Neurological disorders, depression and inflammation - Future Medicine

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Neurological disorders, depression and inflammation: is there a common link? Angelos Halaris*

ABSTRACT To understand the origin of co-morbidity between neurological disorders and depressive illness, a multifactorial model is in order. Diverse approaches have been undertaken to elucidate the co-morbidity. Of these, the concept that inflammatory processes contribute to brain-related pathologies has been gaining traction. Inflammatory processes have been identified in most, if not all, neurological conditions. Similarly, major depressive disorder has been associated with a chronic proinflammatory status. Activation of the immune response can alter neurotransmission leading, among others, to serotonin deficiency, and increased production of neurotoxic substances contributing to primary disease progression. Therefore, inflammatory factors might serve as biomarkers to predict and ultimately prevent the development and progression of neuropsychiatric disorders as well as to identify the most efficacious treatments. Depressive illness is a very common disorder afflicting an estimated 120 million people worldwide and is the leading cause of disability [1] . The life-time prevalence of depressive illness is estimated to be as high as 16% while the 12-month prevalence ranges from 3% in Japan to over 9% in USA [2–4] . The incidence of depressive illness has been steadily increasing over the past decades. Using the Disability Adjusted Life-Years major depressive disorder (MDD), the most common mood disorder, was classed in 1990 as the fourth leading burden of disease worldwide for both sexes. By 2004 it advanced to third place, and, according to the WHO’s estimate, will rank second to heart disease by the year 2020 [5] . It will be the leading cause of disease burden by 2030 [4] . Co-morbidity between depression and neurological diseases is well known and numerous studies have documented high prevalence of depression among most, if not all, neurological disease entities. Depression is one of the most frequent co-morbid psychiatric disorders and represents a common and often characteristic feature in a number of neurological disorders. The prevalence rates range between 20 and 50% of patients with epilepsy, multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD) and stroke. Indeed, poststroke depression (PSD) can be identified in over 35% of stroke survivors. It represents a major and potentially debilitating poststroke complication. In a large prospective epidemiological study, Thielscher et al. [6] followed ∼43,000 newly diagnosed patients with epilepsy, MS, PD and Alzheimer’s dementia for 5 years to determine whether they had developed depression. They established that all disease entities studied increased the risk of developing depression with female patients being at much higher risk than males. Overall, approximately one-third of neurological patients (somewhat less those with epilepsy) were diagnosed with depression and almost half of them developed depression within the first year of observation. On the other hand, depressive syndromes may also be considered as a risk factor for certain neurological disorders, and depression may predate neurological signs and symptoms in the evolution of neurodegenerative

KEYWORDS

• Alzheimer’s disease • cytokines • depression • kynurenine • neuroinflammation • neurological disorders • Parkinson’s disease • poststroke depression • serotonin

*Professor of Psychiatry, Department of Psychiatry & Behavioral Sciences, Loyola University Chicago Stritch School of Medicine, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA Tel.: +1 708 216 3275; Fax: +1 708 216 6480; [email protected]

10.2217/FNL.15.18 © 2015 Future Medicine Ltd

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Review Halaris disorders. There is evidence that depressive illness itself may be a risk factor in the etiology of some dementias and depression not infrequently predates the emergence of PD. It is duly recognized that depression exerts strong and adverse impact on both quality of life and outcome of the primary neurological disorder in that it diminishes compliance with treatment and has overall a negative impact on the recovery from neurological syndromes. Unfortunately, despite these facts and the relatively high prevalence rates, depression is frequently undiagnosed and undertreated in these patients. In this review article the author will focus on the association of inflammation in general and neuroinflammation in particular, as they relate to representative neurological disorders and depression. Space limitations preclude an exhaustive discussion of the origins and complexities of neuroinflammation or all of neurological conditions that are known to be comorbid with depression. Rather, the author will limit the discussion to depression as it relates to a few representative neurological conditions and the likely mechanisms by which neuroinflammation can be neurotoxic and depressogenic. The author will emphasize the association between stress and inflammation, especially if the former is associated with chronic and debilitating illnesses with little or no hope for full recovery. Of direct relevance is the compelling evidence that inflammation can interfere with normal neurotransmission resulting in deficiencies causally related to depression. It is also important to emphasize at the outset that inflammatory processes reflecting immune system activation have not been clearly or consistently identified in all psychiatric or neurological disorders. Nor for that matter do all patients in a particular disorder which has generally been associated with a sustained inflammatory response show uniformly such changes. Psychiatric disorders for one are heterogeneous disorders and there is overlap of symptoms among them. Other pathological mechanisms, yet to be elucidated, are accountable and most likely include genetic polymorphisms and epigenetic modifications. Mental stress & its consequences Mental stress can produce profound alterations in the physiology and chemistry of the CNS and the autonomic nervous system (ANS), peripheral organs and the endocrine, vascular and immune systems. Mental stress can vary, with differences

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in intensity and duration, and the perception of mental stress is subject to high individual variability and vulnerability. This is based, at least in part, on genetically determined and epigenetically modified stress susceptibility and resilience. Any illness, physical or mental, is of itself stressful to the individual. Chronic, and especially inescapable stress, leads to pervasive mental status changes and pathological alterations to the structure and function of the vascular system, which may lead to irreversible tissue and organ damage. As Selye postulated, when the demands placed on the organism eventually exceed the available energy and adaptation, the system fails [7,8] . The complexity of the interactions between stress and medical and psychiatric illnesses remains a topic of intense scientific endeavor. Stress (physical, mental or mixed) is a state of short term or prolonged disturbance of homeostasis, ultimately leading to a state of allostasis and allostatic load, as suggested by McEwen [9] . In addition to activating the hypothalamic–pituitary–adrenal axis (HPA), stress activates the sympathetic branch of the ANS. This activation leads to a reduction in vagal tone that can have consequences on the body’s immune response. Efferent signals from the vagus nerve, which can be controlled by brain networks, inhibit the production of inflammatory mediators, notably cytokines, via pathways dependent on the α7 subunit of the nicotinic acetylcholine receptor (AChR) on macrophages and other cells [10] . The imbalance in ANS function, especially if prolonged, as is invariably the case with psychiatric and neuropsychiatric disorders, has profound effects on vascular physiology and the immune system (Figure 1) . These pathophysiological changes significantly contribute to the high co-morbidity observed between psychiatric and neurological and cardiovascular (CVD) disorders. Thus, to quote Thayer, autonomic imbalance and decreased parasympathetic activity in particular, may be the final common pathway to numerous diseases and conditions associated with increased morbidity and mortality [11] . Neuroinflammation at the core of CNS pathology Neuroinflammatory processes underlie neurological disorders and many excellent reviews are available [13,14] . Inflammation is the response of the innate immune system in an attempt to protect and defend the organism against any threat to its integrity and homeostasis. Such threats

