Stress induces the release of corticotrophin-releasing hormone (CRH) by the hypothalamus, which triggers the release of adrenocorticotrophic hormone (ACTH) by the pituitary, which in turn stimulates adrenocortical secretion of glucocorticoids. Circulating titers of corticosteroids finally suppress subsequent release of CRH and ACTH through steroid-sensitive receptor sites in the brain and in the pituitary, thus preventing prolonged exposure to elevated levels of cortisol following stress. The adrenal cortical axis therefore acts as a closed-loop feedback system where circulating titers of glucocorticoids act to maintain secretion of corticosteroids in-between narrow limits. However, approximately 50% of individuals with AD present higher cortisol titers than patients without dementia, and these levels increase proportionately as the dementia increases.29 Furthermore, AD patients also demonstrate resistance to inhibition by dexamethasone of ACTH release caused by CRH, suggesting a higher incidence of stress-adaptation failure in AD. Studies have shown that glucocorticoids induce a generalized state of metabolic vulnerability in hippocampal neurons and that cumulative exposure to glucocorticoids such as occurs in aged rats, or following chronic stress, is a cause of loss of hippocampal neurons. These effects appear to be mediated through brain glucocorticoid receptors (GR), probably via inhibition of glucose transport in hippocampal neurons.30 Taken together, these findings would suggest that the higher incidence of chronic stress-adaptation in AD could be of specific etiopathological significance. Search for specific agents enhancing feedback inhibition of CRH and ACTH secretion, i.e., restoring stress-adaptation of the adrenocortical axis or inhibiting the effect of corticoids (cortisol) on glucose transport may hold promise for future understanding of neurodegenerative mechanisms and drug discovery.
anti-inflammatory therapy in ad
Most data available suggest that AD is a chronic disease, characterized by a long preclinical period during which several initiation factors (genetic, environmental, or both) cause neuronal death. The aging process probably acts as a promoting factor for the disease.31 Immunohistochemical evidence points to a chronic inflammatory state of the brain in AD. The senile plaques are associated with reactive microglial cells that contribute to the inflammatory response, including the production of the cytokine interleukin-I (IL-I) (both IL-Ia and IL-Ip). There is an approximately 30fold increase in the level of IL-I in the brain and cerebrospinal fluid of AD and Down syndrome patients compared to aged matched controls. IL-Ip is a potent and rapid inducer of glial phospholipase A2 (PLA^) and cyclooxygenase (COX) leading to the production of both prostaglandins and thromboxanes.32 33 Interestingly, a significant increase in the formation of prostaglandin D2 in the frontal cortex of AD patients has been detected. Anti-inflammatory drugs such as indomethacin are powerful inhibitors of cytokine (IL-Ip and TNF-a) dependent increases in prostaglandin production (Figure 2.10). Long-term anti-inflammatory therapy might therefore retard the development of AD. This notion has been tested by comparing the prevalence of AD in the general population with that in patients with rheumatoid arthritis (RA) because such patients receive anti-inflammatory drugs and often contract arthritis before the age of risk for AD. The data published showed an unexpectedly low prevalence of AD in patients with RA.34 Several reports have now demonstrated that anti-inflammatory drugs may retard or even prevent progress of AD symptoms.35 Although further studies with anti-inflammatory drugs are necessary before definite conclusions can be drawn about the possible preventive effects of such treatments in AD, research has opened a new approach to the design of drugs for treating neuro-degenerative diseases. Inhibitors of IL-I transcription, such as E-5090,36 and of post-translational processing of IL-I, such as pentamidine,37 are potential candidates for the study of brain inflammatory processes (Figure 2.11). Compounds of unknown mechanism, but screened in cellular models to decrease cytokine production and/or
FIGuRE 2.10 Anti-inflammatory agents under experimental and clinical evaluation for their potential to inhibit the signal transduction cascade initiated by microglial cytokines.
secretion, have been described, e.g., danazol, which decreases both IL-ip and TNF-a synthesis. Zinc protoporphyrin sodium is a purported IL-I receptor antagonist that reduces ischemia brain lesion in the rat.38 The anti-inflammatory agent sulfasalazine is a TNF-a receptor antagonist, but its effect in brain inflammatory processes has not been reported. An alternative approach involves inhibition of phosphodiesterase with pentoxifylline, which increase c-AMP levels and suppresses TNF-a (see also zardaverine39) and also IL-Ia and IL-ip production.40 Propentofylline (HWA 285) (Figure 2.12), a structural analog of pentoxifylline, has been reported to improve symptoms in chronically treated (6 to 12 months) AD patients.41
Whether the clinical improvement observed was caused by suppression of microglial hyperactivity, and hence the inflammatory disease process, has yet to be established. Activated microglial cells also produce increased amounts of superoxide anions, which are potentially neurotoxic via oxidation of cellular proteins and cell membrane. Free radical scavengers may, therefore, offer some interest in retarding the progression of AD.
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