, Mirnajafi-Zadeh J (2011) Improvement of the pilocarpine epilepsy model in rat using bone marrow stromal cell therapy. Neurol Res 33:625–632. https://doi.org/10.1179/1743132810y.0000000018 CrossRefPubMed

Bechstein M, Haussler U, Neef M, Hofmann HD, Kirsch M, Haas CA (2012) CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy. Exp Neurol 236:141–150. https://doi.org/10.1016/j.expneurol.2012.04.009 CrossRefPubMed

Buckmaster PS (2004) Prolonged infusion of Tetrodotoxin does not block mossy Fiber sprouting in pilocarpine-treated rats. Epilepsia 45:452–458. https://doi.org/10.1111/j.0013-9580.2004.67103.x CrossRefPubMed

Cavalheiro EA, Leite JP, Bortolotto ZA, Turski WA, Ikonomidou C, Turski L (1991) Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 32:778–782CrossRefPubMed

Cavazos JE, Das I, Sutula TP (1994) Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures. J Neurosci 14:3106–3121CrossRefPubMed

Deister C, Schmidt CE (2006) Optimizing neurotrophic factor combinations for neurite outgrowth. J Neural Eng 3:172–179. https://doi.org/10.1088/1741-2560/3/2/011 CrossRefPubMed

Falcicchia C, Paolone G, Emerich DF, Lovisari F, Bell WJ, Fradet T, Wahlberg LU, Simonato M (2018) Seizure-suppressant and neuroprotective effects of encapsulated BDNF-producing cells in a rat model of temporal lobe epilepsy. Mol Ther Methods Clin Dev 9:211–224. https://doi.org/10.1016/j.omtm.2018.03.001 CrossRefPubMedPubMedCentral

Friedman W (2012) Chapter 29 - growth factors. In: Brady ST, Siegel GJ, Albers RW, Price DL (eds) Basic neurochemistry (eighth edition). Academic Press, New York, pp 546–557. https://doi.org/10.1016/B978-0-12-374947-5.00029-8 CrossRef

Hansen KF, Sakamoto K, Pelz C, Impey S, Obrietan K (2014) Profiling status epilepticus-induced changes in hippocampal RNA expression using high-throughput RNA sequencing. Sci Rep 4:6930. https://doi.org/10.1038/srep06930 CrossRefPubMedPubMedCentral

Heinrich C, Lähteinen S, Suzuki F, Anne-Marie L, Huber S, Häussler U, Haas C, Larmet Y, Castren E, Depaulis A (2011) Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis 42:35–47. https://doi.org/10.1016/j.nbd.2011.01.001 CrossRefPubMed

Henderson CE (1996) Role of neurotrophic factors in neuronal development. Curr Opin Neurobiol 6:64–70. https://doi.org/10.1016/S0959-4388(96)80010-9 CrossRefPubMed

Hollands C (1986) The animals (scientific procedures) act 1986. Lancet (London, England) 2:32–33CrossRef

Iughetti L, Lucaccioni L, Fugetto F, Predieri B, Berardi A, Ferrari F (2018) Brain-derived neurotrophic factor and epilepsy: a systematic review. Neuropeptides 72:23–29. https://doi.org/10.1016/j.npep.2018.09.005 CrossRefPubMed

Ivanisevic L, Saragovi HU (2013) Chapter 224 - Neurotrophins A2 - Kastin, Abba J. In: Handbook of biologically active peptides (second edition). Academic Press, Boston, pp 1639–1646. https://doi.org/10.1016/B978-0-12-385095-9.00224-4 CrossRef

Johnson EM, Tuszynski MH (2008) 4 - NEUROTROPHIC FACTORS. In: Kordower JH, Tuszynski MH (eds) CNS regeneration (second edition). Academic Press, San Diego, pp 95–144. https://doi.org/10.1016/B978-012373994-0.50006-3 CrossRef