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Neurological disorders, depression & inflammation

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Neurologic response ↑ excitotoxicity ↓ monoamines

STRESS Early adversity Interpersonal conflict Social isolation

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Figure 1. Effects of stress on the body. Reproduced with permission from [12].

can range from invasion by microorganisms, to environmental stressors and emotional stresses leading to allostasis [9] . The inflammatory response is implemented by orchestrated mobilization and complex interactions of various cell types and signaling molecules. The composite response can be localized or systemic or both. The ultimate goal is to control and eliminate the initial noxious stimulus by means of phagocytosis and activation of the inflammasome (an intracellular multiprotein oligomer that is a component of the innate immune system) that activates inflammatory processes to enable tissue repair and regeneration. Neurons express inflammasomes which are involved in the maturation of the proinflammatory cytokines, IL-1β and IL-18. Trauma increases inflammasome expression in rat neurons and programmed cell death, known as pyroptosis, is induced by the inflammasome [15–17] . The inflammatory response is intended to be beneficial and protective, however, if it is excessive and/or prolonged, it can cause tissue damage and induce pathological changes. It is also noteworthy that once activated and deployed, participating cells (leucocytes, monocytes, endothelial cells) target not only


the initial site of inflammation but also remote sites including penetration into the brain parenchyma. Thus, peripheral inflammation can trigger a neuroinflammatory response that involves the blood–brain barrier (BBB), neurons, astrocytes and microglia. Contrary to previously held beliefs, the BBB is permeable, not only at the site of circumventricular organs, to proinflammatory mediators that originate in the periphery and can allow leucocyte migration. Additionally, the BBB can itself, upon stimulation, release proinflammatory mediators. Consequently, neuroinflammation is a term used to connote the broad range of CNS immune responses that may result in synaptic impairment, neurotransmitter dysregulation or deficiency, neuronal cell death and exacerbation of brain pathology. In the periphery, macrophages are the key elements responsible for the first-line immune response. Upon stimulation by IFN-γ and TNF-α they produce and release proinflammatory mediators, known as cytokines. Centrally this function is carried out predominantly by microglia, the resident immune cells in the brain and their activation is believed to be related to neuroinflammation. Activated microglia

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Review Halaris produce cytotoxic factors, such as TNF-α, IL-1β, eicosanoids, nitric oxide and reactive oxygen species. Astrocytes can also release proinflammatory mediators, such as TNF-α, when stimulated, in cortex and midbrain. It is believed that the combined glial response is at least in part related to the neurodegeneration seen in dementia [18] . Cytokines are small molecules, proteins or glycoproteins, less than 30kDa in size; they are the ‘messengers of the immune system’ and play an essential role in the immune response to infectious agents. They exert their effects more locally than hormones. Usually they are secreted by T helper cells or macrophages and centrally by astroglial cells. There are over 30 different cytokines grouped together according to the class of molecule they belong. They are roughly divided into two key groups, proinflammatory and anti-inflammatory, but this distinction should not be rigidly adhered to, as the actual effect of the signaling molecule may change depending on location and pathological state. In the CNS activated astrocytes and microglia are major sources of inflammatory molecules, notably cytokines, chemokines, reactive oxygen species and nitric oxide. The released cytokines, in particular TNF-α, IL-1β and IL-6, are the key effectors of neuroinflammation and have been shown to impact cognition and memory and symptoms akin to depression. The reader is referred to the comprehensive review by Lyman et al. [14] for more information. Depression & inflammation cause or effect? Evidence supporting a connection between mood disturbances and the immune system dates back to more than two decades ago [19,20] and continues to be actively studied [21,22] . The high co-morbidity between depressive illness and CVD, cerebrovascular (CVBD) and neurodegenerative diseases (NDD) has stimulated the search for a possible common link. Although many factors contribute to the co-morbidity and have been addressed in numerous publications, the contributory role of the immune system remains a critical factor. Thus, activation of inflammatory processes, as such a common link, has received increased attention and proinflammatory cytokines have been implicated in the pathogenesis of all of these conditions. Inflammation is also viewed as a major causal factor to depressive illness with proinflammatory

