Keywords

1 Introduction

The concept that the immune system plays a role in mental ill health goes back to antiquity. Hippocrates, in the fourth century BC, suggested that melancholia was caused by black bile thereby suggesting that some endogenous factor(s) were responsible for the mood state. By the nineteenth century, it was widely recognised that bacterial and parasitic infections could contribute to altered mental states and, in the case of syphilis infection, to dementia. However, it is only relatively recently that clinicians have observed that chronic neuroinflammation plays an important role in the pathophysiology of affective disorders and other major psychiatric illnesses.

The purpose of this review is to summarise the evidence that chronic neuroinflammation has a major impact on brain structure and function. Of the various components of the immune system involved, the cytokines appear to play a prominent part and will therefore receive major attention in describing how the proinflammatory cytokines may trigger irreversible neuronal damage and thereby precipitate neurodegenerative changes.

Neuroinflammation is a key factor in the genesis of neurodegenerative, developmental and stress-related brain disorders. Such changes are an expression of inflammation-induced dysfunction of neuroplasticity which is expressed in deficits in learning, memory and cognition. Major neurological disorders, such as Alzheimer’s and Parkinson’s disease, and psychiatric disorders, as illustrated by major depression, schizophrenia and bipolar disorder , are important examples of the chronic impact of neuroinflammation (Altamura et al. 2013; Schwarz and Schechter 2010). However, besides the pathological consequences of neuroinflammation which arises when the immune system is activated by stress , infection, trauma, etc., neuroinflammation also plays an important physiological role in brain homeostasis involving such inflammatory mediators as the proinflammatory cytokines , prostaglandins and various neurotrophic factors which promote synaptogenesis. Hippocampal long-term potentiation is an expression of such a role. The neurotoxic effects of these mediators arise when they are over-produced in pathological situations (Yirmiya and Goshen 2011; Xanthos and Sandkuehler 2014).

In recent years, depression research has extended from the consideration of the consequences of neurotransmitter dysfunction to the role that the endocrine and immune systems may contribute to the pathophysiology of the disorder. There are a number of reasons for these changes. Thus, the occurrence of low-grade inflammation has been shown to impact on neurotransmitter function and shown to be associated with many of the metabolic changes associated with depression (Leonard 2010; Maes 1995; Smith 1991). These observations have led to the identification of a link between the consequences of chronic inflammation and an increase in the frequency of type 2 diabetes and heart disease in chronically depressed patients and also with the increased possibility of dementia in the elderly patient (McIntyre et al. 2012; Leonard 2013).

The question therefore arises whether such disparate changes are epiphenomena of a chronic psychiatric condition reflecting lifestyle changes involving nutrition and poor diet, lack of self-care associated with exposure to pathogens, etc. or more fundamentally that the metabolic changes are initiated by cytokines and other inflammatory mediators that are ultimately responsible for the psychopathological and chronic physical ill health which characterise many chronic psychiatric disorders.

Of the many processes that may be involved in linking inflammation with neurodegenerative changes in the brain, the role of the tryptophan-kynurenine pathway has recently received much attention. Overactivity of the glutamatergic system results in damage to neuronal networks. The link between the activation of the microglia by stress and major psychiatric and neurological disorders results in an increase in the release of proinflammatory cytokines . While proinflammatory cytokines activate many different neurodegenerative processes, the activation of indoleamine dioxygenase (IDO) activates the catabolism of tryptophan to kynurenine in many areas of the brain. The proinflammatory cytokines also activate the enzymes in the neurodegenerative arm of the tryptophan-kynurenine pathway which results in the synthesis of quinolinic acid. Quinolinic acid is an agonist for the N-methyl-d-aspartate (NMDA)-glutamate receptor and acts as a neurotoxin when present above physiological concentrations thereby affecting the functional integrity of the neuronal circuits (see Fig. 16.1).