Jongbloets BC, van Gassen KLI, Kan AA, Olde Engberink AHO, de Wit M, Wolterink-Donselaar IG, Groot Koerkamp MJA, van Nieuwenhuizen O, Holstege FCP, de Graan PNE (2015) Expression profiling after prolonged experimental febrile seizures in mice suggests structural remodeling in the Hippocampus. PLoS One 10:e0145247. https://doi.org/10.1371/journal.pone.0145247 CrossRefPubMedPubMedCentral

Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V (2018) The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia 59:2179–2193. https://doi.org/10.1111/epi.14596 CrossRefPubMed

Kandratavicius L, Monteiro MR, Assirati JA Jr, Carlotti CG Jr, Hallak JE, Leite JP (2013) Neurotrophins in mesial temporal lobe epilepsy with and without psychiatric comorbidities. J Neuropathol Exp Neurol 72:1029–1042. https://doi.org/10.1097/nen.0000000000000002 CrossRefPubMed

Lee J-K, Won J-S, Singh AK, Singh I (2008) Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett 440:260–264. https://doi.org/10.1016/j.neulet.2008.05.112 CrossRefPubMedPubMedCentral

Lee CY, Jaw T, Tseng HC, Chen IC, Liou HH (2012) Lovastatin modulates glycogen synthase kinase-3beta pathway and inhibits mossy fiber sprouting after pilocarpine-induced status epilepticus. PLoS One 7:e38789. https://doi.org/10.1371/journal.pone.0038789 CrossRefPubMedPubMedCentral

Leroy C, Roch C, Koning E, Namer IJ, Nehlig A (2003) In the lithium-pilocarpine model of epilepsy, brain lesions are not linked to changes in blood-brain barrier permeability: an autoradiographic study in adult and developing rats. Exp Neurol 182:361–372. https://doi.org/10.1016/s0014-4886(03)00122-5 CrossRefPubMed

Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, Mahmood A, Chen J, Li Y, Chopp M (2007) Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma 24:1132–1146. https://doi.org/10.1089/neu.2007.0288 CrossRefPubMedPubMedCentral

Maness LM, Kastin AJ, Weber JT, Banks WA, Beckman BS, Zadina JE (1994) The neurotrophins and their receptors: structure, function, and neuropathology. Neurosci Biobehav Rev 18:143–159. https://doi.org/10.1016/0149-7634(94)90043-4 CrossRefPubMed

McFarland AJ, Anoopkumar-Dukie S, Arora DS, Grant GD, McDermott CM, Perkins AV, Davey AK (2014) Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci 15:20607–20637. https://doi.org/10.3390/ijms151120607 CrossRefPubMedPubMedCentral

Paolone G, Falcicchia C, Lovisari F, Kokaia M, Bell WJ, Fradet T, Barbieri M, Wahlberg LU, Emerich DF, Simonato M (2019) Long-term, targeted delivery of GDNF from encapsulated cells is neuroprotective and reduces seizures in the pilocarpine model of epilepsy. J Neurosci 39:2144–2156. https://doi.org/10.1523/jneurosci.0435-18.2018 CrossRefPubMed

Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294CrossRefPubMed

Rangel P et al (2005) Lovastatin reduces neuronal cell death in hippocampal CA1 subfield after pilocarpine-induced status epilepticus: preliminary results. Arquivos de neuro-psiquiatria 63:972–976. https://doi.org/10.1590/S0004-282X2005000600013 CrossRefPubMed

Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, Luan CH, Gonzalez FJ, Pahan K (2015) HMG-CoA reductase inhibitors bind to PPARalpha to upregulate Neurotrophin expression in the brain and improve memory in mice. Cell Metab 22:253–265. https://doi.org/10.1016/j.cmet.2015.05.022 CrossRefPubMedPubMedCentral

Ryuta K, Yuji I (2005) To BDNF or not to BDNF: that is the epileptic Hippocampus. Neuroscientist 11:282–287. https://doi.org/10.1177/1073858405278266 CrossRef