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cytokines being associated with specific behavioral and cognitive symptoms that constitute the syndrome of depression. Additionally, certain components of the inflammatory response shunt the metabolic pathways of key neurotransmitters, notably serotonin, leading to the accumulation of neurotoxic metabolites. Last but not least, inflammation has been postulated to play a major role in endothelial damage of the cerebral vasculature. This has led to the designation of the entity of ‘vascular depression’ that presents with many of the typical symptoms of depression. Interestingly, elevations in inflammatory markers have been shown in depressed patients with or without vascular disease [23–25] , in cancer patients with depression [26] and in neurodegenerative disorders, notably PD [27–29] . One cytokine, IL-6, secreted in response to stress, is one of the most potent stimulators of the HPA axis, and induces the release of other proinflammatory cytokines and proteins including CRP production in the liver. HPA axis activation, in turn, further contributes to the ‘kynurenine (KYN) shunt’ of tryptophan metabolism via stimulation of tryptophan dioxygenase (TDO), and adversely impacts upon glucocorticoid receptor signaling. These and related observations have led Leonard to postulate that depression is a disease of inflammation in response to chronic psychological stress [30–33] . Since a sustained proinflammatory status has been clearly associated with widespread pathology, the assertion is appropriate that depressive illness is a whole-body disease, including its potential to at least contribute to the development of CVD, CBVD and NDD. Numerous reports have shown that proinflammatory cytokines are endogenously overexpressed in depression and other stress-induced disorders [34] . However, genetic polymorphisms regulating the expression of inflammation mediators, inability of the immune system to stage a response to the stressor or epigenetic factors have yet to be fully elucidated. As has been stated, numerous reports and reviews have confirmed that inflammation is closely related to depressive disorder in a bidirectional manner [35,36] . A number of clinical studies have found individuals with depression to have higher circulating levels of proinflammatory cytokines: IFN-γ [35]), IL-1β [37] , TNF-α [38] or IL-6 [39] . Inflammatory IFN-α [40] induces depressive symptoms in humans, while symptoms terminate with cessation of IFN-α


Neurological disorders, depression & inflammation therapy [41] and are abrogated by antidepressant treatment [42] . In our study of depressed patients treated with venlafaxine we confirmed the presence of a proinflammatory status but failed to observe normalization of the inflammation biomarkers studied at the conclusion of the course of treatment utilized in that study [43] . Proinf lammatory cytokines are causally linked to plaque formation contributing to the association between depression and CBVD and CAD [44–46] ; proinflammatory cytokine overproduction in depression may be one common link. Although the cytokine elevations in depression are moderate in comparison to those during physical injury and/or infection [47] , by being chronically overexpressed in depression, cytokines stand to have long-term adverse consequences on the brain, the CVD and CVBD systems [48] , indeed the entire organism. Studies of injected cytokines [49] have also shown that proinflammatory cytokines, by themselves, are ‘dysphoric’ possessing the capacity to induce a syndrome known as ‘sickness behavior’ that simulates many of the classical symptoms of depression [50,51] . The Cytokine Theory of Depression was originally formulated by Smith as ‘The macrophage theory of depression’ [52] and later expanded by Ur et al. [53] . In essence this theory postulates that psychological stress, probably in conjunction with genetic and epigenetic factors, increases cytokine production and leads to depressive symptoms when specific neurobiological systems are affected, for example, serotonin and HPA axis function. High circulating levels of proinflammatory cytokines may thus be central to the pathophysiology of MDD. Cytokines may firstly participate in the etiology of depression, and later in the high incidence of CVD and CVBD sequelae observed among depressed patients [54] . Key questions that have yet to be fully clarified are whether inflammation, directly or indirectly, interferes with the action of antidepressants, thereby contributing to treatment resistance, and whether antidepressant drug therapy normalizes the inflammatory immune response. A number of reports indicate beneficial effects of antidepressant drug therapy in normalizing abnormally elevated levels of proinflammatory cytokines [55–59] . However, not all reports agree. Differences in study design, mainly the length of treatment and the type of antidepressant agent utilized, appear to be crucial variables that must be controlled in future studies. Additionally,


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the time course of cytokine normalization may not fully coincide with the time frame of clinical antidepressant response. The article by Janssen et al. [60] offers a comprehensive review of cytokine involvement in antidepressant treatment response. Clearly more studies are required to clarify the temporal associations between mood improvement and cytokine normalization, or, for that matter, inadequate response, treatment resistance and vulnerability toward relapse. Lastly, there is emerging evidence that co-administration of an antidepressant with an anti-inflammatory agent (e.g., a COX-2 inhibitor) may produce a more rapid response in depressed patients and may even convert poor responders to previous antidepressant trials to full responders [61] . Poststroke depression Approximately 15 million individuals suffer a stroke annually worldwide at a significant cost to the individual and society. A major sequelae of stroke is PSD, a common and relevant complication following ischemic brain infarction. Approximately 33% of stroke survivors experience clinical depression in the course of the disease compared with ∼13% of the general population [62–64] . On the other hand, depression is also a major risk factor for ischemic events in depressed patients as has been demonstrated in prospective cohort studies. PSD is associated with poorer recovery and rehabilitation, reduced quality of life and lowered functional ability. Therefore, prompt diagnosis of depression and vigorous treatment for prolonged periods of time are of the essence. At the same time, identification of causal factors contributing to PSD will lead to more effective treatments and ultimately prevention. Although the pathogenesis of PSD is complicated, the neurobiological and pathological profiles of ischemia and major depression share a number of commonalities involving neuroanatomical, neuronal, biochemical and immunological factors which interact in complex ways. For example, numerous studies have suggested that large lesions in critical CNS areas, such as left frontal lobe and basal ganglia, or accumulation of silent cerebral lesions might interrupt the pathways of monoamines or relevant pathways of mood control, thus leading to depression. A number of pertinent and related hypotheses have been proposed to explain PSD, such as the lesion location hypothesis, the vascular depression hypothesis, the neurotransmitter hypothesis


