US20160250274A1 - Protective Effects of Oil Palm Composition on Alzheimer's Disease - Google Patents

Protective Effects of Oil Palm Composition on Alzheimer's Disease Download PDF

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US20160250274A1
US20160250274A1 US15/028,265 US201415028265A US2016250274A1 US 20160250274 A1 US20160250274 A1 US 20160250274A1 US 201415028265 A US201415028265 A US 201415028265A US 2016250274 A1 US2016250274 A1 US 2016250274A1
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composition
opp
amyloid
alzheimer
disease
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Robert P. Weinberg
ChoKyun Rha
Anthony J. Sinskey
Yew Ai Tan
Ravigadevi Sambanthamurthi
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Palm Oil Research and Development Board
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding

Definitions

  • the present invention relates to a composition with protective effects treating Alzheimer's disease. More particularly, relates to the use of palm oil-based phenolics in impeding ⁇ -amyloid peptide aggregation.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • Amyloid hypothesis discloses the pathogenesis of AD to be essentially-related to beta amyloid peptide (BAP) (MW 4514 Da).
  • BAP beta amyloid peptide
  • Amyloid beta is a peptide composed of 36-43 amino acids, which is processed from a transmembrane cellular glycoprotein amyloid precursor protein (APP).
  • APP transmembrane cellular glycoprotein amyloid precursor protein
  • An autosomal dominant mutation in the APP results in a hereditary form of early-onset Alzheimer's disease, with increase in amyloid beta peptide.
  • the amyloid beta peptide can form dimers which are quite toxic to neurons.
  • Amyloid beta precursor protein APP
  • Trisomy 21 patient with Down's syndrome
  • APP amyloid beta precursor protein
  • APOE4 inheritable AD
  • This allelotype results in an excessive accumulation of beta amyloid in the brain, preceding the very early appearance of AD at only 40 years of age.
  • Another research on transgenic mice expressing a mutation of the human APP gene shows that these mice develop fibrillar deposits of amyloid peptide in the brain and develop Alzheimer's-like neuropathology with specific spatial learning deficits.
  • the APP protein located transmembranal within plasma membrane and spanned from cytoplasm into the surrounding extracellular space.
  • Post-translational processing of APP involves several secretase enzymes to cleave APP into smaller polypeptides. It is normal for a healthy person to have some beta amyloid peptide in his/her cerebrospinal fluid (CSF) and bloodstream as these peptides may diffuse out or be actively transported out from the brain; however people with AD have a pathologic accumulation of the beta amyloid peptide within their brains and are unable to excrete the peptide from the brain.
  • CSF cerebrospinal fluid
  • FIG. 2 shows the pathologic appearance of beta amyloid peptide in the brain of persons with AD.
  • the beta amyloid peptide aggregates into fibrils and becomes deposited as insoluble precipitate in senile neuritic plaques, which may be stained histochemically and be detected using magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • Amyloid beta found to be the primary constituent of fibrils in the extraneuronal senile neuritic plaques of Alzheimer's patients' brains. It is believed that the mature fibrils of A ⁇ peptide are not neurotoxic per se, but may serve as a reservoir of small, diffusible soluble oligomers of A ⁇ . It has been shown that cortical levels of soluble A ⁇ correlate with both the extent of synaptic loss and severity of the clinical symptoms.
  • a ⁇ 40 and A ⁇ 42 are two common isoforms of the peptide where A ⁇ 42 is more fibrillogenic, aggregates more quickly, and higher toxicity especially in the dimer state. A ⁇ has little toxicity while in the monomeric state. Therefore, inhibiting formation of soluble A ⁇ dimers will nullify the neurotoxicity and be effective in preventing and/or treating Alzheimer's disease.
  • soluble A ⁇ dimers to rodent hippocampal slices will potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD), and reduce the neuronal dendritic spine density in the normal rodent hippocampus. These soluble A ⁇ dimers are also known to interfere with memory of learning behavior in rodents' brains.
  • Shankar's lab showed that the level of soluble A ⁇ -dimers is correlated to the clinical Alzheimer's disease state and the degree of progression of the dementia. It is known that the hippocampus is important in memory formation and consolidation, the pathologic appearance of amyloid plaques correlates well with the progression of Alzheimer's disease and the concomitant memory and cognitive losses. Clearance of these soluble A ⁇ dimers from the brain will ameliorate the cognitive deficits.
