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WO2009013506A1 - Cannabidiol destiné à être utilisé dans le traitement d'états neurodégénératifs transmissibles - Google Patents

Cannabidiol destiné à être utilisé dans le traitement d'états neurodégénératifs transmissibles Download PDF

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Publication number
WO2009013506A1
WO2009013506A1 PCT/GB2008/002545 GB2008002545W WO2009013506A1 WO 2009013506 A1 WO2009013506 A1 WO 2009013506A1 GB 2008002545 W GB2008002545 W GB 2008002545W WO 2009013506 A1 WO2009013506 A1 WO 2009013506A1
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Prior art keywords
cbd
cannabidiol
prpres
treatment
cells
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Philip Robson
Joëlle CHABRY
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GW Pharma Ltd
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GW Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings

Definitions

  • the present invention relates to the use of cannabidiol for use in the prevention or treatment of neurodegenerative conditions.
  • the neurodegenerative condition to be prevented or treated is prion disease.
  • Neurodegenerative conditions can be described as the progressive damage or death of neurones.
  • Neurones are nerve cells in the brain whose primary function is to assist in the memory process .
  • the damage or death of neurones leads to a gradual deterioration of the functions controlled by the affected part of the nervous system.
  • Prion diseases are a large group of related neurodegenerative conditions. These diseases affect both animals and humans and have long incubation periods but all typically rapidly progress once clinical symptoms begin.
  • Prion diseases are a unique type of disease in that they can be inherited; they can occur sporadically; or they can be infectious.
  • the infectious agent in the prion disease is composed almost entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein.
  • a prion can be defined as "small proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acids”.
  • the first type of prion disease to be described was scrapie, which is a disease that affects sheep and has been recognised for over 250 years.
  • the disease symptoms are hyperexcitability, itching, and ataxia, which leads on to paralysis and death.
  • the transmission of this disease was first demonstrated in 1943 when a population of Scottish sheep was accidentally inoculated against a common virus using a formalin extract of lymphoid tissue from an animal with scrapie .
  • Prion diseases are often called spongiform encephalopathies because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum.
  • prion diseases Most mammalian species are susceptible to prion diseases, specific examples include: Scrapie, which affects sheep,- TME (transmissible mink encephalopathy) , which affects mink; CWD (chronic wasting disease) , which affects muledeer and elk; and BSE (bovine spongiform encephalopathy), which affects cows.
  • Humans are also susceptible to several different prion diseases: these include: CJD (Creutzfeld-Jacob Disease); GSS (Gerstmann-Straussler-Scheinker) syndrome; FFI: (Fatal Familial Insomnia); Kuru,- and Alpers Syndrome.
  • the incidence of sporadic CJD is about 1 per million per year. GSS occurs at about 2% of the rate of CJD. It is estimated that 1 in 10,000 people are infected with CJD at the time of death. These figures are likely to be underestimates since prion diseases may be misdiagnosed as other neurological disorders .
  • prion diseases are characterised by loss of motor control; dementia; paralysis wasting and eventually death; typically following pneumonia.
  • Visible end results at post-mortem are non-inflammatory lesions, vacuoles, amyloid protein deposits and astrogliosis.
  • GSS is distinct from CJD, it occurs typically in people aged between 30 to 50, and is characterised by cerebellar ataxia and concomitant motor problems, dementia is less common and the disease course lasts several years before death.
  • CJD typically occurs in people aged between 40 and 60, and cerebral involvement makes dementia a more common symptom. Additionally the patient seldom survives a year.
  • FFI pathology is characterised by severe selective atrophy of the thalamus and Alpers syndrome is the name given to prion diseases in infants.
  • Prion diseases are both infectious and hereditary diseases. In addition, they can also be sporadic, in that there are cases in which there is no known risk factor although it seems likely that infection was acquired in one of the two ways listed above.