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Review Halaris and the immune dysfunction hypothesis (for review see [65]). Of particular interest is that both ischemia and depression are associated with an increased inflammatory state and greater rates of neuronal cell death. In individuals diagnosed with major depression, inflammation mediates both depressive symptoms and cell death, and treatment methods may normalize inflammatory markers and prevent progressive cell death [66,67] . Ischemic cell death elicits the inflammatory mechanisms that precede PSDassociated depressive symptoms, and later, longlasting clinical depression. By the same token, MDD has been associated with abnormal physiological and immunological responses and a resultant increase in inflammatory markers [68] . Parkinson’s disease The pathogenesis of PD has been linked, at least in part, to neuroinflammation, notably microglia activation. Since the substantia nigra (SN) is enriched with microglia, this brain region can be expected to be particularly sensitive to cytotoxic compounds released by activated microglia. During the past two decades numerous studies have substantiated the hypothesis that inflammation-derived oxidative stress and cytokinedependent toxicity contribute to the degeneration of the nigrostriatal pathway. Indeed SN samples analyzed from postmortem brains of PD patients strongly suggest that microglia are involved in the pathogenetic process of PD. Furthermore, the presence of ongoing inflammatory processes contributing to the progression of PD is based on findings of cytokine accumulation, activation of the NF-κB pathway and oxidative damage to proteins in CSF and postmortem brains of PD patients [69] . For a comprehensive review see [70] . Finally, to test the hypothesis that microglial activation can produce dopaminergic neurodegeneration, Gao et al. [71] infused lipopolysaccharide into an area adjacent to the SN of rat brain. Lipopolysaccharide-induced rapid activation of microglia was followed by selective and progressive destruction of nigral dopaminergic neurons in vivo and in vitro. Of note is the study of Lindqvist et al. [27] . These authors studied 87 PD patients and 33 control subjects and measured a battery of inflammation biomarkers in CSF. They found increased levels to be associated with more severe symptoms of depression, anxiety, fatigue and cognitive impairment. After controlling for confounding factors, high CRP levels were associated with more severe symptoms of

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depression and fatigue and high levels of the chemokine, MCP-1, were significantly associated with more severe symptoms of depression. Alzheimer’s disease AD is a progressive, irreversible and debilitating neuropsychiatric disorder. Several hypotheses have been proposed over the decades to explain the cause of AD, such as the cholinergic, Aβ plaque and neurofibrillary tangle formation, τ-protein accumulation, and, more recently, the inflammation hypothesis. The cholinergic hypothesis, postulating a deficiency in cholinergic transmission, although theoretically valid, has been questioned due to minimally successful clinical results with available pharmacological agents. However, the role of cholinergic transmission not only in AD but in other neuropsychiatric disorders with an established strong neuroinflammatory component should be revisited in the context of the cholinergic anti-inflammatory pathway [10] . The Aβ and τ-hypotheses postulate that Aβ deposits or τ-protein abnormalities are the fundamental causes of the disease. Although they are based on neuropathological evidence, abnormal levels of Aβ plaques have been found among normal healthy elderly individuals [72] . In addition, highly expressed Aβ or τ-protein in animal models of AD has failed to demonstrate significant neurodegenerative changes [73] . Therefore, neuroinflammation must be considered as a key pathogenetic factor. This contention is supported by observations of microglial activation, astrocyte reactivity and elevations in cytokine expression in AD patients, but also by epidemiological evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) could delay the onset and reduce severity of AD symptoms. The increase in Aβ during the early stages of AD stimulates the expression of TNF-α and IL-1β which affect negatively synaptic plasticity and increase vulnerability to excitatory neuronal activity [74] . Postmortem studies of AD brain samples have revealed highly expressed inflammatory cytokines during the early stages of AD [75] , and genome-wide studies show an upregulation of inflammatory genes, indicating a potential role of inflammation in the progression of AD [75–77] . The relationship between AD and depression has been addressed in the literature in as much as the two disorders share common risk factors (vascular disease, inflammation, genetics). However, the relationships are more complex


Neurological disorders, depression & inflammation than initially assumed. Clearly, symptoms of depression appear rather early in the dementia process and intensify with the progression of cognitive decline as long as the patient retains awareness of their declining cognitive and executive function. In advanced stages of dementia the severity of depressive symptoms appears to diminish ostensibly due to reduced awareness of the person’s debilitation. In this context, the Texas Alzheimer’s Research Consortium has pursued a longitudinal, multicenter, multifaceted study of AD. The array of inflammatory biomarkers studied confirmed the presence of inflammation the severity of which was highly correlated to age at onset and was also associated with cognitive decline. On the other hand, the association with depression, although confirmed, proved to be a more complex and intriguing one, pointing in research directions to be undertaken in the future. For example, there was a significant association between apathy and C-reactive protein (CRP) and this association was even stronger among female patients [78] . Inflammation & neurotoxicity: the tryptophan/kynurenine pathway It is now recognized that depression involves a complex and bidirectional interaction between the brain and the immune system. As the immune system responds to stress and other factors, such as infection and trauma, with increased production of proinflammatory biomarkers, notably cytokines, these inflammatory responses exert a powerful influence on the HPA axis and neurotransmitters critical to mood regulation and cognition. HPA activation contributes to reduced serotonergic activity centrally and peripherally and serotonergic transmission has emerged as a possible ‘common denominator’ between depressive illness and the immune system. This is not meant to ignore the role of other neurotransmitters, notably acetylcholine, norepinephrine, dopamine, GABA and glutamate, and complex effects on them by immune system activators and mediators. In addition to the effects described above, a more compelling case for the interaction between inflammation and serotonergic transmission can be made on the basis of data involving the tryptophan/KYN pathway. Serotonin is synthesized from about 1% of the available tryptophan in the body and its synthesis occurs predominantly in the gut with only 10–20% occurring in the brain. Under physiological conditions, about