  • researchers have theorized that dementia is resulted from clearance of soluble A ⁇ dimers in the brain.
  • soluble A ⁇ dimers interfere with glutamatergic synaptic transmission, where mGluRs are necessary for LTD induction.
  • oligomeric A ⁇ are the neurotoxic species which cause the cognitive losses of Alzheimer's disease.
  • oligomeric A ⁇ have also been called A ⁇ -derived diffusible ligands (ADDLs).
  • ADDLs A ⁇ -derived diffusible ligands
  • a ⁇ dimers at subnanomolar concentrations directly induce Tau hyperphosphorylation, disruption of the microtubule cytoskeleton and neuritic degeneration in the rat hippocampus.
  • Others have demonstrated that A ⁇ oligomers induce key characteristics of the AD phenotype including dendritic spine loss, altered hippocampal synaptic plasticity, and impaired memory for learned behaviors.
  • small soluble oligomers of A ⁇ underlie the key phenotypic characteristics of Alzheimer's disease is supported by experimental data showing that these small soluble oligomers may: (1) cause synaptic loss and decreased dendritic spine density; (2) cause hyperphosphorylation of tau proteins with resulting intraneuronal neurofibrillary tangles and collapse of the neuritic cytoskeleton; (3) memory impairment and cognitive losses in the absence of amyloid plaques.
  • AD diagnosis can be done; some of the examples are behavioral and cognitive testing, and an MRI of the brain.
  • the presence of senile plaques in brain MRI is the indicator used in diagnostic of AD.
  • These senile plaques are composed of fibrils of polymerized and precipitated beta amyloid.
  • the aggregated oligomers and fibrils formed are neurotoxic and can caused neuronal cell death, thus it is speculated to be key events in the pathogenesis and progression of AD.
  • Some therapeutic strategies include but not limited to: (1) decreasing proteolytic production of A ⁇ through ⁇ -secretase inhibitors which block the first cleavage of APP in extracellular; (2) ⁇ -secretase inhibitors which block the second cleavage of APP in the cell membrane; (3) increasing the clearance of soluble A ⁇ dimers through immunotherapy to induce antibody formation to amyloid beta; and (4) anti-aggregation drugs to inhibit the aggregation and polymerization of amyloid beta peptide.
  • Natural agents such as apple procyanidins, grape-derived polyphenols, Resveratrol and polyphenol curcumin (diferuloylmethane) are found to be inhibiting A ⁇ aggregation.
  • Other polyphenol compounds which inhibit ⁇ -amyloid aggregation include: tannic acid, nordihydroguaiaretic acid, curcumin, rosmarinic acid, kaempferol, ferulic acid, (+)-catechin, ( ⁇ )-epicatechin, and tetracycline.
  • Blueberry-enriched polyphenols have been shown to prevent synaptic failure and adenosine triphosphate imbalance.
  • Flavonoids are also shown to have anti-aggregatory properties, examples like myricetin, chrysin, fisetin (3,3′,4′,7-tetrahydroxyflavone), 3′,4′,7-trihydroxyflavone, 3,3′,4′-trihydroxyflavone, 3,3′,7-trihydroxyflavone, 5-deoxykaempferol and synthetic derivatives.
  • the glycosaminoglycan homotaurine (3-aminopropanesulfonic acid) also has anti-aggregation properties, however this compound has failed Phase III clinical trials in US and therefore it is no longer in use clinically.
  • Oil palm ( Elaies guineensis ) has demonstrated various biological effects in treating diseases and improving health condition using palm oil and other palm-based materials such as palm oil vegetation liquor and oil palm phenolics.
  • Oil palm phenolics is a complex aqueous derived from plant which mainly comprises polyphenol compounds, shikimic acid, oligosaccharides, and lipid.
  • gallic acid, protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid, syringic acid, p-coumaric acid and ferulic acid are also presence in OPP through high-performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LS/MS/MS) analyses.
  • HPLC high-performance liquid chromatography
  • MS/MS/MS liquid chromatography-tandem mass spectrometry
  • the major polyphenol compounds are protocatechuic acid, p-hydroxybenzoic acid, 3-caffeoylshikimic acid, 4-caffeoylshikimic acid, and 5-caffeoylshikimic acid. These polyphenol compounds are known to have significant antioxidant properties as assayed by the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay as well as the GAE (Gallic Acid Equivalent) assays.
