The overall ability of the brain to synthesise
neuroactive steroids led us to the identification of compounds that would reproduce aspects of
neurosteroid pharmacology. The rate-determining step in
neurosteroid biosynthesis is the import of the substrate
cholesterol into the mitochondria, where it is metabolised into
pregnenolone via the intermediate
22R-hydroxycholesterol. The levels of translocator
protein 18-kDa, mediating the import of
cholesterol into mitochondria, correlated with increased
pregnenolone formation and reduced levels of
22R-hydroxycholesterol in biopsies from
Alzheimer's disease (AD), but not age-matched control, brains.
22R-hydroxycholesterol was shown to protect against β-
amyloid (Aβ(42) )-induced neurotoxicity. In search of
22R-hydroxycholesterol stable analogues, we identified the naturally occurring heterospirostenol, (22R,25R)-20α-spirost-5-en-3β-yl
hexanoate (
caprospinol) and derivatives that protect neuronal cells against Aβ(1-42) neurotoxicity. The
neuroprotective effect of
caprospinol is the result of a combination of overlapping properties, including: (i) the ability to bind to Aβ(42) and reduce plaque formation in the brain in vivo; (ii) interaction with components of the mitochondria respiratory chain resulting in an anti-uncoupling effect; (iii) the capacity to scavenge Aβ(42) monomers present in mitochondria; and (iv) the property of being a
sigma-1 receptor ligand. In vivo,
caprospinol crosses the blood-brain barrier, accumulates in the brain, and restores
cognitive impairment in a pharmacological rat model of AD.
Caprospinol is stable, does not bind to known
steroid receptors, is devoid of mutagenic and genotoxic properties, and is devoid of acute toxicity in rodents. The pharmacokinetics and pharmacodynamics of
caprospinol were studied, and long-term toxicity studies are under investigation, aiming to develop this compound as a disease-modifying
drug for the treatment of AD.