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99% of tryptophan is metabolized to KYN in the liver by tryptophan dioxygenase (TDO). TDO is also activated by steroids in conjunction with HPA axis activation in depression. In inflammatory conditions, infections or oxidative stress, the first rate-limiting enzymatic step involving the enzyme, indoleamine 2,3-dioxygenase (IDO), is activated. The IDO enzymatic activity is enhanced by proinflammatory cytokines, such as IFN-γ, IL-1, IL-2, IL-6 and TNF-α, and inhibited by IL-4, an anti-inflammatory cytokine [79] . Overstimulation of IDO leads to tryptophan depletion resulting in serotonin deficiency in the brain. Treatment with antidepressant agents which enhance serotonergic activity via reuptake inhibition seek to offset this deficit but are not always effective. Additionally, during inflammatory states, peripheral KYN formation is increased; it is transported through the BBB, thereby increasing the brain concentration of this substance. KYN is further metabolized into several neurotoxins, including 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. An increase in tryptophan breakdown and increased KYN formation has been demonstrated in depression [80] and the metabolism of KYN has been implicated in the pathophysiology of depression, especially the chronicity of the disorder [81] . Postmortem studies in individuals with schizophrenia and affective disorders have provided evidence in support of the KYN shunt in anterior cingulated cortex [82] . This group of investigators [80,83] has observed a lower plasma tryptophan index and neuroprotective kynurenic acid and higher tryptophan breakdown also in bipolar patients compared to controls (see Figure 2 for a schematic diagram depicting metabolic pathways of tryptophan). Novel therapeutic targets ●●Cholinergic transmission &

acetylcholinesterase inhibitors (AChEI)

Over the past two decades the function of cholinergic transmission has been expanded beyond neurons and synapses to include modulation of various aspects of immune function, whether innate or adaptive. The description by Tracey [10] of the cholinergic anti-inflammatory pathway (CAIP) and the α7-nicotinic acetylcholine receptor (nAChRα7) mediating this activity has revealed that cholinergic transmission affects immune cell proliferation, cytokine production, T-helper cell differentiation and antigen presentation. Two key enzymes, acetylcholinesterase


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Figure 2. Metabolic pathways of tryptophan. Immunological activation and tryptophan metabolism in macrophages and microglia. Adapted with permission from [84].

(AChE) and cholineacetyltransferase and muscarinic and nicotinic receptors which are present in immune cells, mediate these effects. It is fairly well established that the cholinergic system can modulate peripheral immune response via the nAChRα7 receptor. Stimulation of the nAChRα7 by nicotine or acetylcholine initiates the CAIP, a mechanism mediating neural inhibition of inflammation. Moreover, the action of this pathway is also implied in human degenerative diseases of the CNS, notably AD and amyotrophic lateral sclerosis (ALS). With the use of preclinical models of inflammatory disorders it was established that nAChRα7 exerts immune suppressive effects and this activation can be accomplished either by direct stimulation or indirectly, by inhibition of AChE. Thus, the immune mediating component of the cholinergic system can provide opportunities to develop novel immunomodulatory agents or to the broadening of use of known cholinomimetic agents [85–87] . Of direct relevance to this discussion are three separate studies published by Lugaresi et al. [88] , Gambi et al. [89] and Reale et al. [90] . Lugaresi et al. evaluated the effect of acetylcholinesterase inhibitors (AChEI) on IL-4 production, an ant-inflammatory cytokine, in AD patients. Patients who were treated with a AChEI had higher levels of the anti-inflammatory cytokine, IL-4, independently of age, gender and co-morbidity. They concluded

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that increased production of IL-4 in AChEI treated patients might represent an additional mechanism through which AChEI can have a positive effect on AD progression. Gambi et al. reported on the expression and production of cytokines in peripheral blood mononuclear cells (PBMCs) of patients with AD treated with the AChEI, donepezil. There was a healthy control group and a group of patients who did not receive the inhibitor. Measurements included IL-1β, IL-6 and TNF-α, all of which have been implicated in the regulation of amyloid peptide protein synthesis and the anti-inflammatory cytokine, IL-4, which suppresses the activity of IL-1β. Patients were assessed for clinical and immunologic features at baseline and after 1 month of treatment with donepezil. PBMCs were cultured with and without phytohemagglutinin stimulation. Compared with untreated patients and healthy control subjects, IL-1β levels and expression decreased significantly in AD patients treated with donepezil while IL-4 levels and expression were significantly increased. Comparable effects were observed with PBMCs [88,89] . Based on reports that elevated levels of cytokines had been detected in brains of AD patients, and peripheral levels of IL-1β, TNF-α and IL-6 were also elevated in these patients, Reale et al. [90] studied the ability of PBMC from AD patients and matched controls, to release proinflammatory and antiinflammatory cytokines and the effect of AChEI


Neurological disorders, depression & inflammation treatment on cytokine release. They determined that AChEI treatment downregulated IL-1, IL-6 and TNF-α, and upregulated the expression and production of IL-4 in PBMCs of AD patients. They concluded that AChEI leads to the ‘remodelling of the cytokine network, probably acting on the lymphocytic cholinergic system’. Taken together, treatment with AChEI can attenuate inflammation and should be further explored in larger studies to establish possible protective and therapeutic activity in some of the most debilitating neuropsychiatric disorders. ●●Cyclooxygenase inhibition

COX is an enzyme that is responsible for the formation of biological mediators called prostanoids which include prostacyclin, thromboxane and prostaglandins (PGs). Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. NSAIDs, such as aspirin and ibuprofen, exert their effects through inhibition of COX. It is the rate limiting enzyme in the production of PGs which are bioactive lipids derived from arachidonic acid by the sequential actions of phospholipase A, COX and specific PG synthases. COX exists as the isozymes COX-1 and COX-2, which is usually expressed at low basal levels and rapidly induced in response to various stimuli. It has been suggested that COX is involved in HPA axis activation and COX-2 and PGs might be common mediators of stresses in the brain [91,92] . COX-2 expression is stimulated by proinflammatory molecules, cytokines and growth factors. The precise mechanism(s) by which stress affects the regulation of COX-2 and PG synthesis and release are unclear although COX-2 signaling has been associated with fever, pain and neurodegenerative disorders [93] . In spite of unresolved questions, however, a few reports have suggested that inhibition mainly of COX-2 can exert antidepressant activity by reducing inflammation and thereby augmenting the action of antidepressant agents and even reversing treatment resistance in depression. At least three clinical studies have reported positive effects of add-on celecoxib (CBX) with various antidepressant agents. Each study independently arrived at the same conclusion, namely, that reducing inflammation at the level of COX-2 was beneficial in the treatment of depression. Using a double-blind, randomized, placebo-controlled design, Mueller et al. [61] demonstrated that combination of reboxetine with CBX showed


