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

Abstract

BackgroundDepression 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.MethodsRats 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.ResultsWe 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.ConclusionBrain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…In support of this notion, brain or cerebrospinal fluid concentrations of kynurenine neurotoxic metabolites are elevated in several neuropsychiatric or neurodegenerative diseases (Campbell et al, 2014;Schwarcz et al, 2001;Steiner et al, 2011;Stone et al, 2012) and have been related to the stretch of brain damages, impaired neurogenesis, and development of neuropsychiatric symptoms (Savitz et al, 2015a;Savitz et al, 2015b;Stone et al, 2012;Zunszain et al, 2012). In line with clinical findings, preclinical studies performed in rodents treated with an immune challenge have documented associations between emotional/cognitive alterations and both peripheral and brain IDO activation (Andre et al, 2008;Corona et al, 2013;Frenois et al, 2007;Gibney et al, 2013;Lawson et al, 2013;Lestage et al, 2002;Moreau et al, 2005Moreau et al, , 2008Salazar et al, 2012;Xie et al, 2014). In addition, aged mice or mice with constitutive microglial overactivation display, upon immune challenge, sustained cytokine production together with protracted brain IDO expression and depressive-like behavior (Corona et al, 2010;Godbout et al, 2008;Kelley et al, 2013).…”

“…In addition, aged mice or mice with constitutive microglial overactivation display, upon immune challenge, sustained cytokine production together with protracted brain IDO expression and depressive-like behavior (Corona et al, 2010;Godbout et al, 2008;Kelley et al, 2013). More importantly, pharmacological or genetic inhibition of IDO prevents the development of depressive-/anxiety-like behaviors and cognitive impairments (Barichello et al, 2013;Henry et al, 2009;O'Connor et al, 2009a;O'Connor et al, 2009b;O'Connor et al, 2009c;Salazar et al, 2012;Xie et al, 2014). Conversely, systemic kynurenine administration dose-dependently impairs emotional behaviors and spatial memory (Alexander et al, 2012;Chess et al, 2009;O'Connor et al, 2009c;Salazar et al, 2012).…”

The comorbidity of epilepsy and depression: diagnosis and treatment

“…In 2014, Xie et al [17] found the expression of IL-1β and IL-6 in the hippocampus of depressed and epileptic rats that that IL-1β mRNA increased 3 weeks after status epilepticus, while IL-6 mRNA increased 6 weeks after status epilepticus.…”

“…Depressive behavior tests showed a taste preference that represents anhedonia symptoms in depression; immobility time was prolonged in a forced swimming test (FST), which is the equivalent of a depressive-like state [17]. Depression improves in epileptics undergoing disarticulation or resection of epileptic foci, resulting in decreased seizures and epileptiform activities.…”

Depression and epilepsy: comorbidities, pathogenesis, principles of therapy

“…Так, в экспериментах на крысах Wistar с индуцированным пилокарпином эпилепти-ческим статусом W. Xie и соавт. [16] было установле-но через 3-6 нед развитие состояния, являющегося эквивалентом депрессии (развитие ангедонии и уве-личение времени неподвижности при проведении теста принудительного плавания). Аналогичные ре-зультаты на крысах Wistar были получены S. Chen и соавт.…”