  • TSEs Transmissible Spongiform Encephalopathies
  • prion diseases in both humans and other mammals are invariably fatal and there is currently no proven treatment.
  • the urgent need to find effective anti-prion therapies has been strengthened by the emergence of variant CJD (vCJD) caused by contaminated beef consumption and the fact that vCJD can be transmitted via blood transfusion.
  • vCJD variant CJD
  • TSE pathogenesis A critical event in TSE pathogenesis is the conversion of the normal protease-sensitive host prion protein (PrPsen) to an aggregated and protease-resistant form, (PrPres) . Both PrP isoforms are required for infection and pathogenesis.
  • PrPres has been recovered in various tissues such as spleen, tonsils and muscles, tissue damage is most severe in the central nervous system (CNS) of the prion affected host. Intra-neuronal vacuolization, severe neuronal cell death, microglia activation and astrogliosis are the main hallmarks of TSEs.
  • PrPres deposits are clearly linked to histopathological lesions. Thus, the presence of PrPres is considered indicative of TSE disease.
  • TSE therapy is the inhibition of PrPres formation in the CNS.
  • BBB blood brain barrier
  • Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids . Synthetic cannabinoids are chemicals with similar structures to plant cannabinoids or endocannabinoids .
  • Cannabinoids possess the characteristics of being cyclic molecules exhibiting particular properties such as the ability to easily cross the BBB, weak toxicity and few side effects. Thus making them of interest as potential anti-prion drugs.
  • Plant cannabinoids can also be isolated such that they are "essentially pure" compounds. These isolated cannabinoids are essentially free of the other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes .
  • Essentially pure compounds have a degree of purity up to at least 95% by total weight.
  • Some essentially pure cannabinoids (whether synthetic or isolated) have been suggested to be neuroprotective agents, either by direct antagonism of the NMDA receptor or by reducing the influx of calcium ions into the cell by another means such as binding with cannabinoid receptors .
  • CBD cannabinoid cannabidiol
  • CBD Cannabidiol
  • CBD increased survival times and inhibited PrPres accumulation in the brains of scrapie- infected mice .
  • CBD cannabidiol
  • a transmissible neurodegenerative disorder is one that can be defined by being capable of transmission by either an infectious agent or by familial means.
  • the transmissible neurodegenerative disorder is a prion disease.
  • references to CBD, particularly with regard to therapeutic use, will be understood to also encompass pharmaceutically acceptable salts of the cannabinoid.
  • pharmaceutically acceptable salts refers to salts or esters prepared from pharmaceutically acceptable nontoxic bases or acids, including inorganic bases or acids and organic bases or acids, as would be well known to persons skilled in the art. Many suitable inorganic and organic bases are known in the art .
  • the scope of the invention also extends to derivatives of CBD that retain the desired activity of the prevention or treatment of neurodegenerative conditions.
  • Derivatives that retain substantially the same activity as the starting material, or more preferably exhibit improved activity may be produced according to standard principles of medicinal chemistry, which are well known in the art. Such derivatives may exhibit a lesser degree of activity than the starting material, so long as they retain sufficient activity to be therapeutically effective. Derivatives may exhibit improvements in other properties that are desirable in pharmaceutically active agents such as, for example, improved solubility, reduced toxicity, enhanced uptake, etc.
  • Known derivatives of CBD include CBDA, CBD-dimethyl heptyl, cannabidivarin (CBDV) , and abnormal CBD .
  • the CBD is an extract from at least one cannabis plant.
  • the CBD extract from at least one cannabis plant is a botanical drug substance.
  • the CBD extract from at least one cannabis plant is produced by extraction with supercritical or subcritical CO 2 .
  • the CBD extract from at least one cannabis plant is produced by contacting plant material with a heated gas at a temperature which is greater than 100 0 C, sufficient to volatilise one or more of the cannabinoids in the plant material to form a vapour, and condensing the vapour to form an extract .
  • the CBD extract from at least one cannabis plant comprises all the naturally occurring cannabinoids in the plant.