  • Present invention discloses OPP containing some active compounds that inhibit the aggregation of amyloid beta peptide and thus reduce the polymerization of the peptide. This inhibition may cause the beta amyloid peptide to remain in the soluble monomeric state and facilitate the clearance of the peptide from the brain via the normal physiologic mechanisms. Therefore, it is an object of present invention to provide a compound in preventing or slowing the progression of Alzheimer's disease.
  • Present invention discloses a composition comprising oil palm phenolics (OPP), wherein said composition is useful in preventing or treatment of Alzheimer's disease and diseases related thereto.
  • OPP oil palm phenolics
  • the composition is useful in impeding aggregation of ⁇ -amyloid into neurotoxic A ⁇ -dimer.
  • the composition is also useful in impeding polymerization of ⁇ -amyloid, impeding folding of ⁇ -pleated sheet secondary structure in ⁇ -amyloid peptide and inhibiting kinetic accumulation of the ⁇ -pleated sheet amyloid peptide.
  • Present invention can be used in preparation of a medicament in a therapeutic effective amount for prevention or treatment of Alzheimer's disease and diseases related thereto in an individual in need thereof, which may be administered orally, conventional treatment forms, pharmaceutical formulations, nutritional supplement or as nutraceutical supplement.
  • FIG. 1 shows the processing of beta amyloid peptide in the brain from amyloid precursor protein (APP);
  • FIG. 2 shows the senile neuritic plaques of beta amyloid
  • FIG. 3 shows the effect on molecular weights of beta amyloid peptide over time after treatment with oil palm phenolics (OPP);
  • FIG. 4 a shows the effect on beta amyloid peptide aggregation after treatment without OPP
  • FIG. 4 b shows the effect on beta amyloid peptide aggregation after treatment with OPP
  • FIG. 5 shows the fluorescence spectrogram of OPP at wavelength of 535 nm
  • FIG. 6 shows the Congo red dye binding curve at various concentrations of OPP
  • FIGS. 7 a and 7 b show the amide-I two-dimensional correlation spectra of the beta-amyloid samples incubated at 37° C. without OPP for 1 hour and 10 hours respectively;
  • FIG. 7 c shows the amide-I two-dimensional correlation spectra of the beta-amyloid samples incubated at 37° C. with OPP for 10 hours.
  • OPP oil palm phenolics
  • OPP is a vegetation liquor which is prepared from the oil-bearing palm fruit ( Elaeis guineensis ), by a proprietary method established by the Malaysian Palm Oil Board (MPOB) as described in the U.S. Pat. No. 7,387,802. Briefly, oil palm fruits are crushed and squeezed mechanically, followed by removal of undissolved solids, oleaginous parts, colloids and higher molecular weight molecules from the remaining vegetation liquor which is an aqueous fraction containing phytochemicals.
  • Oil palm phenolics comprise phytochemicals include but not limited to polyphenols, flavonoids, phenolic acids, hydroxyl acids, oligosaccharides, lipids (fatty acids and oils), shikimic acid and metal ions.
  • Predetermined amount of lyophilized ⁇ -amyloid powder was redissolved in 50 ml of DMSO (dimethylsulfoxide) and 950 ml of PBS (phosphate-buffered saline, 10 mM, pH 7.4).
  • Predetermined amount of lyophilized Ab42 powder was pretreated and resolubilized with 69.5 ⁇ l of a mixture comprising of CH 3 CN/300 mM Na 2 CO 3 /250 mM NaOH (48.3:48.3:3.4, v/v/v).
  • the resulting alkaline Ab42 solution (500 ⁇ M) was diluted 1:10 with phosphate buffer (10 mM, pH 7.7) containing NaCl (11 mM) to obtain a 50- ⁇ M Ab42 solution at pH 8.0 and NaCl concentration of 10 mM.
  • the final assay conditions were as follows: 50 ⁇ M Ab42 in phosphate buffer (8.7 mM) containing 10 mM NaCl, 14.5 mM Na 2 CO 3 , 0.85 mM NaOH, and 8.2% ACN (acetonitrile, pH 8.0). The Ab42 solutions were incubated at 30° C. without any stirring. Analyses were then performed at selected times.
  • Thioflavin-T (ThT)-based fluorometric assays were performed with a spectrofluorometer using 96-well microtiter plates.
  • the solution containing Ab42 (50 ⁇ M) or Ab42 in the presence of ThT (1.5 ⁇ M) up to a final volume of 2.0 ml is subjected to time scan in spectroflurometer after incubation.
