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Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.

ABSTRACT: Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development of a range of depressive symptoms, including deficits in cognition and memory. Additionally, preclinical work has demonstrated a number of mood-related depressive-like behaviors to be dependent on indoleamine 2,3-dioxygenase-1 (IDO1), the inflammation-induced rate-limiting enzyme of the kynurenine pathway. Here, we demonstrate in a mouse model, that peripheral administration of endotoxin induced a deficit in recognition memory. Mice deficient in IDO were protected from cognitive impairment. Furthermore, endotoxin-induced inflammation increased kynurenine metabolism within the perirhinal/entorhinal cortices, brain regions which have been implicated in recognition memory. A single peripheral injection of kynurenine, the metabolic product of IDO1, was sufficient to induce a deficit in recognition memory in both control and IDO null mice. Finally, kynurenine monooxygenase (KMO) deficient mice were also protected from inflammation-induced deficits on novel object recognition. These data implicate IDO-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders.

SUBMITTER: Heisler JM

PROVIDER: S-EPMC4631688 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.

Heisler Jillian M JM O'Connor Jason C JC

Brain, behavior, and immunity 20150627

Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development ...[more]

PMID: 26130057

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Project description:AimPoststroke depression (PSD), which occurs in approximately one-third of stroke survivors, is clinically important because of its association with slow functional recovery and increased mortality. In addition, the underlying pathophysiological mechanisms are still poorly understood.MethodsWe used a mouse model of PSD to examine the neurobiological mechanisms of PSD and the beneficial effects of aripiprazole, an atypical antipsychotic drug. PSD was induced in mice by combining middle cerebral artery occlusion (MCAO) with spatial restraint stress. The body weight, sucrose preference, and forced swim tests were performed at 5, 7, and 9 weeks and the Morris water maze test at 10 weeks after completing MCAO and spatial restraint stress.ResultsMice subjected to MCAO and spatial restraint stress showed significant depressive-like behavior in the sucrose preference test and forced swim test as well as cognitive impairment in the Morris water maze test. The PSD-like phenotype was accompanied by an indoleamine 2,3-dioxygenase 1 (IDO1) expression increase in the nucleus accumbens, hippocampus, and hypothalamus, but not in the striatum. Furthermore, the increased IDO1 levels were localized in Iba-1(+) cells but not in NeuN(+) or GFAP(+) cells, indicating that microglia-induced IDO1 expression was prominent in the PSD mouse brain. Moreover, 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), quinolinic acid (QUIN), and reactive oxygen species (ROS) were significantly increased in the nucleus accumbens, hippocampus, and hypothalamus of PSD mice. Importantly, a 2-week aripiprazole (1 mg/kg, per os) regimen, which was initiated 1 day after MCAO, ameliorated depressive-like behavior and impairment of cognitive functions in PSD mice that was accompanied by downregulation of IDO1, HAAO, QUIN, and ROS.ConclusionsOur results suggest that the IDO1-dependent neurotoxic kynurenine metabolism induced by microglia functions in PSD pathogenesis. The beneficial effect of aripiprazole on depressive-like behavior and cognitive impairment may be mediated by inhibition of IDO1, HAAO, QUIN, and ROS.

Dataset Information

Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.

Publications

Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.

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