  • CBD is in a substantially pure or isolated form.
  • a “substantially pure" preparation of cannabinoid is defined as a preparation having a chromatographic purity (of the desired cannabinoid) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99% and most preferably greater than 99.5%, as determined by area normalisation of an HPLC profile.
  • the substantially pure CBD used in the invention is substantially free of any other naturally occurring or synthetic cannabinoids, including cannabinoids that occur naturally in cannabis plants.
  • substantially free can be taken to mean that no cannabinoids other than CBD are detectable by HPLC.
  • Substantially pure CBD can be prepared from a botanical drug substance.
  • a technique has been established by the applicant and is described in their granted United Kingdom patent, GB2393182.
  • the CBD is in a synthetic form.
  • the CBD is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the invention also encompasses pharmaceutical compositions comprising CBD, or pharmaceutically acceptable salts or derivatives thereof, formulated into pharmaceutical dosage forms, together with suitable pharmaceutically acceptable carriers, such as diluents, fillers, salts, buffers, stabilizers, solubilizers, etc.
  • suitable pharmaceutically acceptable carriers such as diluents, fillers, salts, buffers, stabilizers, solubilizers, etc.
  • the dosage form may contain other pharmaceutically acceptable excipients for modifying conditions such as pH, osmolarity, taste, viscosity, sterility, lipophilicity, solubility etc.
  • diluents, carriers or excipients will depend on the desired dosage form, which may in turn be dependent on the intended route of administration to a patient.
  • Suitable dosage forms include, but are not limited to, solid dosage forms, for example tablets, capsules, powders, dispersible granules, cachets and suppositories, including sustained release and delayed release formulations. Powders and tablets will generally comprise from about 5% to about 70% active ingredient. Suitable solid carriers and excipients are generally known in the art and include, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, etc. Tablets, powders, cachets and capsules are all suitable dosage forms for oral administration.
  • Liquid dosage forms include solutions, suspensions and emulsions .
  • Liquid form preparations may be administered by intravenous, intracerebral, intraperitoneal, parenteral or intramuscular injection or infusion.
  • Sterile injectable formulations may comprise a sterile solution or suspension of the active agent in a non- toxic, pharmaceutically acceptable diluent or solvent.
  • Liquid dosage forms also include solutions or sprays for intranasal, buccal or sublingual administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • dosage forms for transdermal administration including creams, lotions, aerosols and/or emulsions. These dosage forms may be included in transdermal patches of the matrix or reservoir type, which are generally known in the art.
  • compositions may be conveniently prepared in unit dosage form, according to standard procedures of pharmaceutical formulation.
  • the quantity of active compound per unit dose may be varied according to the nature of the active compound and the intended dosage regime. Generally this will be within the range of from O.lmg to 5000mg.
  • CBD cannabidiol
  • neurodegenerative condition is used to describe different groups of conditions and diseases. These groups include but are not limited to: neurodegenerative diseases, ischemic diseases, brain injury or damage and age-related or autoimmune neural degeneration.
  • Neurodegenerative diseases arise when degeneration of the neural pathway occurs as a result of a specific disease.
  • Prion disease is an example of a neurodegenerative disease .
  • Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the central nervous system of the protease-resistant prion protein (PrPres) , a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation.
  • PrPres protease-resistant prion protein
  • Cannabidiol (CBD) was tested in its ability to inhibit PrPres accumulation in both mouse and sheep scrapie-infected cells, along with other structurally related cannabinoid analogs.
  • test articles were also tested by in their ability to limited cerebral accumulation of PrPres and their effect on the survival time of infected mice.
  • Test articles Drugs were dissolved at ICT 2 M in ethanol and stored at -20 0 C until used.
  • Nil microglia were grown in RPMI1640 containing 10% FCS and P/S.
  • Epithelial cells (Rov9) chronically infected with natural sheep scrapie (Rov9sc+) were grown in DMEM supplemented with 10% FCS, P/S and l ⁇ g/tnl doxycycline.
