Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Apoptosis in the Dentate Nucleus Following Kindling-induced Seizures in Rats

Author(s): Elisa Taddei, Artemio Rosiles, Leonardo Hernandez, Rudy Luna* and Carmen Rubio

Volume 21, Issue 6, 2022

Published on: 07 December, 2021

Page: [511 - 519] Pages: 9

DOI: 10.2174/1871527320666211201161800

Price: $65

Abstract

Background: Epilepsy is a common neurological disorder characterized by abnormal and recurrent neuronal discharges that result in epileptic seizures. The dentate nuclei of the cerebellum receive excitatory input from different brain regions. Purkinje cell loss due to chronic seizures could lead to decreased inhibition of these excitatory neurons, resulting in the activation of apoptotic cascades in the dentate nucleus.

Objective: The present study was designed to determine whether there is a presence of apoptosis (either intrinsic or extrinsic) in the dentate nucleus, the final relay of the cerebellar circuit, following kindling-induced seizures.

Methods: In order to determine this, seizures were triggered via the amygdaloid kindling model. Following 0, 15, or 45 stimuli, rats were sacrificed, and the cerebellum was extracted. It was posteriorly prepared for the immunohistochemical analysis with cell death biomarkers: TUNEL, Bcl-2, truncated Bid (tBid), Bax, cytochrome C, and cleaved caspase 3 (active form). Our findings reproduce results obtained in other parts of the cerebellum.

Results: We found a decrease of Bcl-2 expression, an anti-apoptotic protein, in the dentate nucleus of kindled rats. We also determined the presence of TUNEL-positive neurons, which confirms the presence of apoptosis in the dentate nucleus. We observed the expression of tBid, Bax, as well as cytochrome C and cleaved caspase-3, the main executor caspase of apoptosis.

Conclusion: There is a clear activation of both the intrinsic and extrinsic apoptotic pathways in the cells of the dentate nucleus of the cerebellum of rats subjected to amygdaloid kindling.

Keywords: Epilepsy, cerebellum, dentate nucleus, apoptosis, amygdaloid kindling, rats.

