[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neuroendocrinology 05/2011; 24(1):93-101. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Schizophrenia is a severe, disabling chronic disorder affecting approximately 1% of the population. Improvements and development of more robust and hopefully predictive screening assays for this disease should enhance the identification and development of novel treatments. The present study describes a rapid and robust method for the testing of potential novel antipsychotics by utilising a simplified [(14)C]2-deoxyglucose (2-DG) autoradiography method following memantine-induced brain activation.
Male C57BL/6JCRL mice were given vehicle, ketamine or memantine (10, 20 and 30 mg/kg, subcutaneously (s.c.)) and sacrificed 45 min post-[(14 C)]2-DG administration. In subsequent reversal studies, the memantine challenge was further validated with haloperidol (0.32 mg/kg, s.c.) and clozapine (2.5 and 10 mg/kg, s.c.) in parallel with the ketamine model (Duncan et al. 1998a). Lastly, the effects of an mGlu2/3 receptor agonist, LY404039 (10 mg/kg, s.c.), on both ketamine and memantine-induced brain activation was determined.
Both N-methyl-d-aspartate (NMDA) antagonists dose-dependently induced significant region-specific increases in 2-DG uptake. Interestingly, memantine elicited a considerably greater brain activation signature with a larger dynamic window than ketamine. The "atypical" antipsychotic clozapine significantly reversed memantine-induced 2-DG uptake whilst the "typical" antipsychotic haloperidol was inactive. Pre-treatment with LY404039 fully reversed both the ketamine- and memantine-induced increase in 2-DG uptake without effects on basal 2-DG uptake.
This novel pre-clinical imaging methodology displays potential for the screening of compounds targeting the NMDA receptor hypofunction hypothesis of schizophrenia and should assist in developing compounds from the bench to clinic.
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: As the world's population ages, the incidence of Alzheimer's disease (AD) is projected to double every 20 years. Understanding the pathogenesis of AD and developing effective treatments is a public health imperative. Memantine is a low- to moderate-affinity, non-competitive NMDA receptor antagonist that is currently approved for the treatment of moderate to severe AD. AREAS COVERED: We discuss the current evidence, emphasizing more recent studies examining the effects of memantine in AD. We also look at the gaps in the current knowledge; the studies that will be required to fill these gaps are also discussed. The present paper reviews: the pharmacology of memantine; evidence for its use in moderate to severe AD, as well as in mild to moderate AD; adverse events related to memantine use; its effects specifically on behaviours including aggression and agitation; the pharmacoeconomics of memantine; and the use of memantine in other dementias. Memantine has shown modest benefits in cognition, function, global and behavioural measures, and has shown little potential for drug-drug interactions. EXPERT OPINION: For the treatment of moderate to severe AD, memantine should be offered as a therapeutic option, either on its own, or in combination with a cholinesterase inhibitor.
Expert Opinion on Pharmacotherapy 04/2011; 12(5):787-800. · 2.86 Impact Factor
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