Fig. 16.1
figure 1

The tryptophan-kynurenine pathway links neuroinflammation to chronic depression (adapted from Leonard 2017). IDO indoleamine dioxygenase, TDO tryptophan dioxygenase, IFN interferon gamma and other proinflammatory cytokines, IL 4 interleukin 4 and other anti-inflammatory cytokines, NAD+ nicotineamide adenine dinucleotide, NMDA N-methyl-d-aspartate, activated by quinolinic acid and blocked by kynurenic acid. 1 = kynureninase; 2 = kynurenine oxygenase; 3 = kynurenine aminotransferase

Full size image

2 Epidemiological Factors Implicating Chronic Depression with Brain Neurodegenerative Processes

Epidemiological studies have reported that the frequency of Alzheimer’s disease and other neurodegenerative disorders increases in those who have chronic depression in comparison to an age- and gender-matched control population (Geerlings et al. 2000; Green et al. 2003). These observations are supported by the finding that a history of depression is an important risk factor for dementia in later life (Jorm 2001).

Pathological findings have also shown that the frequency of amyloid plaques and neurofibrillary tangles is also greater in patients with Alzheimer’s disease who have been diagnosed with major depression (Rapp et al. 2006; Sun et al. 2008). Furthermore neurodegenerative changes in the hippocampus and prefronta l cortex occur in patients with major depression (Seline 2002). Thus, there is substantial evidence to indicate that neurodegenerative changes, and severe cognitive deficits, are a frequent outcome of depression. Such changes become more prevalent in middle-aged and elderly depressed patients. Further support for this hypothesis has been reviewed by Leonard (2001) and by Leonard (2006).

3 The Link Between Brain Neurodegenerative Changes and Neurotoxic Changes

From a historical perspective, the potential importance of the components of the tryptophan-kynurenine pathway was recognised following the behavioural changes induced in rodents by some of the main components of neurodegenerative arm of the pathway. Thus, 40 years ago, Lapin and colleagues, from the Bekhterev Psychoneurological Research Institute in Leningrad, published a series of experimental studies demonstrating the importance of the tryptophan-kynurenine pathway in the action of imipramine and suggested that depression resulted as a consequence of the adverse effects of the metabolic products of this pathway (Lapin and Oxenkrug 1969; Lapin 1973). As such metabolic products included quinolinic acid and 3-hydroxykynurenine that were shown experimentally to cause anxiety and stress-like changes in rodents, Lapin further characterised the ‘neurokynurenines’ as the neurochemical link between depression and anxiety states (Lapin 2003).

Since that time, there have been a plethora of experimental and clinical studies that demonstrate changes in the tryptophan-kynurenine pathway (Stone 1993; Myint and Kim 2003, 2014; Oxenkrug 2011) and which implicate quinolinic acid and 3-hydroxykynurenine as important neurotoxins which compromise neuronal function by enhancing oxidative stress (3-hydroxyanthranilic acid and 3-hydroxykynurenine) and by activating the N-methyl-d-aspartate glutamate receptor thereby causing neuronal apoptosis (Guillemin and Brew 2002).

4 The Tryptophan-Kynurenine Pathway and Deficits in Intermediary Metabolism of Glucose

In recent years, attentio n has centred on the neurotoxic consequences of the increase in quinolinic acid and the intermediates formed from kynurenine in the tryptophan-kynurenine pathway . While such neurotoxins undoubtedly play a critical role in the neurodegenerative changes associated with chronic psychiatric disorders such as depression and schizophrenia, it is often overlooked that quinolinic acid is also an important substrate for the formation of nicotinamide adenine dinucleotide (NAD+). As NAD+ is a key component of the respiratory chain, chronic pathological changes that reduce its formation are liable to have adverse consequences for intermediary metabolism particularly in neurons that are critically dependent on high-energy sources. It is estimated that approximately 99% of tryptophan that is not used for protein and serotonin synthesis is metabolised to NAD+ via the tryptophan-kynurenine pathway, and therefore this pathway is important for the synthesis of this vital cofactor (Gal and Sherman 1980; Han et al. 2010).

5 The Link Between Brain Energy Metabolism, Inflammation and Neurodegeneration

Alth ough there are numerous experimental studies to illustrate how low-grade inflammation produces changes in brain structure and function, it is only relatively recent that changes in the human brain have been evaluated. Thus, Harrison et al. (2014) demonstrated that peripheral inflammation impairs spatial memory by reducing glucose metabolism in the medial temporal lobe . This provides evidence for a link between inflammation, dysfunctional brain energy metabolism and neurodegenerative changes and will be considered further in this review.