  • Neuroblastoma cells chronically infected with the murine Chandler strain (N2asc+) were grown in Opti-MEM supplemented with 10% FCS, P/S and l ⁇ g/ml G418.
  • PrPres-cured neuroblastoma cells (N2asc-) were obtained by treatment with Congo red (l ⁇ g/ml) for several passages.
  • N2asc+ and Rov9sc+ cells were seeded at 10% confluent density in the appropriate medium and treated with the indicated concentration of drugs for four days (pi) .
  • Control experiments were performed in the presence of ethanol alone, the amount of ethanol being fixed to 1% in all conditions. Cultures were split every four days at a 1:4 dilution and incubated in the presence of the drug for the indicated number of passages.
  • lysis buffer 5OmM Tris-HCl pH 7.4 containing 15OmM NaCl, 0.5% Triton X-100, 0.5% sodium deoxycholate , 5mM EDTA
  • PrPsen one-tenth of a post- nuclear supernatant was mixed with the denaturing loading buffer.
  • PrPres lysates were digested with 20 ⁇ g of proteinase K (PK) /mg of total protein for 30min at 37°C before centrifugation at 20,000xg for 90min.
  • PK proteinase K
  • Pellets were resuspended in denaturing loading buffer, boiled and loaded onto a 12% polyacrylamide gel.
  • Mouse and sheep PrPres were assayed with the SAF83 or SAF70 monoclonal antibodies, respectively. Blots were developed using an enhanced chemoluminescence system (ECL, Amersham) with a LAS3000 detector (Fuji) . To correct for any loading artifact, blots with non-PK digested proteins were re-probed with the anti-Erk antibody.
  • In vivo CBD treatments Tga20 mice, which overexpress murine PrP, and C57BL/6 mice were intraperitoneally (ip) infected with lOO ⁇ l of a 2% homogenate prepared from the brains of terminally ill 139A scrapie-infected C57BL/6 mice.
  • PrnpO/0 mice were infected under the same experimental conditions .
  • Mice were treated ip three times a week for the indicated period of time with 200 ⁇ l of 20 or 60mg/kg CBD diluted 1:1:2 in an ethanol: cremophor: NaCl 0.9% mixture.
  • a control group of scrapie-infected animals was treated only with the vehicle mixture.
  • scrapie-free mice were treated with the higher CBD dose (i.e. 60mg/kg) three times a week for twelve weeks.
  • Mo3F4 (GPINEG) -F3 cells were metabolically labeled with ImCi of Tran35S methionine/cysteine (Perkin Elmer) and Mo3F4 (GPINEG) PrP- sen immunoprecipitated with the 3F4 antibody.
  • reaction buffer (0.75M guanidine hydrochloride, 1.25% sarkosyl, 5mM cetyl pyridinium chloride, 5OmM sodium citrate buffer pH 6.0) for 2 days at 37°C.
  • One tenth of the reaction was methanol precipitated and used to assay the amount of total radiolabeled PrP.
  • the remainder of the reaction was digested with 12 ⁇ g/ml PK for 1 hr at 37 0 C. Proteolysis was stopped by the addition of 1OmM PefablocTM and 400ng of bovine thyroglobulin and proteins were methanol precipitated. Radiolabeled products were analyzed by SDS-PAGE and quantified using the Storm Phosphor Imager system.
  • N2a cells were cultured in the presence of 5 ⁇ M CBD or with ethanol alone then trypsinated and resuspended in PBS pH7.4 supplemented with 0.1% BSA and 0.1% NaN3.
  • cells were fixed in Lyse/Fix Buffer (BD Biosciences) then permeabilized in Perm Buffer III (BD Biosciences) according manufacturer recommendations .
  • Intact or permeabilized cells were incubated with anti-PrP SAF83 antibody (1/200) in PBS-O.1% BSA for 30 min at room temperature and then incubated with Alexa488-conjugated secondary antibody (1/400) .
