Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy

Journal of Neuroinflammation

Yuanzheng Liu⁴  Zhijun Ren⁴  Qianchao He²  Limin Xiao¹  Liang Gao¹  Yunhong Yu³  Lun Cai¹  Wei Xie¹ 

[1] Southern Medical University, Guangzhou, People’s Republic of China;Department of Encephalopathy, The first affiliated hosipital of Guangxi University of Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China;Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guang Zhou 510080, China;School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China

关键词: Depression;    Epilepsy;    Forced swim test;    Taste preference test;    Interleukin-6;    Interleukin-1β;    Serotonin;    Tryptophan;    Kynurenine;    Minocycline;    1-methyltryptophan;   

Others  :  812598
DOI  :  10.1186/1742-2094-11-41

 received in 2013-12-21, accepted in 2014-02-13,  发布年份 2014

【 摘 要 】

Background

Depression has most often been diagnosed in patients with temporal lobe epilepsy (TLE), but the mechanism underlying this association remains unclear. In this study, we report that indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in epilepsy-associated depressive-like behavior.

Methods

Rats which develop chronic epilepsy following pilocarpine status epilepticus exhibited a set of interictal disorders consistent with depressive-like behavior. Changes of depressive behavior were examined by taste preference test and forced swim test; brain IL-1β, IL-6 and IDO1 expression were quantified using real-time reverse transcriptase PCR; brain kynurenine/tryptophan and serotonin/tryptophan ratios were analyzed by liquid chromatography-mass spectrometry. Oral gavage of minocycline or subcutaneous injection of 1-methyltryptophan (1-MT) were used to inhibite IDO1 expression.

Results

We observed the induction of IL-1β and IL-6 expression in rats with chronic TLE, which further induced the upregulation of IDO1 expression in the hippocampus. The upregulation of IDO1 subsequently increased the kynurenine/tryptophan ratio and decreased the serotonin/tryptophan ratio in the hippocampus, which contributed to epilepsy-associated depressive-like behavior. The blockade of IDO1 activation prevented the development of depressive-like behavior but failed to influence spontaneous seizures. This effect was achieved either indirectly, through the anti-inflammatory tetracycline derivative minocycline, or directly, through the IDO antagonist 1-MT, which normalizes kynurenine/tryptophan and serotonin/tryptophan ratios.

Conclusion

Brain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.