Sampaio T, Savall A, Gutierrez M, Pinton S (2017) Neurotrophic factors in Alzheimer's and Parkinson's diseases: implications for pathogenesis and therapy. Neural Regen Res 12:549–557. https://doi.org/10.4103/1673-5374.205084 CrossRefPubMedPubMedCentral

Scharfman HE (2005) Brain-derived neurotrophic factor and epilepsy—a missing link? Epilepsy Currents 5:83–88. https://doi.org/10.1111/j.1535-7511.2005.05312.x CrossRefPubMedPubMedCentral

Shishkina TV, Mishchenko TA, Mitroshina EV, Shirokova OM, Pimashkin AS, Kastalskiy IA, Mukhina IV, Kazantsev VB, Vedunova MV (2018) Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro. Brain Res 1678:310–321. https://doi.org/10.1016/j.brainres.2017.10.023 CrossRefPubMed

Simonato M, Zucchini S (2010) Are the neurotrophic factors a suitable therapeutic target for the prevention of epileptogenesis? Epilepsia 51(Suppl 3):48–51. https://doi.org/10.1111/j.1528-1167.2010.02609.x CrossRefPubMed

Simonato M, Tongiorgi E, Kokaia M (2006) Angels and demons: neurotrophic factors and epilepsy. Trends Pharmacol Sci 27:631–638. https://doi.org/10.1016/j.tips.2006.10.002 CrossRefPubMed

Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS (2005) Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia 46:1133–1139. https://doi.org/10.1111/j.1528-1167.2005.01605.x CrossRefPubMed

Téllez-Zenteno JF, Hernández-Ronquillo L (2012) A review of the epidemiology of temporal lobe epilepsy. Epilepsy research and treatment 2012:630853–630853. https://doi.org/10.1155/2012/630853 CrossRefPubMed

Wood WG, Mΰller WE, Eckert GP (2014) Statins and neuroprotection: basic pharmacology needed. Mol Neurobiol 50:214–220. https://doi.org/10.1007/s12035-014-8647-3 CrossRefPubMed

Xu B, Michalski B, Racine RJ, Fahnestock M (2002) Continuous infusion of neurotrophin-3 triggers sprouting, decreases the levels of TrkA and TrkC, and inhibits epileptogenesis and activity-dependent axonal growth in adult rats. Neuroscience 115:1295–1308CrossRefPubMed

Xu L, Xu H, Cao Y, Yang P, Feng Y, Tang Y, Yuan S, Ming J (2017) Validation of reference genes for quantitative real-time PCR during bicolor Tepal development in Asiatic hybrid lilies (Lilium spp.). Front Plant Sci 8:669. https://doi.org/10.3389/fpls.2017.00669 CrossRefPubMedPubMedCentral

Yang D, Han Y, Zhang J, Chopp M, Seyfried DM (2012) Statins enhance expression of growth factors and activate the PI3K/Akt-mediated signaling pathway after experimental intracerebral hemorrhage. World journal of neuroscience 2:74–80. https://doi.org/10.4236/wjns.2012.22011 CrossRefPubMedPubMedCentral

Yeh LK, Liu CY, Chien CL, Converse RL, Kao WWY, Chen MS, Hu FR, Hsieh FJ, Wang IJ (2008) Molecular analysis and characterization of zebrafish keratocan (zKera) gene. J Biol Chem 283:506–517. https://doi.org/10.1074/jbc.M707656200 CrossRefPubMed

Title: Neuroprotective effects of lovastatin in the pilocarpine rat model of epilepsy according to the expression of neurotrophic factors
Authors: Pooyan Moradi
Mahin Ganjkhani
Iraj Jafari Anarkooli
Alireza Abdanipour
Publication date: 01-08-2019
Publisher: Springer US
Keywords: Statins
Lovastatin
Epilepsy
Published in: Metabolic Brain Disease / Issue 4/2019
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-019-00424-1

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Neuroprotective effects of lovastatin in the pilocarpine rat model of epilepsy according to the expression of neurotrophic factors

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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