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a significantly greater antidepressant response by week 5 than the group on reboxetine plus placebo. Nery et al. [94] studied nonresponsive bipolar patients during depressive or mixed episodes in double-blind fashion by adding CBX or placebo to mood stabilizing medication for 6 weeks. A statistically significant improvement was noted in the first week of treatment with add-on CBX in those who completed treatment. Akhondzadeh et al. [95] performed a double-blind study of acutely depressed patients who were randomized to either fluoxetine + PBO or fluoxetine + CBX. At the end of 6 weeks patients receiving the combination showed statistical superiority over the placebo group. These studies point to the efficacy of CBX in augmenting antidepressant response. Some evidence also supports the use of a COX-2 inhibitor as add-on therapy in the treatment of schizophrenia [96–98] . Studies of the use of NSAIDS, and COX-2 inhibitors more specifically, in inflammatory and degenerative brain diseases have not uniformly reported positive results. This may be due to drug selection and dose, length of treatment, stage of the disease (mild vs advanced stages) and study design (controlled vs naturalistic). Contradictory findings may also be attributable to the use of animal models of degenerative and inflammatory diseases versus clinical trials. For example, Aisen [99] demonstrated neuroprotective effects of COX-2 inhibition in an AD animal model. By contrast, conflicting results were reported about the effectiveness of NSAIDS to reduce neurodegeneration in cellular and animal models of PD [100] . For the study of MS, an inflammatory demyelinating CNS disease that shows high co-morbidity with depression, experimental autoimmune encephalomyelitis is often used as an animal model. Using this model, Miyamoto et al. [101] tested the effectiveness of celecoxib to inhibit the infiltration of inflammatory cells into the CNS and the expression of inflammation mediators. They concluded that celecoxib may prove to be a beneficial agent for the treatment of MS and may stimulate the development of novel COX-2 inhibitors. In a clinical trial of a nonselective and a selective COX-2 inhibitor, naproxen and rofecoxib respectively, Aisen et al. [102] failed to detect a significant beneficial effect on cognitive decline in patients with mild to moderated AD, although rofecoxib delayed the time to institutionalization. In both animal models of PD and PD patients it has been demonstrated that COX-2 is


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Review Halaris upregulated in the dopaminergic neurons of the SN and that pretreatment with NSAIDs protects against degeneration induced by the injection of neurotoxic compounds, such as 6-hydroxydopamine [103] . Epidemiological studies of NSAID use have indicated that the risk of developing PD is diminished but it is not clear whether NSAIDs can be of benefit to patients in advance stages of PD. Using the US Veterans Affairs Health Care System, Vlad et al. [104] tested the association between AD development and prior exposure to NSAIDs. Their cohorts were veterans 55 years of age and older with incident AD and an even larger cohort of controls. They concluded that long-term NSAID use was protective although differences were noted among the various agents prescribed. In summary, there are encouraging reports in the literature that administration of a COX-2 inhibitor may be beneficial in at least slowing down disease progression. To the best of my knowledge, none of these clinical studies specifically assessed the effect of NSAIDs on co-morbid depression in their patients. For a comprehensive review and discussion of COX-2 and NDDs, the reader is referred to the excellent paper by Minghetti [105] . ●●TNF-α inhibition

A key cell signaling protein involved in systemic inflammation and the acute phase reaction is TNFα, a cytokine with proinflammatory and proapoptotic properties. Although many cell types can produce it, namely, NK cells, white blood cells, mast cells, eosinophils, endothelial cells, fibroblasts, cardiac myocytes, neurons and adipose tissue, it is predominantly produced by activated macrophages. It is also expressed in microglia (the brain resident macrophage) in response to various stimuli and has been detected around developing amyloid plaque in brain tissue. It plays a major role in CNS neuroinflammation-mediated cell death in AD, PD and ALS as well as several other CNS conditions. The primary role of TNF-α is in the regulation of immune cells. As an endogenous pyrogen it can induce fever, apoptotic cell death, cachexia, and inflammation. Dysregulation of TNF-α production has also been implicated in a variety of human diseases including AD, cancer, inflammatory bowel disease and major depression. The precise role of TNF-α in depression is unclear although several studies have shown elevations in peripheral blood in a significant percentage of patients. It should be stated, however, that

336


TNF-α and other cytokines involved in CNS degenerative disorders can exhibit both beneficial as well as harmful effects. For example, they exert neuroprotective action in β-amyloid toxicity [106] , focal cerebral ischemia and epileptic seizures [107] . The dichotomy of protective versus harmful action most likely depends on the time course of its production and release. At early time points and in response to an insult, injury, stress, it promotes the healing process while chronic stimulation and production is associated with harmful effects. The few available studies of neurodegenerative conditions in which anti-TNFα therapies were utilized, improvements in indices of clinical dementia have been documented in AD [108] , and animal models of PD and ALS have shown promising preliminary outcomes [109] . The introduction into the market of inhibitors of soluble TNF-α (etanercept, infliximab) for the management of rheumatoid arthritis has provided opportunities to test these agents in conditions in which overproduction of TNF-α has been clearly documented. These medications, however, are large macromolecules that only minimally cross the BBB requiring subcutaneous and intravenous injection to enable clinical efficacy. Hence such anti-TNFα strategies will be of limited use for routine use in CNS neurodegenerative disorders. Tweedie et al. [110] make a strong case that thalidomide analogs that are orally active and readily cross the BBB have the potential for widespread utility assuming their safety can be established and are not used during pregnancy. Raison et al. [111] used infliximab infusions in treatment-resistant depressed patients. They found no overall difference in change of depression scores between treatment groups across time was found. However, depression scores (baseline to week 12) favored infliximab-treated patients whose baseline hs-CRP concentration was greater than 5 mg/l. Additionally, baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (p < 0.05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebotreated responders (p < 0.01), and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/l or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/l


