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TGFβ1 Treatment Reduces Hippocampal Damage, Spontaneous Recurrent Seizures, and Learning Memory Deficits in Pilocarpine-Treated Rats

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Abstract

Studies have demonstrated the neuroprotective activity of transforming growth factor beta-1 (TGFβ1), protecting neurons against different kinds of insults. However, the role of exogenous TGFβ1 in the neuronal damage following status epilepticus (SE) and the related spontaneous recurrent seizures (SRS) is unknown. The present study aimed to determine the effect of intranasal TGFβ1 administration on SRS and cognitive function following lithium–pilocarpine-induced SE and associated hippocampal damage. We found that intranasal TGFβ1 significantly attenuated the hippocampal insults marked by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and Fluoro-Jade B staining by 24, 48, and 72 h after SE was induced. The expression of the apoptosis-suppressing protein, Bcl-2, was elevated, whereas the expression of the apoptosis-promoting proteins, Bax and Caspase-3, was suppressed in TGFβ1-treated rats compared to rats without TGFβ1 treatment by 24, 48, and 72 h following induction of SE. The seizure number, severity, and duration of SRS over a 1-month period of monitoring starting 15 days after SE induction as well as the cognitive deficits detected 45 days after SE induction were significantly reduced in TGFβ1-treated rats compared to those without TGFβ1 treatment. Our results indicate that intranasal delivery of TGFβ1 immediately after SE induction not only protected against SRS but also improved cognitive function. The anti-epileptogenic properties of TGFβ1 may be related to its effect of neuroprotection or to its effect of apoptosis pathway changes.

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References

  • Acharya MM, Hattiangady B, Shetty AK (2008) Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol 84:363–404

    Article  PubMed  CAS  Google Scholar 

  • Bahar AS, Shirvalkar PR, Shapiro ML (2011) Memory-guided learning: CA1 and CA3 neuronal ensembles differentially encode the commonalities and differences between situations. J Neurosci 31:12270–12281

    Article  PubMed  CAS  Google Scholar 

  • Battaglia G, Cannella M, Riozzi B, Orobello S, Maat-Schieman ML, Aronica E, Busceti CL, Ciarmiello A, Alberti S, Amico E, Sassone J, Sipione S, Bruno V, Frati L, Nicoletti F, Squitieri F (2011) Early defect of transforming growth factor beta1 formation in Huntington’s disease. J Cell Mol Med 15:555–571

    Article  PubMed  CAS  Google Scholar 

  • Bernasconi A, Tasch E, Cendes F, Li LM, Arnold DL (2002) Proton magnetic resonance spectroscopic imaging suggests progressive neuronal damage in human temporal lobe epilepsy. Prog Brain Res 135:297–304

    Article  PubMed  CAS  Google Scholar 

  • Biagini G, Baldelli E, Longo D, Contri MB, Guerrini U, Sironi L, Gelosa P, Zini I, Ragsdale DS, Avoli M (2008) Proepileptic influence of a focal vascular lesion affecting entorhinal cortex–CA3 connections after status epilepticus. J Neuropathol Exp Neurol 67:687–701

    Article  PubMed  Google Scholar 

  • Boche D, Cunningham C, Gauldie J, Perry VH (2003) Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo. J Cereb Blood Flow Metab 23:1174–1182

    Article  PubMed  CAS  Google Scholar 

  • Brionne TC, Tesseur I, Masliah E, Wyss-Coray T (2003) Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40:1133–1145

    Article  PubMed  CAS  Google Scholar 

  • Bumanglag AV, Sloviter RS (2008) Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation-induced status epilepticus in awake rats. J Comp Neurol 510:561–580

    Article  PubMed  Google Scholar 

  • Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, Heinemann U, Friedman A, Kaufer D (2009) Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci 29:8927–8935

    Article  PubMed  CAS  Google Scholar 

  • Caraci F, Battaglia G, Bruno V, Bosco P, Carbonaro V, Giuffrida ML, Drago F, Sortino MA, Nicoletti F, Copani A (2011) TGF-beta1 pathway as a new target for neuroprotection in Alzheimer’s disease. CNS Neurosci Ther 17:237–249