  • the fluorescence intensity values at the plateau (300 s) were averaged after subtracting the background fluorescence from 1.5 ⁇ M ThT and tested compound.
  • ThT is a well-known and well-used assay for beta amyloid peptide aggregation, it is not possible to be used with OPP due to its strong fluorescent signal that overlaps with fluorescent signal from ThT. Thus ThT experiments were performed to examine the kinetics of beta amyloid peptide aggregation in the absence of OPP.
  • the stock solution of Ab42 (50 ⁇ M) was added into predetermined amount of OPP or phosphate buffer before diluted to a final concentration of 10 ⁇ M.
  • the mixture is incubated and added with 6 ⁇ L of Congo Red dye.
  • the Congo Red binding assays were performed with microplate reader and 96-well microtiter plates. The absorption readings were monitored at both wavelength of 492 nm and 540 nm, this is because the spectral shift occurs when Congo Red is bound to aggregated beta amyloid peptide. The data is then used to generate a bound Congo Red curve as described later on.
  • Mass spectroscopy is useful in detecting and quantitating the molecular weights of polypeptides and their aggregates. The location and size of the peaks observed correlate well with the molecular weight and the quantity of substance present.
  • the analysis was performed by spotting on the target plate with 1.0 ⁇ l of the sample mixed with an equal volume of the matrix solution, 10 mg/ml sinapinic acid, in CH 3 CN/H 2 O (50:50, v/v) containing 0.1% (v/v) trifluoroacetic acid. 10 ⁇ l of the sample was C4 ziptipped, eluted in 1 ⁇ l of 70% ACN (acetonitrile), mixed with 1 ⁇ l of matrix, spotted, and allowed to air dry.
  • MALDI-TOF matrix-assisted laser desorption ionisation-time of flight mass spectrometry analyses were performed using a MALDI-TOF mass spectrometer equipped with a pulsed nitrogen laser operating at 337 nm. Small oligomer positive ion spectra were acquired in linear mode over an m/z range from 2000 to 50,000 using a 20-kV accelerating voltage and a 150-ns delay extraction time. The spectrum for each spot was obtained by averaging the results of 200 laser shots.
  • Amyloid-beta samples were prepared in D2O at a concentration of 10 mg/ml and buffered to a final pH of 7.4 in a 10 mM deuterated phosphate and held between CaF2 windows in a 50 ⁇ m path-length cell. Spectra were collected in the perpendicular (ZZYY) polarization geometry to enhance the intensity of the cross peak.
  • beta-sheets are characterized by the presence of two peaks centered near 1620 and 1680 cm ⁇ 1 , whose individual amide oscillators vibrate in-phase perpendicular ( ⁇ ⁇ ) or parallel ( ⁇ ⁇ ) to the ⁇ -strands, respectively.
  • the splitting between these modes and the frequency of ⁇ ⁇ in particular are related to the size of the folded ⁇ -sheet.
  • ⁇ ⁇ perpendicular
  • ⁇ ⁇ parallel
  • the ⁇ ⁇ peak is masked by a strong diagonal peak at 1672 cm ⁇ 1 , arising from the carbonyl stretch in tetrafluoroacetic acid (TFA), a compound used to cleave the peptide during the solid-state synthesis.
  • TFA tetrafluoroacetic acid
  • TFA is particularly difficult to remove since lyophillization causes beta-amyloid aggregation. Since TFA does not have any other transitions in the CO stretching region, the off-diagonal features observed in the spectrum are only possible to cause by ⁇ -sheet structure. This describes the ability of 2DIR spectroscopy in extracting structural information even when the IR transitions of interest are masked by other species present in solution.
  • the three spectra shown in FIGS. 7 a, b and c are corresponded to the amyloid-beta sample incubated for a period of 1 hour and 10 hours at 37° C. in the absence of OPP, as well as incubated with OPP for 10 hours at 37° C. respectively.
  • the increase in amplitude relates to an overall increase in ⁇ -sheet content of the sample as well as the increase in growth of ⁇ -fibrils in within the sample.
  • FIG. 7 c shows sample incubated with OPP resulting in a very small cross peak even after incubation for 10 hours.
  • the diagonal peaks associated with ⁇ -sheet become significantly broader and signal near the 1650 cm ⁇ 1 region increases.
  • Part of the spectrum is associated with helical and random-coil conformations, the absence of signal in FIG. 7 c suggesting that OPP disrupts the secondary structure of amyloids, and thus preventing the formation of ⁇ -fibrils.