Neurological disorders, depression & inflammation revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximabtreated patients versus 33% (3 of 9 patients) in placebo-treated patients (p = 0.19). ●●Bupropion

Another potentially useful pharmacologic agent is bupropion which is widely used as an antidepressant exerting mainly reuptake inhibition of dopamine and to a lesser degree norepinephrine. In animal experiments it has been shown to suppress TNF-α synthesis by mediating increased signaling at β-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF-α synthesis. Bupropion is well tolerated also in nonpsychiatric populations and has lower risk with long-term use than current anti-inflammatory, immunosuppressive or TNF-α suppressive treatments, such as prednisone, azathioprine, infliximab or methotrexate. Bupropion’s potential utility as an antinflammatory agent should be studied in as much as it is often used by neuropsychiatrists in neurological conditions that are co-morbid with depression. Nevertheless, a search for innovative anti-inflammatory treatments is overdue. ●●Statins as anti-inflammatory agents

CRP is a plasma acute phase protein that participates in the systemic response to inflammation. IL-6 is the main regulator of CRP in plasma. As a prototypic marker of inflammation, CRP has emerged as a CVD risk marker. Its levels have also been associated with depression, cognitive impairment, stroke, AD, dementia and possibly PD. Inflammation plays a critical role in atherosclerosis and arteriosclerosis and therefore controlling inflammation and reducing abnormally elevated levels of CRP can be of therapeutic and preventive value. The coenzyme A reductase inhibitors, known as statins, exert beneficial effects not only in lowering cholesterol and decreasing CVD events, but also in reducing CRP levels. This reduction has been confirmed in several studies and does not correlate with normalization of cholesterol. Additional beneficial effects of statins on endothelial function, platelets and macrophages have been described. Since CRP is now accepted as a risk marker, and since clinical evidence supports an anti-inflammatory effect of statins, their utility especially is early stages of disease progression should be explored [112] .


Review

Conclusion Co-morbidity between neurological disorders and MDD is high but varies among neurological conditions. The prevalence rates range between 20 and 50% of patients with stroke, epilepsy, MS, AD and PD. On the other hand, depressive syndromes may also be considered as a risk factor for certain neurological disorders, and depression may predate neurological signs and symptoms in the evolution of neurodegenerative disorders. This review focused on the association of inflammation in general and neuroinflammation in particular, as they relate to representative neurological disorders and depression. Mental stress can produce profound alterations in the physiology and chemistry of the CNS and the autonomic nervous system, peripheral organs, and the endocrine, vascular and immune systems. Chronic, and especially inescapable stress, leads to pervasive mental status changes and pathological alterations to the structure and function of the vascular system, which may lead to irreversible tissue and organ damage. The inflammatory response is implemented by orchestrated mobilization and complex interactions of various cell types and signaling molecules. Consequently, neuroinflammation is a term used to connote the broad range of CNS immune responses that may result in synaptic impairment, neurotransmitter dysregulation or deficiency, neuronal cell death and exacerbation of brain pathology. Centrally immune responses are carried out predominantly by microglia, the resident immune cells in the brain, and their activation is believed to be related to neuroinflammation. Peripherally immune responses are carried out by monocytes–macrophages and the inflammation mediating messengers are cytokines and chemokines. By measuring these substances in blood and CSF, where feasible, an index of the organism’s inflammation status can be obtained. Utilizing this approach, a number of studies have confirmed the presence of a proinflammatory status both in the neurological conditions studied and in depression, whether or not the latter was co-morbid with another pathological condition. Only a few studies have attempted to test the effectiveness of reducing inflammation in an effort to ameliorate the underlying condition and the concomitant depression. Central to such attempts is the identification of the anti-inflammatory cholinergic pathway which points to the possible


337

Review Halaris therapeutic utility of cholinomimetic compounds. Similarly, inhibition of the enzymatic steps critical to the formation of proinflammatory compounds through inhibition of COX-2 holds great promise, at least as adjunctive pharmacologic intervention. Although more large scale, multicenter studies must be conducted, there is sufficient reason for optimism that innovative diagnostic and therapeutic modalities can soon be developed to address the burden of some of the most debilitating illnesses worldwide. Future perspective Based on the burgeoning dataset of findings – basic, clinical, translational – that inflammation in general and neuroinflammation specifically underlie most, if not all, neurological disorders, and the recognition that depression is highly co-morbid with such disorders, a therapeutic approach targeting inf lammation is long overdue. Such an approach should be undertaken early in the disease process, whether or not depression is present, and should be multipronged. The inflammatory response of the organism is complex and multifaceted and it can be blocked or modulated pharmacologically at different levels and stages. The interventions can range from cholinergic enhancement, enzymatic inhibition and receptor blockade, to name a few. It is understood that interfering with the ability of the immune system to stage a response commensurate with the offending agent or condition is of utmost importance. The author is not advocating a ‘shotgun’ approach toward containing inflammation. The ability of the immune system to protect the organism against infection, trauma or any threat to the homeostasis must be preserved while interventions are being considered to achieve modulation of excessive and/ or unduly prolonged immune responses. The key word in this context is modulation of neuroinflammation by appropriate and adequately researched interventions that will not jeopardize the safety of the patient. To that end, the author proposes a systematic examination of key inflammation biomarkers utilizing a carefully compiled and cost-effective laboratory panel to be added to the otherwise established

338


routine blood and CSF tests. Blood and CSF analyses of such biomarkers would: ●● provide evidence that (neuro)inflammation is present; ●● assess the degree of differentiation among bio-

markers and magnitude of immune response; ●● establish associations with specific cognitive

and behavioral symptoms and ●● enable the longitudinal assessment of success

in containing, if not reversing, the excessive inflammatory response. To the extent that positron emission tomography ligands become commercially available for routine imaging studies, the author submits that demonstration of microglial activation would be enormously helpful in visualizing the presence of neuroinflammation and correlating it to peripherally measured biomarkers. Again, the goal is to modulate and not to inhibit the inflammatory response. The author believes the time is now to introduce innovative investigative and therapeutic approaches to some of the most debilitating disorders that afflict populations worldwide. To achieve these lofty goals, three critical conditions must be met: Teams of clinician investigators must be assembled with expertise in neuropsychiatry, neurology, neuropsychology, immunology, molecular biology, genetics, brain imaging and bioinformatics; Large multicenter studies must be designed and executed to shorten the time required to generate the data that would allow commercial use of tested compounds; Government and private funding to support consortia in North America, EU, Asia and any other countries wishing to participate.Executive summary Financial & competing interests disclosure The author has no relevant affiliations or financial involvementwith any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.