    Article  PubMed  CAS  Google Scholar 

  • Chauviere L, Rafrafi N, Thinus-Blanc C, Bartolomei F, Esclapez M, Bernard C (2009) Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy. J Neurosci 29:5402–5410

    Article  PubMed  CAS  Google Scholar 

  • Chin J, Angers A, Cleary LJ, Eskin A, Byrne JH (1999) TGF-beta1 in aplysia: role in long-term changes in the excitability of sensory neurons and distribution of TbetaR-II-like immunoreactivity. Learn Mem 6:317–330

    PubMed  CAS  Google Scholar 

  • de Lanerolle NC, Kim JH, Williamson A, Spencer SS, Zaveri HP, Eid T, Spencer DD (2003) A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. Epilepsia 44:677–687

    Article  PubMed  Google Scholar 

  • Dhandapani KM, Hadman M, De Sevilla L, Wade MF, Mahesh VB, Brann DW (2003) Astrocyte protection of neurons: role of transforming growth factor-beta signaling via a c-Jun–AP-1 protective pathway. J Biol Chem 278:43329–43339

    Article  PubMed  CAS  Google Scholar 

  • Docagne F, Nicole O, Gabriel C, Fernandez-Monreal M, Lesne S, Ali C, Plawinski L, Carmeliet P, MacKenzie ET, Buisson A, Vivien D (2002) Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis. Mol Cell Neurosci 21:634–644

    Article  PubMed  CAS  Google Scholar 

  • Engel T, Tanaka K, Jimenez-Mateos EM, Caballero-Caballero A, Prehn JH, Henshall DC (2010a) Loss of p53 results in protracted electrographic seizures and development of an aggravated epileptic phenotype following status epilepticus. Cell Death Dis 1:e79

    Article  PubMed  CAS  Google Scholar 

  • Engel T, Murphy BM, Hatazaki S, Jimenez-Mateos EM, Concannon CG, Woods I, Prehn JH, Henshall DC (2010b) Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma. FASEB J 24:853–861

    Article  PubMed  CAS  Google Scholar 

  • Fannjiang Y, Kim CH, Huganir RL, Zou S, Lindsten T, Thompson CB, Mito T, Traystman RJ, Larsen T, Griffin DE, Mandir AS, Dawson TM, Dike S, Sappington AL, Kerr DA, Jonas EA, Kaczmarek LK, Hardwick JM (2003) BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. Dev Cell 4:575–585

    Article  PubMed  CAS  Google Scholar 

  • Fujikawa DG (1996) The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res 725:11–22

    PubMed  CAS  Google Scholar 

  • Gonzalez-Aparicio R, Flores JA, Fernandez-Espejo E (2010) Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor beta1 is enhanced after co-infusion in rats. Exp Neurol 226:136–147

    Article  PubMed  CAS  Google Scholar 

  • Gorter JA, Goncalves Pereira PM, van Vliet EA, Aronica E, Lopes da Silva FH, Lucassen PJ (2003) Neuronal cell death in a rat model for mesial temporal lobe epilepsy is induced by the initial status epilepticus and not by later repeated spontaneous seizures. Epilepsia 44:647–658

    Article  PubMed  Google Scholar 

  • Graciarena M, Depino AM, Pitossi FJ (2010) Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFbeta1 downregulation. Brain Behav Immun 24:1301–1309

    Article  PubMed  CAS  Google Scholar 

  • Hanson LR, Frey WH (2008) Intranasal delivery bypasses the blood–brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9(Suppl 3):S5

    Article  PubMed  Google Scholar 

  • Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A (2007) TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535–547

    Article  PubMed  Google Scholar 

  • Jiao S, Li Z (2011) Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70:758–772

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Mateos EM, Hatazaki S, Johnson MB, Bellver-Estelles C, Mouri G, Bonner C, Prehn JH, Meller R, Simon RP, Henshall DC (2008) Hippocampal transcriptome after status epilepticus in mice rendered seizure damage-tolerant by epileptic preconditioning features suppressed calcium and neuronal excitability pathways. Neurobiol Dis 32:442–453

    Article  PubMed  CAS  Google Scholar 

  • Kang TC, Kim DS, Kwak SE, Kim JE, Won MH, Kim DW, Choi SY, Kwon OS (2006) Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy. Glia 54:258–271