  • Cells were gated according to size and scatter to eliminate dead cells and debris from analysis. Experiments were repeated three times for consistency.
  • N2a cells were cultured for four passages in the presence of 5 ⁇ M CBD or with ethanol alone then transferred to glass coverslips.
  • coverslips were washed twice with cold PBS and fixed in paraformaldehyde 2% for 10 min at room. After 20 minutes in PBS-5% BSA, each coverslip was incubated for 30 minutes in PBS-5% BSA containing the anti-PrP antibody SAF83 (1/200) . Where indicated, the incubation with primary antibodies was done on permeabilized cells, i.e., in PBS-5%BSA supplemented with 0.1% Triton X-100.
  • Cells were rinsed three times in PBS and then incubated with the appropriate conjugated secondary antibodies (1/200) in PBS-5% BSA. Coverslips were mounted on glass slides containing l ⁇ g/ml diamidino- 4 ' , 6-phenylindol-2 dichlorhydrate (DAPI) to stain nuclei. Cells were observed under a laser scanning confocal microscope (SP5) equipped with a DMIRBE inverted microscope and an argon-krypton laser. Images were acquired as single transcellular optical sections and averaged over at least 4 scans/frame.
  • SP5 laser scanning confocal microscope
  • N2asc+ homogenates (hgtsc+) , used as a source of PrPres, were obtained in detergent-free conditions. The preparation was up to 75% PrPres with a final concentration of about 20pg/ ⁇ l. N2asc- homogenates (hgtsc-) from uninfected cells are PrPres-free and were used as negative controls .
  • Neurotoxicity assay on primary cultures of neurons Cortical neurons from embryonic day- 14 mice were prepared. Cells were plated at a density of 5 x 104 cells/well in 96-well tissue-plastic dishes. Neurons were grown in Neurobasal medium supplemented with B27 and lO ⁇ M cytosine ⁇ -D-arabinofuranoside to prevent glial growth. Cultures used after 6-8 days of differentiation were 95% neurons. Cultures were incubated with the indicated concentration of drug or ethanol alone before the addition of 5 or lO ⁇ l of hgtsc- or hgtsc+ (1 and 2ng/ml PrPres, respectively) . After overnight incubation, microglia were added to neurons in the ratio 1:10.
  • Neuronal viability was determined using the MTS method.
  • Microglia migration assay Neurons (5 x 105 cells/well) plated in 24-wells were incubated with PBS, hgtsc-, or hgtsc+ (0.2ng/ml PrPres) in the absence or presence of
  • CBD for 24h at 37 0 C.
  • Nil microglia were added to the top of a Boyden' s chamber (5 x 10 4 cells/200 ⁇ l) and allowed to migrate through polyester filters for 6h. Cultures were then fixed with 3% paraformaldehyde, stained with Crystal violet and the cells counted (5 random fields/filter) under an inverted microscope .
  • the cannabinoid derivatives belonged to three different groups: endocannabinoids (AEA, AG), natural components of cannabis sativa (THC, CBD) and synthetic non-metabolized molecules (MAFE, RMA) .
  • AEA endocannabinoids
  • THC natural components of cannabis sativa
  • MAFE synthetic non-metabolized molecules
  • N2asc+ and Rov9sc+ cells were treated continuously with 5 ⁇ M of each tested drug over four passages of the cells.
  • PrPres accumulation was dependent on both the number of passages of treated cells and the CBD concentration . Similar effects of CBD were observed on N2asc+ infected with another murine scrapie strain named 22L.
  • CBD is a unique cannabinoid derivative able to strongly prevent PrPres formation, regardless of scrapie strain, in both mouse and sheep scrapie- infected cells.
  • the in vivo PrPres accumulation was also tested. This was investigated by inoculating mice with the 139A murine scrapie strain followed by treatment with 20mg/kg of CBD.