At the cellular level, dysfunctional brain energy metabolism which occurs in major depression and schizophrenia is linked to a decreased expression of insulin receptors in the dorsolateral prefrontal cortex (Bernstein et al. 2009; Zhao 2006).

This situation would be compounded by a reduction in the availability of insulin, a key factor in the transport of glucose into neurons (Oxenkrug 2013). As there is evidence that insulin receptor resistance is a frequent feature of depression, and other major psychiatric disorders and with age-related pathology associated with the dementias (Lee et al. 2013), it seems reasonable to conclude that a chronic decrease in high-energy substrates resulting from a deficit in glucose and essential cofactors may be of crucial importance in understanding the causes of increased neuronal apoptosis (Lee et al. 2013). This situation is further complicated by mitochondrial dysfunction in depression which results in a decrease in the synthesis of adenosine triphosphate (ATP) and related high-energy molecules, combined with an increase in oxidative damage, while the synthesis of superoxide radicals resulting from a decrease in the respiratory chain increases the damage to the mitochondrial membranes by opening the permeability transition pores (Sas et al. 2009). In addition, oxygen-free radical synthesis is enhanced by xanthine, uric acid and 3-hydroxykynurenine which are formed in the brain as a result of the inflammation-enhanced tryptophan-kynurenine pathway . However, it still remains to be unequivocally established that the changes in brain glucose are a reflection of defective cellular mechanisms rather than a reflection of reduced neuronal activity which is a characteristic feature of major affective disorders and schizophrenia.

Peters et al. (2004) proposed the selfish brain hypothesis to explain the changes in brain glucose that has been observed in major psychiatric disorders.

This hypothesis postulates that the brain regulates glucose flux preferentially at the expense of other tissues. Thus, even though the brain occupies only about 2% of the body mass, it consumes at least 20% of the available glucose. The selfish brain hypothesis also accounts for the dietary changes which occur in some patients with depression or schizophrenia who prefer a carbohydrate-rich diet rather than a balanced, healthy diet. This might be a mechanism for increasing brain glucose availability.

An essential cofactor in the control of many of the intermediates in the tryptophan-kynurenine pathway is pyridoxal-5-phosphate (P5P), the active form of vitamin B6. It is well established that vitamin B6, together with vitamin B12 and folate, is involved in the methylation reactions that contribute to the synthesis of the monoamine neurotransmitters, phospholipids and nucleotides, all of which are functionally compromised in depression. Thus, a deficiency of dietary vitamin B6 could have an impact on depression, and recent studies have demonstrated that low plasma P5P levels are inversely correlated with the severity of depressive symptoms particularly in the elderly (Merete et al. 2008). Other investigators have reported that the B vitamins reduced the symptoms of major depression in post stroke patients (Almeida et al. 2010), while, in a Japanese study, a higher vitamin B6 status was associated with a decreased risk of depression (Nanri et al. 2013). It should be noted however that not all epidemiological studies on the vitamin status have reported the beneficial effects of vitamin B6 (Sanchez-Villegas et al. 2009).

Conclusion

The hypothesis which links the activation of the tryptophan-kynurenine pathway by proinflammatory cytokines to dysfunctional brain energy metabolism may help to explain how chronic neuroinflammation contributes to the neurodegenerative processes which characterise some major psychiatric and neurological disorders.

However, there are many aspects of this hypothesis which must be addressed.

For example, why do a substantial number of elderly patients with chronic affective disorders not develop dementia even though there are many well-designed clinical studies to indicate that neuroinflammation commonly occurs? What determines the differences in the behavioural and neurochemical changes in patients with affective and psychiatric disorders, and to what extent are the changes induced by genetic and environmental factors? Furthermore, if the common pathway leading to neurodegeneration involves dysfunctional brain glucose metabolism, to what extent is it possible to limit or, even reverse, the neurodegenerative changes by normalising brain glucose metabolism? Perhaps the selfish brain hypothesis has opened up a new chapter in our understanding of the relationship between neuroinflammation and neuroprogression!