(-)-Oleocanthal Nutraceuticals for Alzheimer’s Disease Amyloid Pathology: Novel Oral Formulations, Therapeutic, and Molecular Insights in 5xFAD Transgenic Mice Model

Abstract

Alzheimer’s disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid S-(–)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. OC also showed positive in vitro, in vivo, and clinical therapeutic effects against cardiovascular diseases, many malignancies, and AD. Due to its pungent, astringent, and irritant taste, OC should be formulated in acceptable dosage form before its oral use as a potential nutraceutical. The objective of this study is to develop new OC oral formulations, assess whether they maintained OC activity on the attenuation of β-amyloid pathology in a 5xFAD mouse model upon 4-month oral dosing use. Exploration of potential OC formulations underlying molecular mechanism is also within this study scope. OC powder formulation (OC-PF) and OC-solid dispersion formulation with erythritol (OC-SD) were prepared and characterized using FT-IR spectroscopy, powder X-ray diffraction, and scanning electron microscopy (SEM) analyses. Both formulations showed an improved OC dissolution profile. OC-PF and OC-SD improved memory deficits of 5xFAD mice in behavioral studies. OC-PF and OC-SD exhibited significant attenuation of the accumulation of Aβ plaques and tau phosphorylation in the brain of 5xFAD female mice. Both formulations markedly suppressed C3AR1 (complement component 3a receptor 1) activity by targeting the downstream marker STAT3. Collectively, these results demonstrate the potential for the application of OC-PF as a prospective nutraceutical or dietary supplement to control the progression of amyloid pathogenesis associated with AD.

Oleocanthal Attenuates Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence by Targeting SMYD2

“…Cells were divided into different treatment groups and exposed to respective control or experimental treatments the next day with various OC or vehicle control concentrations for 24 or 48 h in media. 3-(4,5-dimethylthiazolyl2)-2,5-diphenyltetrazolium bromide (MTT) was applied to quantify the viable cell number at the end of experiment [ 34 , 35 ]. A final concentration of 1.0 mg/mL MTT was added to each well.…”

“…These groups were (i) placebo control and (ii) 10 mg/kg OC administered orally daily by gavage. OC was formulated as powder formulation (PF) for oral dosing, as previously described by this study team [ 35 ]. Briefly, 10 mg OC adsorbed on Aerosil 200 (3 mg) then mixed with Mg stearate (0.5 mg) and Na lauryl sulfate (2 mg).…”

“…Briefly, 10 mg OC adsorbed on Aerosil 200 (3 mg) then mixed with Mg stearate (0.5 mg) and Na lauryl sulfate (2 mg). About 84.5 mg lactose was then added, and all ingredients were uniformly blended to afford OC-PF [ 35 ]. This mixture was then passed over a 40-mesh screen to afford OC-PF [ 35 ].…”

“…About 84.5 mg lactose was then added, and all ingredients were uniformly blended to afford OC-PF [ 35 ]. This mixture was then passed over a 40-mesh screen to afford OC-PF [ 35 ]. Mice were treated orally with either OC-PF or placebo control for 11 days.…”

“…The IHC slides prepared from paraffin-embedded tumor tissue samples were sectioned to 5 μm thick sections at AML Laboratories (Jacksonville, FL, USA). IHC protocol followed our earlier studies [ 35 ]. Following the de-paraffinization in xylene and graded ethanol, sections were boiled in citrate buffer (10 mM sodium citrate, pH 6) for 20 min and then permeabilized in TBST solution for 15 min at 25 °C.…”