    Article  PubMed  Google Scholar 

  • Kastin AJ, Akerstrom V, Pan W (2003) Circulating TGF-beta1 does not cross the intact blood–brain barrier. J Mol Neurosci 21:43–48

    Article  PubMed  CAS  Google Scholar 

  • Kim DS, Kim JE, Kwak SE, Choi KC, Kim DW, Kwon OS, Choi SY, Kang TC (2008) Spatiotemporal characteristics of astroglial death in the rat hippocampo-entorhinal complex following pilocarpine-induced status epilepticus. J Comp Neurol 511:581–598

    Article  PubMed  Google Scholar 

  • Konig HG, Kogel D, Rami A, Prehn JH (2005) TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol 168:1077–1086

    Article  PubMed  Google Scholar 

  • Krieglstein K, Zheng F, Unsicker K, Alzheimer C (2011) More than being protective: functional roles for TGF-beta/activin signaling pathways at central synapses. Trends Neurosci 34:421–429

    Article  PubMed  CAS  Google Scholar 

  • Kubova H, Druga R, Haugvicova R, Suchomelova L, Pitkanen A (2002) Dynamic changes of status epilepticus-induced neuronal degeneration in the mediodorsal nucleus of the thalamus during postnatal development of the rat. Epilepsia 43(Suppl 5):54–60

    Article  PubMed  Google Scholar 

  • Kudryashova IV, Onufriev MV, Kudryashov IE, Gulyaeva NV (2009) Caspase-3 activity in hippocampal slices reflects changes in synaptic plasticity. Neurosci Behav Physiol 39:13–20

    Article  PubMed  CAS  Google Scholar 

  • Kundrotiene J, Wagner A, Liljequist S (2004) Fluoro-Jade and TUNEL staining as useful tools to identify ischemic brain damage following moderate extradural compression of sensorimotor cortex. Acta Neurobiol Exp (Wars) 64:153–162

    Google Scholar 

  • Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, Itohara S, Simon RP, Boison D (2008) Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest 118:571–582

    Article  PubMed  CAS  Google Scholar 

  • Lochhead JJ, Thorne RG (2012) Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64:614–628

    Article  PubMed  CAS  Google Scholar 

  • Ma YP, Ma MM, Ge S, Guo RB, Zhang HJ, Frey WH 2nd, Xu GL, Liu XF (2007) Intranasally delivered TGF-beta1 enters brain and regulates gene expressions of its receptors in rats. Brain Res Bull 74:271–277

    Article  PubMed  CAS  Google Scholar 

  • Ma M, Ma Y, Yi X, Guo R, Zhu W, Fan X, Xu G, Frey WH 2nd, Liu X (2008) Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci 9:117

    Article  PubMed  Google Scholar 

  • Muller CJ, Bankstahl M, Groticke I, Loscher W (2009) Pilocarpine vs. lithium–pilocarpine for induction of status epilepticus in mice: development of spontaneous seizures, behavioral alterations and neuronal damage. Eur J Pharmacol 619:15–24

    Article  PubMed  Google Scholar 

  • Narkilahti S, Pirttila TJ, Lukasiuk K, Tuunanen J, Pitkanen A (2003) Expression and activation of caspase 3 following status epilepticus in the rat. Eur J Neurosci 18:1486–1496

    Article  PubMed  Google Scholar 

  • Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I (2006) Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 67:1383–1389

    Article  PubMed  CAS  Google Scholar 

  • Pitkanen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186

    Article  PubMed  Google Scholar 

  • Qian L, Wei SJ, Zhang D, Hu X, Xu Z, Wilson B, El-Benna J, Hong JS, Flood PM (2008) Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J Immunol 181:660–668

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sander JW (2003) The epidemiology of epilepsy revisited. Curr Opin Neurol 16:165–170

    Article  PubMed  Google Scholar 

  • Schmued LC, Hopkins KJ (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874:123–130

    Article  PubMed  CAS  Google Scholar 

  • Simonato M, Tongiorgi E, Kokaia M (2006) Angels and demons: neurotrophic factors and epilepsy. Trends Pharmacol Sci 27:631–638

