P0001 - A Possible role for Cyclosporin-A, at smaller Rheumatoid Arthritis treatment doses, in the treatment of Alzheimer's Disease

Abstract

Steroids as testosterone (T), progesterone (P) as well as gluco/mineralocorticoids, are reduced by steroid 5alpha-reductase (5AR) to 5alpha-dihydrotestosterone (DHT) and 5alpha-dihydroprogesterone (DHP). DHT and DHP are further reduced by 3alpha-hydroxysteroid dehydrogenase (3AHSD) to 3alpha-androstanediol (A-diol), and 3alpha, 5alpha-tetrahydroprogesterone (THP/allopregnanolone); 5AR is the rate-limiting enzyme. Cyclosporin-A (CSA) stimulates 5AR. CSA is given to organ transplant patients to prevent organ rejection. A dose-dependent side effect of CSA is hypertrichosis, from increased production of DHT etc.

Both DHT and A-diol have cognitive enhancing effects; Adiol may be more potent. T and P metabolites potentiate GABA. They are neuroprotective, and reverse diabetic neuropathy. Allopregnanolone promoted “neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease (AD).” Allopregnanolone “levels are inversely correlated with neuropathological disease stage” in prefrontal cortex of AD patients. Such ‘positive effects’ are substantially reduced by finasteride, a 5AR inhibitor. CSA has also been used to alleviate rheumatoid arthritis symptoms at smaller doses.

Plausibly, CSA could enhance cognitive functions, reverse diabetic neuropathy, and could be used in the treatment of confirmed cases of AD. Indomethacin inhibits 3AHSD; it is given to AD as a ‘NSAID’, which could even be counterproductive. Since animal models of both AD and diabetic neuropathy can be created, CSA at varying doses can be tried in such models in several ways, such as adding P, and/or T, to CSA to enhance the production of allopregnanolone and A-diol, and of other neuroactive steroid metabolites. Furthermore, more potent 5AR stimulators could be synthesized.