<h5>Background</h5> Age-related depletion of testosterone in men is an established risk factor for the development of Alzheimer's disease (AD). Although testosterone therapy is a promising strategy for preventing and or treating AD, testosterone has the potential risk of promoting prostate cancer. To overcome this limitation, novel compounds termed selective androgen receptor modulators (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues of interest, including muscle and bone. Several SARMs are currently in clinical trials for treatment of non-neural endpoints in men. The efficacy of such drugs in brain and their potential to mimic the beneficial actions of testosterone against AD pathogenesis (e.g., neuroprotection, lowering of β -amyloid accumulation, inhibition of tau phosphorylation) are not known.</P><h5>Methods</h5> To begin assessing the potential utility of SARMs to protect against AD, we compared the neuroprotective efficacy of SARM RAD140 with testosterone using in vitro and in vivo models of neural injury.</P><h5>Results</h5> In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing apoptosis induced by the insults β -amyloid peptide and apoptosis activator II. Like testosterone, RAD140 neuroprotection was specific to apoptotic insults and mechanistically was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MEK inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit: (i) peripheral tissue-specific androgen action that largely spared prostate, (ii) neural efficacy as demonstrated by activation of neural androgen effects, and (iii) neuroprotection of hippocampal neurons against cell death induced by systemic administration of the excitotoxin kainate.</P><h5>Conclusions</h5> These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to AD.</P>
Alzheimer's and Dementia – Elsevier
Published: Jul 1, 2013
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