Chronic 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.
[Show abstract][Hide abstract] ABSTRACT: Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory
cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis
and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic
neuroinflammation,which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated
hypothalamus–pituitary–adrenal (HPA) axis have close interactionswith pro-inflammatory cytokines and
neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most
widely investigated factors in the pathophysiology of depression. These two major components create a vicious
cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory
cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an
imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression.
Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they
are essential components of a whole system of inflammatory and endocrine interactions, rather than playing
independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the
pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship
between depression and neuroinflammation.
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