    Article  PubMed  CAS  Google Scholar 

  • Stienen MN, Haghikia A, Dambach H, Thone J, Wiemann M, Gold R, Chan A, Dermietzel R, Faustmann PM, Hinkerohe D, Prochnow N (2011) Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFbeta1 regulation. Br J Pharmacol 162:491–507

    Article  PubMed  CAS  Google Scholar 

  • Sun M, Gewirtz JC, Bofenkamp L, Wickham RJ, Ge H, O’Connor MB (2010) Canonical TGF-beta signaling is required for the balance of excitatory/inhibitory transmission within the hippocampus and prepulse inhibition of acoustic startle. J Neurosci 30:6025–6035

    Article  PubMed  CAS  Google Scholar 

  • Tasch E, Cendes F, Li LM, Dubeau F, Andermann F, Arnold DL (1999) Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy. Ann Neurol 45:568–576

    Article  PubMed  CAS  Google Scholar 

  • Thom M, Eriksson S, Martinian L, Caboclo LO, McEvoy AW, Duncan JS, Sisodiya SM (2009) Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol 68:928–938

    Article  PubMed  Google Scholar 

  • Vezzani A, Aronica E, Mazarati A, Pittman QJ (2012) Epilepsy and brain inflammation. Exp Neurol (in press)

  • Wang Y, Symes AJ (2010) Smad3 deficiency reduces neurogenesis in adult mice. J Mol Neurosci 41:383–396

    Article  PubMed  Google Scholar 

  • Wang Y, Liu PP, Li LY, Zhang HM, Li T (2011) Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats. CNS Neurosci Ther 17:271–280

    Article  PubMed  CAS  Google Scholar 

  • Wu CL, Huang LT, Liou CW, Wang TJ, Tung YR, Hsu HY, Lai MC (2001) Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss. Neurosci Lett 312:113–117

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Roth-Eichhorn S, Braun N, Culmsee C, Rami A, Krieglstein J (2000) The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res 866:286–298

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Yang GY, Ahlemeyer B, Pang L, Che XM, Culmsee C, Klumpp S, Krieglstein J (2002) Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22:3898–3909

    PubMed  CAS  Google Scholar 

  • Zhu Y, Culmsee C, Klumpp S, Krieglstein J (2004) Neuroprotection by transforming growth factor-beta1 involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways. Neuroscience 123:897–906

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Natural Science grants to Y Wang (grant number: 30970997) and to Y Fang (grant number: 30640010) from the National Natural Science Foundation of China, by Natural Science grants to Y Wang (grant number: 09020103008) from the Natural Science Foundation of Anhui Province, and by the Key Scientific and Technological Project to Y Wang (grant number: 11010402168) from Anhui Science and Technology Department. The authors thank the innominate referees for their review and suggestions.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Epilepsy and Headache Group, Department of Neurology, the First Hospital of Anhui Medical University, Jixi Road 218, Hefei, 230022, China

    Liang-Yong Li, Jia-Lin Li, Hui-Min Zhang, Kai Wang & Yu Wang

  2. Department of Neurology, the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, China

    Liang-Yong Li & Wen-Ming Yang

  3. Department of Anatomy, Tongling Vocational and Technical College, Tongling, 244000, China

    Jia-Lin Li

  4. Department of Neurology, Shaoxing Second Hospital, Shaoxing, 312000, China

    Hui-Min Zhang

  5. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yuan Fang

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  1. Liang-Yong Li
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Correspondence to Yuan Fang or Yu Wang.

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Ethical Considerations

The protocol for this research project has been approved by the Ethics Committee of the Anhui Medical University and Huazhong University of Science and Technology within which the work was undertaken and that it conforms to the provisions of the Declaration of Helsinki.

Liang-Yong Li and Jia-Lin Li contributed equally to this work.

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Li, LY., Li, JL., Zhang, HM. et al. TGFβ1 Treatment Reduces Hippocampal Damage, Spontaneous Recurrent Seizures, and Learning Memory Deficits in Pilocarpine-Treated Rats. J Mol Neurosci 50, 109–123 (2013). https://doi.org/10.1007/s12031-012-9879-1

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