  • the 2DIR spectrum correlates the frequency of initial vibrational excitation ( ⁇ l ) with a final detection frequency ( ⁇ 3 ).
  • the frequencies of diagonal peaks can be assigned to chemically distinct vibrational modes.
  • the presence and splitting of cross-peaks characterizes the anharmonic coupling of the vibrations and helps decompose congested spectra.
  • Present invention concentrates on the diagonal and cross-peaks between two vibrational bands of ⁇ -sheets ( ⁇ ⁇ and ⁇ ⁇ ), whose individual amide oscillators vibrate in-phase perpendicular or parallel to the ⁇ -strands, respectively.
  • the splitting between these modes and the frequency of ⁇ ⁇ in particular are indicators of the size of the folded ⁇ -sheet and provide an important signature in transient experiments.
  • Absorptive spectra were acquired with parallel (ZZZZ) and perpendicular (ZZYY) probing polarizations.
  • ZZZZ parallel
  • ZZYY perpendicular
  • the overtone transition lies below the fundamental along the ⁇ 3 axis because of the anharmonicity of the vibrational potential.
  • the ⁇ ⁇ and ⁇ ⁇ modes have nearly orthogonal transition moments where the cross-peaks are small in the parallel polarization geometry but are enhanced and form a cross-peak ridge in the upper left corner in the perpendicular polarization geometry. Loss of negative intensity (a positive change) in the lower right corner also indicates the presence of a positive cross-peak in this region.
  • the overall Z-shape of the perpendicular spectrum which arises from interference effects between ⁇ ⁇ and ⁇ ⁇ diagonal and cross-peaks, is a characteristic signature of the ⁇ -sheet structure.
  • the mass spectrograms show that the beta amyloid peptide tend to spontaneously form aggregates consisting of dimers, trimers, tetramers, pentamers and higher order aggregates.
  • the presence of OPP impedes the aggregation process of beta-amyloid peptide, and mostly the monomer beta amyloid peptide is observed without the higher order aggregates.
  • the molecular weights of the beta amyloid peptide and its aggregates with or without the presence of OPP are shown in FIG. 3 .
  • FIGS. 4 a and 4 b show the raw data mass spectrograms of beta amyloid peptide aggregation assay generated from the MALDI-TOF apparatus.
  • FIG. 4( a ) shows beta amyloid peptides are aggregated up to septamers with molecular weight of 31.5 kDa (7 peptides) in the absence of OPP, whereas in FIG. 4( b ) only the monomer (4.5 kDa) of beta amyloid is observed in the presence of OPP.
  • Beta amyloid peptide is incubated in PBS at 37° C. and maintained at pH 7.4.
  • FIG. 4( a ) shows the aggregates of several molecular size forms, i.e. dimers, trimers, pentamers, hexamers and septamers, whereas in FIG. 4( b ) addition of OPP at a concentration of 0.9 mg/ml into the previous condition inhibits the peptides from aggregating and remains in the monomeric form.
  • the mass spectroscopy data clearly shows that the presence of OPP will inhibit the aggregation and polymerization of beta amyloid peptide.
  • Thioflavin-T assay is performed to observe the normal aggregation kinetics of the beta-amyloid peptide in the absence of OPP.
  • FIG. 5 shows a spectrogram of titrated concentrations of OPP fluorescing at a wavelength of 535 nm as similar to many antioxidant polyphenols.
  • OPP The fingerprinting analysis of OPP (Sambandan et al.) reveals 5 “signature” polyphenols present in OPP. These include p-hydroxybenzoic acid, protocatechuic acid, and 3 structural isomers of caffeoylshikimic acid. Based upon their spectroscopic properties, these 5 polyphenol components of OPP most probably account for the strong autofluorescence observed at a wavelength of 535 nm.
  • the Congo Red assay is based on the spectral shift occurs in the absorption of Congo Red bounded to beta amyloid peptide aggregates or fibrils at 2 different reference wavelengths.
  • the dilution of OPP is directly proportional to the amount of Congo Red bound to the peptide aggregates and oligomers.
  • An inverse linear relationship between the amount of OPP solids and the quantity of beta amyloid aggregates can be observed.
  • the degree of Congo Red binding relates to beta amyloid peptide aggregation, also show that OPP inhibits the aggregation and polymerization of beta amyloid peptide.
