Brian E. Leonard

Inflammation, Depression and Dementia: Are they Connected?

AbstractChronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer’s disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life.n

Cytokine Changes and Tryptophan Metabolites in Medication-Naïve and Medication-Free Schizophrenic Patients

Cytokine imbalances especially between T helper type (Th) 1 and Th2 and tryptophan breakdown were reported to be involved in the pathophysiology of schizophrenia. The hyperactive inflammatory response system could induce enhanced tryptophan breakdown. This study aimed to investigate the relationship between cytokine changes, tryptophan breakdown parameter changes and clinical parameters in patients with schizophrenia in comparison with normal controls. In the plasma of schizophrenic patients, Th1-specific interferon-γ was significantly higher (F = 7.485, p = 0.007) and Th2-specific interleukin (IL)-4 was significantly lower (F = 126.327, p < 0.0001). The Th1-related cytokine IL-2 was lower (F = 5.409, p = 0.021) but tumor necrosis factor-α (TNF-α) and Th2-related IL-6 were higher (F = 95.004, p < 0.0001 and F = 408.176, p < 0.0001, respectively) in the plasma of schizophrenic patients. After 6 weeks of treatment, IL-6 and TNF-α were significantly reduced (t = –3.762, p < 0.0001 and z = –2.668, p = 0.008). At the time of admission, plasma tryptophan concentrations were lower (F = 6.339, p = 0.012) in schizophrenic patients and were negatively correlated with the total positive symptoms score (r2 = -0.343, p = 0.004). After 6 weeks of medication, both plasma tryptophan and kynurenine concentrations were increased (t = –2.937, p = 0.005 and t = –3.214, p = 0.002, respectively). The findings of this study indicate a hyperactive pro-inflammatory response inducing a change in tryptophan metabolism that might be related to the development of positive symptoms in schizophrenia.

Neuropsychiatric disorders related to interferon and interleukins treatment

Certain cytokines such as interferon-α and interleukin-2 are often used in the treatment certain cancers and chronic diseases such as melanoma, hepatitis C infection and multiple sclerosis. Several neuropsychiatric side effects such as depression, anxiety, psychosis, suicidal ideation, hypomanic mood and cognitive impairment were reported in those patients who received those medications. In certain patients with those neuropsychiatric side effects, the symptoms ceased when the medication was stopped. However, in some cases, the cognitive impairment persisted even for years after cessation of the medication. In animal studies, those cytokines could induce sickness behaviour, anxiety behaviour and social anhedonia. The increased in pro-inflammatory cytokines in certain neuropsychiatric disorders was widely reported. In addition, in animal studies, the treatment with interferon-α or interleukin-1 could induce depressive like behaviour. Recently, the role of certain pro-inflammatory cytokines that could enhance the activity of the enzyme, indoleamine 2–3, dioxygenase (IDO) which in turn would increase tryptophan degradation into kynurenine and decrease tryptophan availability of tryptophan in the brain to synthesize serotonin, a neurotransmitter which is necessary for the normal mood state became of interest in pathophysiology of psychiatric disorders. Furthermore, the imbalance in the further downward catabolic kynurenine pathway and their interactions with other neurotransmitters has been proposed to play an important role. The presence of such an imbalance in patients being treated with cytokines and in patients with psychiatric disorders and the possible consequence of those changes on the neuroprotective function in the brain are discussed in this review.

T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients.

It has been reported that the balance between T-helper type 1 (Th1) cytokines and T-helper type 2 (Th2) cytokines plays a role in psychiatric disorders such as bipolar disorder. The T-helper type 3 (Th3) cytokine, which transforming growth factor beta-1 (TGF-beta1), has been shown to modulate the production of Th1 and Th2 cytokines. However, the role of TGF-beta1 in bipolar disorder has not yet been explored. A total of 70 manic patients with bipolar disorder and 96 normal controls was recruited. The plasma levels of IFN-gamma, IL-4, and TGF-beta1 were studied at the time of admission and 8 weeks after mood stabilizer treatment. The detection rate and plasma concentrations of IFN-gamma and IL-4 and the IFN-gamma/TGF-beta1 and IL-4/TGF-beta1 ratios were significantly higher in patients than in controls, while the TGF-beta1 level was significantly lower. The TGF-beta1 level increased significantly after treatment and the IFN-gamma/TGF-beta1 and IL-4/TGF-beta1 ratios returned to control values. TGF-beta1 may play a role in the pathophysiology of bipolar disorder through the action of TGF-beta1 in modulating the IL-4/TGF-beta1 ratio.

Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression

Background: The olfactory bulbectomised (OBX) rat model is a chronic model of depression in which behavioural and neuroimmunoendocrine changes are reversed only after chronic antidepressant treatment. The cyclooxygenase 2 (COX-2) inhibitor celecoxib has been shown to improve the depressive symptoms in patients with major depression. Methods: The association between blood and brain immunological and behavioural changes in chronic treatment with COX-2 inhibitor was explored in the OBX rats and their sham-operated controls. Results: The OBX group showed significantly higher locomotor activity than the other groups in the first 5 min in the open field. In the home cage emergence test, the OBX group showed a significantly shorter latency period compared to the sham group (z = –3.192, p = 0.001) but there was no difference between the other three groups. In the hypothalamus, the OBX group had a significantly higher interleukin 1β (IL-1β) concentration than the OBX + celecoxib group (z = –1.89, p = 0.05) as well as a significantly higher IL-10 concentration (z = –1.995, p = 0.046). In the prefrontal cortex, the OBX group showed significantly higher concentrations of tumour necrosis factor α (z = –2.205, p = 0.028) and IL-1β (z = –3.361, p = 0.001) than the OBX + celecoxib group, but a significantly lower concentration of IL-10 (p = –3.361, p = 0.001) than the OBX + celecoxib group. Conclusions: The results of this study supported the potential therapeutic role of the COX-2 inhibitor celecoxib. It is possible that the behavioural changes following the chronic administration of celecoxib to the OBX rats are associated with an attenuation of the increase in the pro-inflammatory cytokines in the brain.

Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1β in rats

Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1β can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10u2009ng IL-1β in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1β-induced memory impairment was indicated by elevated corticosterone levels after IL-1β administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1β-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1β on working memory. IL-1β-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1β can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1β. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.

Gestational Stress Leads to Depressive-Like Behavioural and Immunological Changes in the Rat

Stress during pregnancy, gestational stress, can increase the chance of developing postpartum depression, which is estimated to occur in 10% of women. Since major depression is accompanied by an activation of the inflammatory response system, the aim of this study was to investigate if stress during pregnancy induces postpartum depressive-like behaviour, and if so, is it accompanied by activation of the inflammatory response system in female Fisher rats. We investigated the effect of gestational stress on the production of depressive-like behaviour in the rats. The pregnant dams underwent daily restraint stress (for 1 week, 3 times/day) or were left undisturbed (control). On postpartum day 22, the rats were introduced to the forced swim test (pre-test). On postpartum days 23 and 24 (test days), the immobility time was measured. Gestational stress significantly elevated immobility scores by 35–40% above the control values on both test days, which suggests that the stressed group displayed postpartum depressive-like behaviour. The concentrations of the pro-inflammatory cytokines interleukin-1β, tumour necrosis factor-α and the anti-inflammatory cytokine interleukin-10 in stimulated whole-blood culture were also analysed. The stressed group showed higher levels of all three cytokines. No significant differences in the cytokine concentrations were detected in the hypothalamus, hippocampus or pre-frontal cortex.

Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naive and medication-free schizophrenic patients

The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.

Inflammation and depression: Is there a causal connection with dementia?

Epidemiological studies show that there is a correlation between chronic depression and the likelihood of dementia in later life. There is evidence that inflammatory changes in the brain are pathological features of both depression and dementia. This suggests that an increase in inflammation-induced apoptosis, together with a reduction in the synthesis of neurotrophic factors caused by a rise in brain glucocorticoids, may play a role in the pathology of these disorders. A reduction in the neuroprotective components of the kynurenine pathway, such as kynurenic acid, and an increase in the neurodegenerative components, 3-hydroxykynurenine and quinolinic acid, contribute to the pathological changes. Such changes are postulated to cause neuronal damage and thereby predispose chronically depressed patients to dementia.

Interleukin 1 beta enhances conditioned fear memory in rats: possible involvement of glucocorticoids

Central administration of 15u2003ng interleukin (IL)‐1β in the rat significantly enhanced conditioned fear memory assessed by a passive avoidance task, when retested at 24 and 48u2003h post‐training. Pain threshold was unaffected by 15u2003ng IL‐1β administration. IL‐1β treatment also increased serum corticosterone. This increase in serum corticosterone was further enhanced in rats given both IL‐1β and footshock. Furthermore, the glucocorticoid receptor antagonist mifepristone blocked IL‐1β‐induced elevation in corticosterone and also attenuated the enhanced conditioned fear memory. Central administration of IL‐1β significantly increased prostaglandin E2 and decreased the anti‐inflammatory cytokine IL‐10 release from whole blood cultures; therefore this treatment appears to be effective in inducing an inflammatory response in both the periphery and the brain. The present study confirms that IL‐1β can enhance conditioned fear memory, an effect which is correlated with changes in glucocorticoid function. This facilitation of defensive behaviour could reflect adaptive responses which may enhance survival during sickness.