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Review
, 19 (9)

Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

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Review

Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

Jennifer L Remus et al. Int J Neuropsychopharmacol.

Abstract

Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission, these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.

Keywords: Depression; glutamate; indoleamine 2,3-dioxygenase; inflammation; quinolinic acid.

Figures

Figure 1.
Figure 1.
Schematic timeline of lipopolysaccharide (LPS) model of depression. LPS administration increases peripheral cytokines and leads to sickness behaviors, including lack of movement and decrease in food and water intake. Around 24 hours postinjection, rodents begin eating and moving similarly to control animals as their sickness behaviors have resolved. Proinflammatory cytokines will cause an elevation of indoleamine 2,3 dioxygenase (IDO) 24 hours after LPS injection. During the same time that IDO is elevated, animals will be anhedonic and spend more time immobile in the forced swim test.
Figure 2.
Figure 2.
Simplified tryptophan metabolism by the kynurenine pathway. Tryptophan is most commonly metabolized into kynurenine via one of two enzymes: indoleamine 2,3 dioxygenase (IDO) or tryptophan 2,3, dioxygenase. Kynurenine can be further broken down into a variety of metabolites that are neuroactive, including 3-hydroxykynurenine (3HK), quinolinic acid, and kynurenic acid. The conversion from 3-hydroxyanthranillic acid to quinolinic acid, represented by a dashed line, requires 2 reactions. The first is an enzymatic and the other is nonenzymatic. Alternatively, tryptophan can also produce serotonin.
Figure 3.
Figure 3.
Possible therapeutic interventions for lipopolysaccharide (LPS)-induced model of depression. This figure demonstrates several possible therapeutic targets (green circles with red font) in our LPS-induced model of depression. One potential antidepressant route would be to block the production of kynurenine by administering inhibitors of indoleamine 2,3 dioxygenase (IDO), such as 1-methyl tryptophan. Downstream kynurenine metabolites are damaging to neurons, and therapies that inhibit their production would also be effective. For example, kynurenine 3-monoxygenase (KMO) inhibitors may be used to decrease 3-hydroxykynurenine (3-HK) or quinolinic acid production. As the majority of kynurenine in the brain is transported from the periphery, a reasonable intervention would be to prevent the transport of kynurenine. Tryptophan and kynurenine are both transported into the brain by L-type amino acid transporter. L-type amino acid transporter has a high affinity for leucine, and leucine administration could result in a decrease in kynurenine transport and thereby reduce downstream kynurenine metabolites in the brain. Lastly, upon activation microglia can release glutamate and inhibit the uptake of glutamate by astrocytes that can cause excessive glutamatergic activity. This excessive glutamatergic activity can lead to excitotoxicity or an increase in oxidative damage. Administration of inhibitors to prevent the release of glutamate from microglia would reduce glutamate receptor activation and possibly prevent depressive-like behaviors. Likewise, LPS and quinolinic acid can interfere with glutamate uptake in astrocytes. The use of riluzole has been demonstrated to increase astrocyte uptake of glutamate, and block glutamate release. GLT-1, glutamate transporter; TLR, Toll-Like Receptor.

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