The common inflammatory etiology of depression and cognitive impairment: a therapeutic target

Abstract

Chronic inflammation has been shown to contribute to the development of a wide variety of disorders by means of a number of proposed mechanisms. Depression and cognitive impairment are two such disorders which may share a closely linked inflammatory etiology. The ability of inflammatory mediators to alter the activity of enzymes, from key metabolic pathways, may help explain the connection between these disorders. The chronic up-regulation of the kynurenine pathway results in an imbalance in critical neuroactive compounds involving the reduction of tryptophan and elevation of tryptophan metabolites. Such imbalances have established implications in both depression and cognitive impairment. This may implicate the immune system as a potential therapeutic target in the treatment of these disorders. The most common treatment modalities currently utilized, involve drug interventions which act on downstream targets. Such treatments help to reestablish protein balances, but fail to treat the inflammatory basis of the disorder. The use of anti-inflammatory interventions, such as regular exercise, may therefore, contribute to the effectiveness of current drug interventions in the treatment of both depression and cognitive impairment.

Figure 1

Simplified depiction of tryptophan breakdown in the kynurenine pathway. Tryptophan (TRP) that is not transported across the blood brain barrier (BBB) for the synthesis of serotonin (5-HT) is degraded into kynurenine (KYN) by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). After this point, KYN is further degraded along one of two distinct branches; either the kynurenine-nicotinamide adenine dinucleotide (KYN-NAD) branch, or the kyneine-kynurenic acid (KYN-KYNA) branch. Within the KYN-NAD branch, KYN is acted on by the enzyme kynurenine 3-monooxygenase (KMO) whereby it is converted to 3-hydroxykynurenine (3-HK) and later quinolinic acid (QUIN) via a spontaneous reaction (and ultimately NAD⁺). Within the KYN-KYNA branch, KYN is acted on by the enzyme kynurenine aminotransferase (KAT) whereby it is converted to kynurenic acid (KYNA).

Figure 2

Peripheral and central kynurenine pathway interaction. As indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are found at only very low concentrations within the brain, concentrations of within-brain tryptophan (TRP) and kynurenines are largely dependent on those from the periphery. TRP from the periphery competes with other large neutral amino acids (LNAA) for passage across the blood brain barrier (BBB) to be used in the synthesis of serotonin (5-HT). Kynurenine (KYN) and 3-hydroxykynurenine (3-HK) are also capable of crossing the BBB whereby they participate in the production of kynurenic acid (KYNA) and quinolinic acid (QUIN) which do not easily cross it.

Figure 3

Influence of chronic inflammation on the kynurenine pathway. Certain proinflammatory cytokines possess the ability to up-regulate enzymes of the kynurenine pathway, thereby increasing the rate of tryptophan (TRP) degradation and production of kynurenines in the periphery. This may result in reduced concentrations of peripheral TRP and elevated peripheral levels of kynurenines. The reduced levels of peripheral TRP may then result in insufficient levels within the brain and a corresponding serotonin (5-HT) deficit. Proinflammatory cytokines also up-regulate enzymes in the brain, housed within astrocytes, microglia, and infiltrating macrophages, which utilize the elevated kynurenine concentrations for the production of further metabolites such as quinolinic acid (QUIN) and kynurenic acid (KYNA).

Figure 4

Inflammatory mechanisms of depression. Proinflammatory cytokines may contribute to depressive symptoms by means of various mechanisms. (1) Proinflammatory cytokines act on serotonin transporter (SERT) proteins within the brain causing a re-uptake of serotonin (5-HT) and corresponding reduced extracellular concentrations. (2) Proinflammatory cytokines up-regulate enzymes such as indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulting in reduced tryptophan (TRP) availability, ultimately contributing to reduced 5-HT synthesis. (3) Both 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) may contribute to elevated levels of reactive oxygen species (ROS) and oxidative stress within the brain. (4) QUIN may induce N-methyl-D-aspartate (NMDA) over-activity thereby contributing to hippocampal atrophy and a loss of glucocorticoid receptors, ultimately leading to a loss of negative feedback and hypothalamic-pituitary-adrenal (HPA) axis over-activity.

Figure 5

Inflammatory mechanism of cognitive impairment. Hippocampal atrophy caused by the over-activation of respective receptors for glucocorticoids and quinolinic acid (QUIN) may contribute to cognitive impairment. Additionally, elevated concentrations of kynurenine (KYN) that is preferentially metabolized along the kynurenine-kynurenic acid (KYN-KYNA) branch of the kynurenine pathway results in elevations of kynurenic acid (KYNA). As KYNA acts as an antagonist for both the alpha-7-nicotinic acetylcholine (α7nACh) and N-methyl-D-aspartate (NMDA) receptors it may contribute to cognitive deficits by reducing neurotransmitters such as glutamate, acetylcholine, and dopamine.

Figure 6

Targets of treatment interventions. Common treatment strategies for disorders associated with depression and cognitive impairment typically target downstream enzymes or receptors. Alternatively, intervention strategies such as regular exercise possess anti-inflammatory properties which helps restore a balance in inflammatory mediators, thereby restoring proper enzyme regulation and protein balances upstream.