« Previous Next »
Graphical Abstract

[1]
Crooks R, Mitchell T, Thom M. Patterns of cerebellar atrophy in patients with chronic epilepsy: a quantitative neuropathological study. Epilepsy Res 2000; 41(1): 63-73.
[http://dx.doi.org/10.1016/S0920-1211(00)00133-9] [PMID: 10924869]
[2]
Hermann BP, Bayless K, Hansen R, Parrish J, Seidenberg M. Cerebellar atrophy in temporal lobe epilepsy. Epilepsy Behav 2005; 7(2): 279-87.
[http://dx.doi.org/10.1016/j.yebeh.2005.05.022] [PMID: 16051525]
[3]
Oyegbile TO, Bayless K, Dabbs K, et al. The nature and extent of cerebellar atrophy in chronic temporal lobe epilepsy. Epilepsia 2011; 52(4): 698-706.
[http://dx.doi.org/10.1111/j.1528-1167.2010.02937.x] [PMID: 21269292]
[4]
Marcián V, Mareček R, Koriťáková E, Pail M, Bareš M, Brázdil M. Morphological changes of cerebellar substructures in temporal lobe epilepsy: A complex phenomenon, not mere atrophy. Seizure 2018; 54: 51-7.
[http://dx.doi.org/10.1016/j.seizure.2017.12.004] [PMID: 29268230]
[5]
Kros L, Eelkman Rooda OHJ, De Zeeuw CI, Hoebeek FE. Controlling cerebellar output to treat refractory epilepsy. Trends Neurosci 2015; 38(12): 787-99.
[http://dx.doi.org/10.1016/j.tins.2015.10.002] [PMID: 26602765]
[6]
Monaghan PL, Beitz AJ, Larson AA, Altschuler RA, Madl JE, Mullett MA. Immunocytochemical localization of glutamate-, glutaminase- and aspartate aminotransferase-like immunoreactivity in the rat deep cerebellar nuclei. Brain Res 1986; 363(2): 364-70.
[http://dx.doi.org/10.1016/0006-8993(86)91024-3] [PMID: 2867817]
[7]
Anchisi D, Scelfo B, Tempia F. Postsynaptic currents in deep cerebellar nuclei. J Neurophysiol 2001; 85(1): 323-31.
[http://dx.doi.org/10.1152/jn.2001.85.1.323] [PMID: 11152732]
[8]
Trump BF, Berezesky IK. Calcium-mediated cell injury and cell death. FASEB J 1995; 9(2): 219-28.
[http://dx.doi.org/10.1096/fasebj.9.2.7781924] [PMID: 7781924]
[9]
Rubio C, Rosiles-Abonce A, Trejo-Solis C, et al. Increase signaling of wnt/β-catenin pathway and presence of apoptosis in cerebellum of kindled rats. CNS Neurol Disord Drug Targets 2017; 16(7): 772-80.
[http://dx.doi.org/10.2174/1871527316666170117114513] [PMID: 28124605]
[10]
Rubio C, Mendoza C, Trejo C, et al. Activation of the extrinsic and intrinsic apoptotic pathways in cerebellum of kindled rats. Cerebellum 2019; 18(4): 750-60.
[http://dx.doi.org/10.1007/s12311-019-01030-8] [PMID: 31062284]
[11]
Ameisen JC. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ 2002; 9(4): 367-93.
[http://dx.doi.org/10.1038/sj.cdd.4400950] [PMID: 11965491]
[12]
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26(4): 239-57.
[http://dx.doi.org/10.1038/bjc.1972.33] [PMID: 4561027]
[13]
Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW. Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochim Biophys Acta 2006; 1762(2): 191-201.
[http://dx.doi.org/10.1016/j.bbadis.2005.07.002] [PMID: 16055309]
[14]
Duprez L, Wirawan E, Vanden Berghe T, Vandenabeele P. Major cell death pathways at a glance. Microbes Infect 2009; 11(13): 1050-62.
[http://dx.doi.org/10.1016/j.micinf.2009.08.013] [PMID: 19733681]
[15]
Coultas L, Strasser A. The role of the Bcl-2 protein family in cancer. Semin Cancer Biol 2003; 13(2): 115-23.
[http://dx.doi.org/10.1016/S1044-579X(02)00129-3] [PMID: 12654255]
[16]
Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 1998; 94(3): 325-37.
[http://dx.doi.org/10.1016/S0092-8674(00)81476-2] [PMID: 9708735]
[17]
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94(4): 481-90.
[http://dx.doi.org/10.1016/S0092-8674(00)81589-5] [PMID: 9727491]
[18]
Yoshida H, Kong YY, Yoshida R, et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 1998; 94(6): 739-50.
[http://dx.doi.org/10.1016/S0092-8674(00)81733-X] [PMID: 9753321]
[19]
Liou AK, Clark RS, Henshall DC, Yin XM, Chen J. To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog Neurobiol 2003; 69(2): 103-42.
[http://dx.doi.org/10.1016/S0301-0082(03)00005-4] [PMID: 12684068]
[20]
Yalcin A, Armagan G, Turunc E, Konyalioglu S, Kanit L. Potential neuroprotective effect of gamma-glutamylcysteine ethyl ester on rat brain against kainic acid-induced excitotoxicity. Free Radic Res 2010; 44(5): 513-21.
[http://dx.doi.org/10.3109/10715761003645964] [PMID: 20214503]
[21]
Paxinos G, Watson C. The rat brain in sterotaxic coordinates New York Academic Press . 1982; p. p. 160.
[22]
Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 1969; 25(3): 295-330.
[http://dx.doi.org/10.1016/0014-4886(69)90128-9] [PMID: 4981856]
[23]
Luan L, Sun Y, Yang K. Surgical strategy for temporal lobe epilepsy with dual pathology and incomplete evidence from EEG and neuroimaging. Exp Ther Med 2018; 16(6): 4886-92.
[http://dx.doi.org/10.3892/etm.2018.6774] [PMID: 30546403]
[24]
Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32(3): 281-94.
[http://dx.doi.org/10.1016/0013-4694(72)90177-0] [PMID: 4110397]
[25]
Rubio C, Custodio V, González E, Retana-Márquez S, López M, Paz C. Effects of kainic acid lesions of the cerebellar interpositus and dentate nuclei on amygdaloid kindling in rats. Brain Res Bull 2011; 85(1-2): 64-7.
[http://dx.doi.org/10.1016/j.brainresbull.2011.02.003] [PMID: 21335069]
[26]
Custodio V, Rubio C, Paz C. Prenatal ozone exposure induces memory deficiencies in newborns rats. Front Mol Neurosci 2019; 12: 244.
[http://dx.doi.org/10.3389/fnmol.2019.00244] [PMID: 31680853]
[27]
Filipkowski RK, Hetman M, Kaminska B, Kaczmarek L. DNA fragmentation in rat brain after intraperitoneal administration of kainate. Neuroreport 1994; 5(12): 1538-40.
[http://dx.doi.org/10.1097/00001756-199407000-00032] [PMID: 7948857]
[28]
Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal cell death. Physiol Rev 2018; 98(2): 813-80.
[http://dx.doi.org/10.1152/physrev.00011.2017] [PMID: 29488822]
[29]
Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005; 25(12): 1557-72.
[http://dx.doi.org/10.1038/sj.jcbfm.9600149] [PMID: 15889042]
[30]
Tummers B, Green DR. Caspase-8: regulating life and death. Immunol Rev 2017; 277(1): 76-89.
[http://dx.doi.org/10.1111/imr.12541] [PMID: 28462525]
[31]
Mañas A, Davis A, Lamerand S, Xiang J. Detection of pro-apoptotic Bax∆2 proteins in the human cerebellum. Histochem Cell Biol 2018; 150(1): 77-82.
[http://dx.doi.org/10.1007/s00418-018-1669-6] [PMID: 29663074]
[32]
Toscano ECB, Vieira ÉLM, Portela ACDC, et al. Bcl-2/Bax ratio increase does not prevent apoptosis of glia and granular neurons in patients with temporal lobe epilepsy. Neuropathology 2019; 39(5): 348-57.
[http://dx.doi.org/10.1111/neup.12592] [PMID: 31392787]
[33]
Gibson CJ, Davids MS. BCL-2 antagonism to target the intrinsic mitochondrial pathway of apoptosis. Clin Cancer Res 2015; 21(22): 5021-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0364] [PMID: 26567361]
[34]
Korhonen L, Belluardo N, Mudo G, Lindholm D. Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. Eur J Neurosci 2003; 18(5): 1121-34.
[http://dx.doi.org/10.1046/j.1460-9568.2003.02826.x] [PMID: 12956712]
[35]
Akcali KC, Sahiner M, Sahiner T. The role of bcl-2 family of genes during kindling. Epilepsia 2005; 46(2): 217-23.
[http://dx.doi.org/10.1111/j.0013-9580.2005.13904.x] [PMID: 15679502]
[36]
Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: Pathogenesis and treatment. CNS Neurosci Ther 2017; 23(1): 5-22.
[http://dx.doi.org/10.1111/cns.12655] [PMID: 27873462]
[37]
Wu Y, Chen M, Jiang J. Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling. Mitochondrion 2019; 49: 35-45.
[http://dx.doi.org/10.1016/j.mito.2019.07.003] [PMID: 31288090]
[38]
Ripple MO, Abajian M, Springett R. Cytochrome C is rapidly reduced in the cytosol after mitochondrial outer membrane permeabilization. Apoptosis 2010; 15(5): 563-73.
[http://dx.doi.org/10.1007/s10495-010-0455-2] [PMID: 20094799]
[39]
Sano N, Nakayama Y, Ishida H, et al. Cerebellar outputs contribute to spontaneous and movement-related activity in the motor cortex of monkeys [published online ahead of print, 2020 Apr 12]. Neurosci Res 2020; S0168-0102(19): 30651-0.
[http://dx.doi.org/10.1016/j.neures.2020.03.010]
[40]
Cicirata F, Zappalà A, Serapide MF, Parenti R, Pantò MR, Paz C. Different pontine projections to the two sides of the cerebellum. Brain Res Brain Res Rev 2005; 49(2): 280-94.
[http://dx.doi.org/10.1016/j.brainresrev.2005.02.002] [PMID: 16111556]
[41]
Guell X, D’Mello AM, Hubbard NA, et al. Functional territories of human dentate nucleus. Cereb Cortex 2020; 30(4): 2401-17.
[http://dx.doi.org/10.1093/cercor/bhz247] [PMID: 31701117]
[42]
Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet Neurol 2004; 3(11): 663-72.
[http://dx.doi.org/10.1016/S1474-4422(04)00906-8] [PMID: 15488459]

Rights & Permissions Print Cite
Article Metrics
31
1
© 2024 Bentham Science Publishers | Privacy Policy