40,41 Such changes,

together with an activation of the proinflammatory cytokines by chronic stress and depression, also enhance apoptosis through their indirect excitotoxic and metabolic actions.42 Thus stress-induced hypercortisolemia and proinflammatory cytokines share a final common pathway that leads to impaired neuronal plasticity and deficits in central neurotransmission. The possible link between hypercortisolemia and depression Inhibitors,research,lifescience,medical is further provided by the changes induced by antidepressants and glucocorticoid receptor antagonists such as mifepristone.43 Thus, preliminary clinical evidence has shown that the sensitization of the central glucocorticoid receptors by such treatments, that results in the re-establishment of the feedback inhibition of Cortisol release, Inhibitors,research,lifescience,medical are correlated with the attenuation of the symptoms of depression.44 Is there a link between depression and demential? The clinical perspective There is overwhelming evidence that

inflammatory changes are an important causative factor in the pathology of Alzheimer’s disease and related dementias.45 The increase in β amyloid (Ab) is not only a major pathological Inhibitors,research,lifescience,medical feature of such dementias, but is also responsible for stimulating inflammatory responses in the brain. These changes include an increased expression of cell adhesion molecules and proinflammatory cytokines, and the activation of click here microglia in the brain parenchyma.46 In vitro studies have also demonstrated that Ab induces IL-lb and IFNg from vascular cells, Inhibitors,research,lifescience,medical thereby inducing a cascade of inflammatory changes.47,48 In addition, the infiltration of macrophages together with CD4+ and CD8+ T-cells, from the periphery have been detected in Ab deposits in cerebral vessels

in patients with cerebral amyloid angiopathy.49 The combination of Ab and proinflammatory cytokines is linked to the increase Inhibitors,research,lifescience,medical in apoptosis in the brains of patients with dementia.50 For example, there is evidence that lymphocytes show a significant increase in DNA fragmentation in Alzheimer patients when compared ADP ribosylation factor with aged, but normal, controls.51 This change has been linked to an increase in the intracellular concentration of calcium ions, a prerequisite for apoptosis52 that has not been recorded in lymphocytes from aged control subjects. Furthermore, apoptotic cell death is preceded by the expression of apoptosis-associated molecules such as p53, Fas (CD95/APO-1) and IL-1b converting enzyme. Whereas the normal brain is partly immunologically privileged, in patients with inflammatory diseases such as multiple sclerosis, stroke, Alzheimer’s disease, and possibly major depression, Fas is widely expressed in the brain.53 This apoptotic protein is expressed on CD4+ and CD8+ T-cells and on NKCs.