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Glucocorticoids may initiate Alzheimer's disease: A Potential therapeutic role for mifepristone (RU-486)

Dr. Ram Manohar Lohia Hospital, New Dilli, NCT, India
Medical Hypotheses (Impact Factor: 1.07). 02/2007; 68(5):1088-92. DOI: 10.1016/j.mehy.2006.09.038
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ABSTRACT Alzheimer's disease (AD) is a relentless neurodegenerative disease of uncertain etiology affecting millions worldwide. Stress is an important etiological factor associated with AD. Stress and glucocorticoids (GCs) are intimately related; so much so that stress is considered to be "a condition that is able to liberate GCs". Normally, GCs are required for various bodily functions but their excess is deleterious. Hippocampus has highest density of GC receptors in brain, is particularly vulnerable to their damaging effects and undergoes reversible atrophy under their influence. Hippocampal atrophy is an initial event for the development of AD, the most common form of dementia. Apart from atrophy, GCs are able to produce a variety of other initial structural and functional changes in hippocampus. For example, these down regulate GC receptors, leading to disruption in negative feedback loop, alter dendtritic morphology and impair axonal transport. Impaired axon transport is probably an initial event that leads to the formation of paired helical filaments. Additionally, they inhibit insulin-degrading enzyme, which degrades A-beta; consequently reducing its clearance. Since GCs mediate a number of initial events in AD pathogenesis, therefore GC antagonists (e.g. mifepristone) can be tried. Mifepristone has intrinsic neuroprotective and antioxidant potential which could offer additional benefits as well. Use of this drug therefore, in those with mild AD or with milder cognitive impairment can be useful. Appropriate dose, duration, safety and efficacy need to be worked out.

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    • "hippocampal GluT4 (Piroli, Grillo et al. 2007), so that insulin resistance might well interact with GC signaling; indeed, removal of adrenal steroids increases sensitivity to central insulin (Chavez, Seeley et al. 1997), suggesting a bidirectional modulation of neural function. GCs have been suggested as a potential causal agent for conditions including Alzheimer's disease, associated with impaired insulin signaling (Dhikav and Anand 2007), and cause impaired neuronal and glial glucose usage (Sapolsky 1986; Brunetti, Fulham et al. 1998; Gip, Hagiwara et al. 2004) whereas damage caused by elevation of GCs can be reversed by supplying additional fuel (Saposky 1986). Moreover, GCs have multiple deleterious effects in the hippocampus, including interference with neurogenesis, and neurogenesis is associated with enhanced memory performance but impaired in T2DM (Gould, Beylin et al. 1999; Drapeau, Mayo et al. 2003; Cao, Jiao et al. 2004; Aimone, Wiles et al. 2006; Lindqvist, Mohapel et al. 2006; Ramirez-Amaya, Marrone et al. 2006; Dupret, Revest et al. 2008; Fontan-Lozano, Lopez-Luch et al. 2008; Lafenêtre, Leske et al. 2009; Lang, Yan et al. 2009; Stangl and Thuret 2009; Deng, Aimone et al. 2010; van der Borght, Kohnke et al. 2011), further suggesting a possible role for GCs in the etiology of cognitive deficits associated with insulin resistance. "
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    • "Thus, a recently developed view suggests that hypercortisolemia, leading to hippocampal atrophy and further HPA axis disinhibition (i.e. " the glucocorticoid cascade hypothesis " ), would peer-00511184, version 1 -24 Aug 2010 Solas M 4 initiate a chain of events, ultimately culminating in the development of lesions typical of AD (Dhikav and Anand, 2007). The mechanisms underlying the effects of altered glucocorticoid levels remain largely unknown. "
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    • "Neuroprotective agents may be able to help reduce further degeneration, although it is unknown whether this would have a large enough effect on the overall pathology of AD. The glucocorticoid antagonist mifepristone has recently been suggested as a neuroprotective treatment for AD (Dhikav and Anand 2007). Stress has been suggested as a factor that contributes to the development of Alzheimer's (Miller and O'Callaghan 2005); therefore, inhibiting glucocorticoid may help protect against AD-related cellular degeneration. "
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