  • IC 50 provides a good indication for the efficacy of inhibiting beta amyloid peptide aggregation by OPP. Based on FIG. 6 OPP inhibition of Congo Red binding data, the IC 50 is 1.29 mg/ml of total solids by dry weight, at which point 23.22% of Congo Red is bound to aggregates.
  • Congo Red dye binds directly to the beta amyloid peptide and resulting in spectral shift when Congo Red bounded to aggregated peptide as opposed to monomeric peptide.
  • FIGS. 7 a , 7 b and 7 c show the Amide-I two-dimensional correlation spectra of the beta-amyloid samples incubated at 37° C. with and without OPP.
  • the diagonal peak at 1672 cm ⁇ 1 is due to tetrafluoroacetic acid (TFA) present in the sample.
  • FIG. 7 c shows broader peaks and a weaker cross peak which indicates lower beta-fibril content.
  • OPP is shown to substantially impeding the aggregation of A ⁇ peptide into dimers by Mass Spectroscopy, 2DIR spectroscopy and Congo Red dye binding assay.
  • the active phytochemical agents in OPP that are useful in inhibiting formation of neurotoxic A ⁇ -dimers in present invention should not be limited to one type.
  • the IC 50 (half-maximal inhibition) for OPP against beta amyloid peptide aggregation is approximately 1.29 mg/ml.
  • the usual concentration of OPP is 9.0% solids, thus the concentration of solids is 90 mg/ml.
  • the IC 50 of 1.29 mg/ml is therefore a dilution of 1.43% of OPP (or a 1:70 dilution of the OPP).
  • FIG. 4 shows the efficiency of OPP in impeding beta amyloid peptide aggregation where amyloid-beta peptide aggregates and polymerize in the absence of OPP ( FIG. 4 a ) and amyloid-beta peptide remains monomeric in the presence of OPP ( FIG. 4 b ).
  • the 2DIR spectroscopy also discloses the efficiency of OPP in inhibiting ⁇ -amyloid peptide from misfolding into beta-pleated sheets on secondary structure.
  • OPP kinetic accumulation of the beta-pleated sheet amyloid peptide is shown in 2DIR spectroscopy, whereas in the presence of OPP there is no formation of beta-pleated sheet structures.
  • Efficacy in maintaining beta amyloid peptide in soluble form and preventing peptide from aggregating into insoluble polymers or fibrils may be important feature for a drug in prevention or treatment of Alzheimer's disease.
  • the peptides maintained in soluble form would allow excretion with body's normal clearance mechanisms before it could fibrillize into the senile neuritic plaques, and therefore preventing occurrence of Alzheimer's disease.
  • OPP binds to beta amyloid peptide, and prevents the hydrogen-bonding and hydrophobic interactions from polymerizing peptide in forming aggregated fibrils. 2DIR spectroscopic are conducted to elucidate the secondary and tertiary structure of this interaction between OPP and beta amyloid peptide.
  • the study of kinetics of aggregation for the 42-amino acid ⁇ -amyloid peptide shows that (1) OPP impede ⁇ -amyloid monomers from aggregating and polymerizing into larger aggregates as shown by the decrease in molecular weights measured on Mass Spectroscopy; (2) OPP inhibit binding of Congo Red dye to ⁇ -amyloid peptide as shown by the decrease in Congo Red dye binding to aggregated ⁇ -amyloid peptide; (3) OPP impede folding of ⁇ -pleated sheet secondary structures, as revealed by 2DIR Spectroscopy.
  • OPP soluble ⁇ -amyloid dimers and oligomers cause extensive pathologic changes in neurons, decrease dendritis spine density, and cause depression of long-term potentiation in neurons and enhancement of long-term depression. Therefore, the inhibitory, anti-aggregatory, and antifibrillogenic properties of OPP may lead to the development of a potential drug for the prevention or treatment of Alzheimer's disease.
  • composition as disclosed in present invention may be provided as compounds with pharmaceutically acceptable carriers.
  • Present invention further discloses the use of therapeutically effective amount of a composition in the preparation of a medicament for preventing or treatment of Alzheimer's disease or disease related thereto in an individual by administering to an individual in need thereof.
  • the composition may be administered orally, conventional treatment forms, pharmaceutical formulations, nutritional supplement or as nutraceutical supplement.

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MY179462A (en) 2020-11-06
US20220387542A1 (en) 2022-12-08
EP3057437A1 (fr) 2016-08-24
US11517607B2 (en) 2022-12-06
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BR112016008035A2 (pt) 2017-08-01

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