Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain

Journal of Neuroinflammation

Raman Sankar²  Andrey Mazarati³  Don Shin³  Stéphane Auvin⁴  Eduardo Pineda³  Young Se Kwon¹ 

[1] Department of Pediatrics, College of Medicine, Inha University, Incheon, Republic of Korea;Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, 22-474 MDCC in CHS, Los Angeles, CA 90095-1752, USA;Department of Pediatric Neurology, Hôpital Robert Debré, INSERM U676, Paris, 75019, France

关键词: COX-2;    IL-1β;    Inflammation;    Status epilepticus;    Hippocampus;    Anti-epileptogenesis;    Epilepsy;   

Others  :  1160022
DOI  :  10.1186/1742-2094-10-30

 received in 2012-09-27, accepted in 2013-02-15,  发布年份 2013

【 摘 要 】

Background

Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.

Findings

We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.

None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.

Conclusions

Deployment of an empirically designed ‘drug cocktail’ targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.

【 授权许可】

   
2013 Kwon et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 2000, 342:314-319.
• [2]2007 Epilepsy Research Benchmarkshttp://www.ninds.nih.gov/research/epilepsyweb/2007_benchmarks.htm webcite
• [3]Temkin NR: Preventing and treating posttraumatic seizures: the human experience. Epilepsia 2009, 2:10-13.
• [4]François J, Koning E, Ferrandon A, Nehlig A: The combination of topiramate and diazepam is partially neuroprotective in the hippocampus but not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy. Epilepsy Res 2006, 72:147-163.
• [5]Brandt C, Gastens AM, Sun M, Hausknecht M, Löscher W: Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006, 51:789-804.
• [6]Brandt C, Glien M, Gastens AM, Fedrowitz M, Bethmann K, Volk HA, Potschka H, Löscher W: Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats. Neuropharmacology 2007, 53:207-221.
• [7]Pitkänen A, Nissinen J, Jolkkonen E, Tuunanen J, Halonen T: Effects of vigabatrin treatment on status epilepticus-induced neuronal damage and mossy fiber sprouting in the rat hippocampus. Epilepsy Res 1999, 33:67-85.
• [8]Vezzani A, Friedman A, Dingledine RJ: The role of inflammation in epileptogenesis. Neuropharmacology 2012. [Epub ahead of print, PMID: 22521336]
• [9]Buckmaster PS: Mossy Fiber Sprouting in the Dentate Gyrus. In Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Edited by Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. Bethesda, MD: National Center for Biotechnology Information (US); 2012.
• [10]Pitkänen A, Nissinen J, Lukasiuk K, Jutila L, Paljärvi L, Salmenperä T, Karkola K, Vapalahti M, Ylinen A: Association between the density of mossy fiber sprouting and seizure frequency in experimental and human temporal lobe epilepsy. Epilepsia 2000, Suppl 6:S24-29.
• [11]El Bahh B, Lespinet V, Lurton D, Coussemacq M, Le Gal La Salle G, Rougier A: Correlations between granule cell dispersion, mossy fiber sprouting, and hippocampal cell loss in temporal lobe epilepsy. Epilepsia 1999, 40:1393-1401.
• [12]Sankar R, Shin DH, Liu H, Mazarati A, Pereira de Vasconcelos A, Wasterlain CG: Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci 1998, 18:8382-8393.
• [13]Sankar R, Shin D, Mazarati AM, Liu H, Katsumori H, Lezama R, Wasterlain CG: Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann Neurol 2000, 48:580-589.
• [14]Auvin S, Shin D, Mazarati A, Nakagawa J, Miyamoto J, Sankar R: Inflammation exacerbates seizure-induced injury in the immature brain. Epilepsia 2007, Suppl 5:27-34.
• [15]Auvin S, Mazarati A, Shin D, Sankar R: Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 2010, 40:303-310.
• [16]Cavazos JE, Golarai G, Sutula TP: Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J Neurosci 1991, 11:2795-2803.
• [17]Jung KH, Chu K, Lee ST, Kim J, Sinn DI, Kim JM, Park DK, Lee JJ, Kim SU, Kim M, Lee SK, Roh JK: Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis 2006, 23:237-246.
• [18]Zhang HJ, Sun RP, Lei GF, Yang L, Liu CX: Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats. J Zhejiang Univ Sci B 2008, 9:903-915.
• [19]Polascheck N, Bankstahl M, Löscher W: The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010, 224:219-233.
• [20]Holtman L, van Vliet EA, van Schaik R, Queiroz CM, Aronica E, Gorter JA: Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 2009, 84:56-66.
• [21]Holtman L, van Vliet EA, Edelbroek PM, Aronica E, Gorter JA: Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy. Epilepsy Res 2010, 91:49-56.
• [22]Levin JR, Serrano G, Dingledine R: Reduction in delayed mortality and subtle improvement in retrograde memory performance in pilocarpine-treated mice with conditional neuronal deletion of cyclooxygenase-2 gene. Epilepsia 2012, 53:1411-1420.
• [23]Ravizza T, Noé F, Zardoni D, Vaghi V, Sifringer M, Vezzani A: Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1β production. Neurobiol Dis 2008, 31:327-333.
• [24]Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, Vezzani A: Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 2011, 8:304-315.
• [25]Gutierrez EG, Banks WA, Kastin AJ: Blood-borne interleukin-1 receptor antagonist crosses the blood–brain barrier. J Neuroimmunol 1994, 55:153-160.
• [26]Greenhalgh AD, Galea J, Dénes A, Tyrrell PJ, Rothwell NJ: Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. Br J Pharmacol 2010, 160:153-159.
• [27]Zucchini S, Buzzi A, Barbieri M, Rodi D, Paradiso B, Binaschi A, Coffin JD, Marzola A, Cifelli P, Belluzzi O, Simonato M: FGF-2 overexpression increases excitability and seizure susceptibility but decreases seizure-induced cell loss. J Neurosci 2008, 28:13112-13124.
• [28]Paradiso B, Marconi P, Zucchini S, Berto E, Binaschi A, Bozac A, Buzzi A, Mazzuferi M, Magri E, Navarro Mora G, Rodi D, Su T, Volpi I, Zanetti L, Marzola A, Manservigi R, Fabene PF, Simonato M: Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc Natl Acad Sci U S A 2009, 106:7191-7196.
• [29]Bovolenta R, Zucchini S, Paradiso B, Rodi D, Merigo F, Navarro Mora G, Osculati F, Berto E, Marconi P, Marzola A, Fabene PF, Simonato M: Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures. J Neuroinflammation 2010, 7:81-86. BioMed Central Full Text