【 授权许可】

   
2014 Xie et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Mazarati AM, Pineda E, Shin D, Tio D, Taylor AN, Sankar R: Comorbidity between epilepsy and depression: role of hippocampal interleukin-1β. Neurobiol Dis 2010, 37:461-478.
• [2]Minami M, Kuraishi Y, Satoh M: Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun 1991, 176:593-598.
• [3]Lehtimäki KA, Peltola J, Koskikallio E, Keränen T, Honkaniemi J: Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Mol Brain Res 2003, 110:253-260.
• [4]De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A: Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 2000, 12:2623-2633.
• [5]Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, Satoh M: Convulsants induce interleukin-1 beta messenger RNA in rat brain. Biochem Biophys Res Commun 1990, 171:832-837.
• [6]Omran A, Peng J, Zhang C, Xiang QL, Xue J, Gan N, Kong H, Yin F: Interleukin-1β and microRNA-146a in an immature rat model. Epilepsia 2012, 53:1215-1224.
• [7]Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ: Kynurenines in the mammalian brain: when physiology meets pathology. Nat rev Neurosci 2012, 13:465-477.
• [8]O’Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R: Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 2009, 14:511-522.
• [9]Kim H, Chen L, Lim G, Sung B, Wang S, McCabe MF, Rusanescu G, Yang L, Tian Y, Mao J: Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest 2012, 122:2940-2954.
• [10]Sublette ME, Postolache TT: Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. Psychosom Med 2012, 74:668-672.
• [11]Myint AM: Kynurenines: from the perspective of major psychiatric disorders. FEBS J 2012, 279:1375-1385.
• [12]Mazarati AM, Siddarth P, Baldwin RA, Shin D, Caplan R, Sankar R: Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 2008, 131:2071-2083.
• [13]Mazarati AM, Shin D, Kwon YS, Bragin A, Pineda E, Tio D, Taylor AN, Sankar R: Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy. Neurobiol Dis 2009, 34:457-461.
• [14]Racine RJ: Modification of seizure activity by electrical stimulation: II. Motor seizures. Electroencephalogr Clin Neurophysiol 1972, 32:281-294.
• [15]Pucilowski O, Overstreet DH: Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains. Brain Res Bull 1993, 32:471-475.
• [16]Pucilowski O, Overstreet DH, Rezvani AH, Janowsky DS: Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 1993, 54:1215-1220.
• [17]Overstreet DH, Pucilowski O, Rezvani AH, Janowsky DS: Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression. Psychopharmacology (Berl) 1995, 121:27-37.
• [18]Zhao F, Cai TJ, Liu MC, Zheng G, Luo W, Chen J: Manganese induces dopaminergic neurodegeneration via microglial activation in a rat model of manganism. Toxicol Sci 2009, 107:156-164.
• [19]Möller M, Du Preez JL, Harvey BH: Development and validation of a single analytical method for the determination of tryptophan, and its kynurenine metabolites in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2012, 898:121-129.
• [20]Gonzalez RR, Fernandez RF, Vidal JL, Frenich AG, Perez ML: Development and validation of an ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS) method for the simultaneous determination of neurotransmitters in rat brain samples. J Neurosci Methods 2011, 198:187-194.
• [21]Fiest KM, Dykeman J, Patten SB, Wiebe S, Kaplan GG, Maxwell CG, Bulloch AG, Jette N: Depression in epilepsy: a systematic review and meta-analysis. Neurology 2013, 80:590-599.
• [22]Pineda E, Shin D, Sankar R, Mazarati AM: Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms. Epilepsia 2010, 51(Suppl 3):110-114.
• [23]Kanner AM, Schachter SC, Barry JJ, Hersdorffer DC, Mula M, Trimble M, Hermann B, Ettinger AE, Dunn D, Caplan R, Ryvlin P, Gilliam F: Depression and epilepsy: epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence. Epilepsy Behav 2012, 24:156-168.
• [24]Järvelä JT, Lopez-Picon FR, Plysjuk A, Ruohonen S, Holopainen IE: Temporal profiles of age-dependent changes in cytokine mRNA expression and glial cell activation after status epilepticus in postnatal rat hippocampus. J Neuroinflammation 2011, 8:29. BioMed Central Full Text
• [25]Pernot F, Heinrich C, Barbier L, Peinnequin A, Carpentier P, Dhote F, Baille V, Beaup C, Depaulis A, Dorandeu F: Inflammatory changes during epileptogenesis and spontaneous seizures in a mouse model of mesiotemporal lobe epilepsy. Epilepsia 2011, 52:2315-2325.
• [26]Ashhab MU, Omran A, Kong H, Gan N, He F, Peng J, Yin F: Expressions of tumor necrosis factor alpha and microRNA-155 in immature rat model of status epilepticus and children with mesial temporal lobe epilepsy. J Mol Neurosci 2013, 51:950-958.
• [27]Teocchi MA, Ferreira AÉ, da Luz de Oliveira EP, Tedeschi H, D’Souza-Li L: Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients. J Neuroinflammation 2013, 10:53. BioMed Central Full Text
• [28]Valente KD, Busatto FG: Depression and temporal lobe epilepsy represent an epiphenomenon sharing similar neural networks: clinical and brain structural evidences. Arq Neuropsiquiatr 2013, 71:183-190.
• [29]Martinez A, Finegersh A, Cannon DM, Dustin I, Nugent A, Herscovitch P, Theodore WH: The 5-HT 1A receptor and 5-HT transporter in temporal lobe epilepsy. Neurology 2013, 80:1465-1471.
• [30]Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R: The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 2011, 35:702-721.
• [31]Christmas DM, Potokar JP, Davies SJ: A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat 2011, 7:431-439.
• [32]Riazi K, Galic MA, Kuzmiski BJ, Ho W, Sharkey KA, Pittman QJ: Microglial activation and TNF-α production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci U S A 2008, 105:17151-17156.
• [33]Andrzejczak D: Epilepsy and pro-inflammatory cytokines. Immunomodulating properties of antiepileptic drugs. Neurol Neurochir Pol 2011, 45:275-285.
• [34]Vezzani A: The role of inflammation in epilepsy. Nat Rev Neurol 2011, 7:31-40.
• [35]Leonard B, Maes M: Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012, 36:764-785.
• [36]Abraham J, Fox PD, Condello C, Bartolini A, Koh S: Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis 2012, 46:425-430.
• [37]Pae CU, Marks DM, Han C, Patkar AA: Does minocycline have antidepressant effect? Biomed Pharmacother 2008, 62:308-311.
• [38]Soczynska JK, Mansur RB, Brietzke E, Swardfager W, Kennedy SH, Woldeyohannes HO, Powell AM: Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res 2012, 235:302-317.
• [39]Russi MA, Vandresen-Filho S, Rieger DK, Costa AP, Lopes MW, Cunha RM, Teixeira EH, Nascimento KS, Cavada BS, Tasca CI, Leal RB: ConBr, a lectin from Canavalia brasiliensis seeds, protects against quinolinic acid-induced seizures in mice. Neurochem Res 2012, 37:288-297.
• [40]Ganzella M, Faraco RB, Almeida RF, Fernandes VF, Souza DO: Intracerebroventricular administration of inosine is anticonvulsant against quinolinic acid-induced seizures in mice: an effect independent of benzodiazepine and adenosine receptors. Pharmacol Biochem Behav 2011, 100:271-274.