Lessons from failures of current clinical trials in AD suggest that drug like Curcumin is a potential candidate by targeting multiple key pathways like Amyloid-beta (Aβ) accumulation, oxidative stress (OS), Inhibition of β-secretase (BACE), Acetylcholinesterase activity (ACh) and inflammation are necessary to halt the disease progression. The objective of this study was to develop a novel curcumin formulation (NCF) based on solid dispersion strategy that can mitigate its limitation of poor oral bioavailability (only 1% in rats) because of low solubility (0.4 mcg/mL) and susceptibility to degradation at physiological pH, limiting the therapeutic applications.
A number of pharmaceutical carriers were screened based on improvement in solubility and stability of curcumin at pH 1.2, 6.8 and 7.4 buffers to develop NCF. The NCF and crude curcumin were evaluated for in-vitro protection by using MTT assay against cytotoxicity induced by CuSO4 and H2O2 on SY5Y695 cells. The effect on BACE1 and ACh expression in-vitro was also assessed. The pharmacokinetic profile was monitored via oral administration followed by assessing water consumption and safety of NCF after dissolving in drinking water, for 4 weeks with APPSwe/PS1deE9 and SAMP8 mice. The long term safety and effectiveness were compared to crude drug and without treatment (n=12 mice) for 3 months in APPSwe/PS1deE9 and SAMP8 mice by evaluating effect on Aβ deposition, OS, Tau hyperphosphorylation, neuroinflammation, and behavioral deficits, are currently in progress.
From preliminary screening, we identified the best carrier for curcumin to prepare SD, providing >7000 fold improvement in solubility and greater stabilizing effect at all physiological pH. According to MTT assay, NCF showed better protection and safety than crude drug against cytotoxicity induced by CuSO4 and H2O2 on SY5Y695 cells. The cell viability was also improved significantly with NCF when treated at 1-50 μM. In the mechanistic studies, greater down regulator BACE1 and AchE expression was observed. NCF was well tolerated in in vivo study.
Our in vitro study reveals that a novel formulation of curcumin holds promise as a therapeutic agent for AD with superior effectiveness and safety. NCF has great potential to prove in in vivo study and pave the way for its clinical development.
© 2016 Published by Elsevier Inc.