  • mice Forty days post-infection mice were sacrificed and western blot analysis was performed on brain and spleen, these are the crucial organs involved in TSE pathology, in order to detect and quantify the amount of PrPres.
  • PrPres was barely detectable whereas substantial amounts of PrPres were present in the brain of pre-symptomatic untreated control mice .
  • CBD-treatment started at 30 dpi (approximately one- third of the incubation time) . no significant delay in the progression of the disease was observed. During the time course of these experiments, no significant side effects were seen in non- infected, CBD-treated mice.
  • CBD could exert its anti- scrapie effect in vivo either by destabilizing preexisting PrPres aggregates or by preventing PrPres formation.
  • PK-digested homogenates prepared from N2asc+ were incubated with lO ⁇ M of each compound for two days. At the end of the incubation time, the homogenates were assayed for PrPres by western blotting. No difference in the amount of PrPres was observed in cannabinoid-treated N2asc+ homogenates versus untreated homogenates .
  • the cells were treated with AG, CBD or THC over four passages. None of the tested cannabinoids, even CBD, was able to modify PrPsen expression level.
  • Neurons exposed to hgtsc+ for two days were clearly damaged as reflected by the disappearance of normal cell bodies and the presence of fragmented neurites when compared to neurons exposed to the PrPres-free N2asc- homogenate (hgtsc-) .
  • CBD appeared to decrease PrPres-induced neurotoxicity since the number and morphology of the neurons was similar to that observed in cells exposed to hgtsc-. Neuronal viability was also monitored by measuring the reduction of mitochondrial activity using the MTS assay. CBD treatment resulted in a concentration dependent increase in the number of viable neurons for both concentrations of hgtsc+ tested.
  • CBD has been shown to regulate microglia migration it was of interest to determine whether or not CBD could affect this PrPres-induced chemotactic mechanism.
  • the migration of Nil microglia toward a chamber containing neurons incubated with PBS, hgtsc- or hgtsc+ was monitored in the presence of increasing concentrations of CBD.
  • Hgtsc ⁇ exposed neurons induced an increase in the number of migrating microglia compared to hgtsc- and PBS- exposed neurons .
  • CBD did not have in vitro chemotactic properties.
  • CBD was able to impair PrPres-induced microglial cell migration in a concentration-dependent manner .
  • CBD cannabidiol

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Abstract

La présente invention concerne l'utilisation de cannabidiol destiné à être utilisé dans la prévention ou le traitement d'états neurodégénératifs transmissibles. De préférence, l'état neurodégénératif à prévenir ou à traiter est une maladie à prions.
PCT/GB2008/002545 2007-07-24 2008-07-24 Cannabidiol destiné à être utilisé dans le traitement d'états neurodégénératifs transmissibles Ceased WO2009013506A1 (fr)

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GB0714447A GB2451254A (en) 2007-07-24 2007-07-24 Cannabidiol for use in the treatment of neurodegenerative conditions
GB0714447.0 2007-07-24

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WO2009013506A1 true WO2009013506A1 (fr) 2009-01-29

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WO2017093986A1 (fr) * 2015-12-05 2017-06-08 Canabuzz-Med Composition vétérinaire et ses procédés de production et d'utilisation
US9962340B2 (en) 2015-06-09 2018-05-08 Life Tech Global, Llc Device and method for the transdermal delivery of cannabidiol
US10143706B2 (en) 2016-06-29 2018-12-04 Cannscience Innovations, Inc. Decarboxylated cannabis resins, uses thereof and methods of making same
US10499584B2 (en) 2016-05-27 2019-12-10 New West Genetics Industrial hemp Cannabis cultivars and seeds with stable cannabinoid profiles
US11040932B2 (en) 2018-10-10 2021-06-22 Treehouse Biotech, Inc. Synthesis of cannabigerol
US11084770B2 (en) 2016-12-07 2021-08-10 Treehouse Biotech, Inc. Cannabis extracts
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