Neurological disorders, depression & inflammation

Review

EXECUTIVE SUMMARY Mental stress & its consequences ●●

Mental stress can alter the physiology and chemistry of the CNS and the autonomic nervous system, peripheral organs and the endocrine, vascular and immune systems.

●●

The imbalance in the autonomic nervous system, especially if prolonged, has profound effects on vascular physiology and the immune system.

Neuroinflammation at the core of CNS pathology ●●

Neuroinflammation connotes the broad range of CNS immune responses that may result in synaptic impairment, neurotransmitter dysregulation or deficiency, neuronal cell death and exacerbation of brain pathology.

●●

Neuroinflammatory processes underlie neurological disorders.

●●

Neurons express inflammasomes which are responsible for activation of inflammatory processes.

Depression & inflammation cause or effect? ●●

High co-morbidity between depressive illness and cardiovascular, cerebrovascular and neurodegenerative diseases.

●●

Inflammation is a major causal factor to depressive illness and proinflammatory cytokines have been associated with behavioral and cognitive symptoms.

●●

Proinflammatory cytokines are causally linked to plaque formation and depression is associated with a high risk for vascular disease.

●●

Proinflammatory cytokine overproduction in depression may be one common link.

Poststroke depression ●●

Poststroke depression is a common and relevant complication following ischemic brain infarction.

●●

The neurobiological and pathological profiles of ischemia and major depression share common neuroanatomical, neuronal, biochemical and immunological factors.

●●

Ischemia and depression are associated with an increased inflammatory state and greater rates of neuronal cell death.

●●

Ischemic cell death elicits the inflammatory mechanisms that precede poststroke depression-associated depressive symptoms, and later, long-lasting clinical depression.

Parkinson’s disease ●●

Inflammation-derived oxidative stress and cytokine-dependent toxicity contribute to the degeneration of the nigrostriatal pathway.

●●

Microglia are involved in the pathogenetic process of Parkinson’s disease.

●●

Microglial activation can produce dopaminergic neurodegeneration.

Alzheimer’s disease ●●

Neuroinflammation is a key pathogenetic factor.

●●

Microglial activation, astrocyte reactivity and elevations in cytokine expression are present in Alzheimer’s disease patients.

●●

Postmortem studies of Alzheimer’s disease brain samples have revealed highly expressed inflammatory cytokines.

●●

Genome-wide studies show an upregulation of inflammatory genes.

●●

Symptoms of depression appear early in the dementia process and intensify with the progression of cognitive decline.



339

Review Halaris EXECUTIVE SUMMARY (CONT.) Inflammation & neurotoxicity: the tryptophan/kynurenine pathway ●●

Tryptophan 2,3-dioxygenase is activated by steroids in conjunction with HPA axis activation in depression.

●●

Indoleamine 2,3-dioxygenase is activated by proinflammatory cytokines, such as IFN-γ, IL-1, IL-2, IL-6 and TNF-α, and inhibited by IL-4, an anti-inflammatory cytokine.

●●

Overstimulation of indoleamine 2,3-dioxygenase leads to tryptophan depletion resulting in serotonin deficiency in the brain.

●●

Kynurenine is further metabolized into several neurotoxins, including 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid.

Novel therapeutic targets ●●

The immune mediating component of the cholinergic system can provide opportunities to develop novel immunomodulatory agents.

●●

Inhibition of COX-2 can exert antidepressant activity by reducing inflammation and thereby augmenting the action of antidepressant agents.

●●

Anti-TNF-α therapies may improve indices of clinical dementia in Alzheimer’s disease.

●●

Bupropion may have potential utility as an anti-inflammatory agent.

●●

The beneficial effects of statins may extend to mechanisms beyond cholesterol reduction, for example, inflammation reduction, endothelial function, monocyte–macrophages and platelets.

Conclusion ●●

Co-morbidity between neurological disorders and major depressive disorder is high.

●●

Neuroinflammation is a term used to connote the broad range of CNS immune responses that may result in synaptic impairment, neurotransmitter dysregulation or deficiency, neuronal cell death and exacerbation of brain pathology.

●●

The presence of a proinflammatory status in neurological conditions and in depression has been confirmed.

●●

Neither all neuropsychiatric disorders nor all patients diagnosed with the specific disorder associated with a proinflammatory status show evidence of biomarker-based inflammation.

●●

No single inflammation biomarker has been linked diagnostically with a specific neuropsychiatric disorder.

●●

Only a few studies have attempted to test the effectiveness of reducing inflammation in an effort to ameliorate the underlying condition and the concomitant depression.

Future perspective ●●

Systematically examine key inflammation biomarkers by utilizing a carefully compiled and cost effective laboratory panel.

●●

Establish specific associations between inflammation and neuropsychiatric disorders.

●●

Establish associations with specific cognitive and behavioral symptoms.

●●

Demonstrate microglial activation using imaging techniques to visualize the presence of neuroinflammation and correlate it to peripherally measured biomarkers.

●●

Assemble teams of clinician investigators to conduct large multicenter studies.

Secure government and private funding to support clinical research consortia.

340



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