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WO2008129529A2 - Cannabinoïde pour le traitement des lésions neuronales chez les patients diabétiques - Google Patents

Cannabinoïde pour le traitement des lésions neuronales chez les patients diabétiques Download PDF

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Publication number
WO2008129529A2
WO2008129529A2 PCT/IL2008/000477 IL2008000477W WO2008129529A2 WO 2008129529 A2 WO2008129529 A2 WO 2008129529A2 IL 2008000477 W IL2008000477 W IL 2008000477W WO 2008129529 A2 WO2008129529 A2 WO 2008129529A2
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Prior art keywords
diabetic
tetrahydrocannabinol
hyperglycemia
cells
neuronal damage
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Ceased
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PCT/IL2008/000477
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WO2008129529A3 (fr
Inventor
Elliot Berry
Raphael Mechoulam
Yosefa Avraham
Yossi Dagon
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Yissum Research Development Co of Hebrew University of Jerusalem
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Yissum Research Development Co of Hebrew University of Jerusalem
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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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention provides for the use of an effective amount of at least one cannabinoid for the manufacture of a pharmaceutical composition for alleviating neuronal damage due to hyperglycemia, or for treating neuronal damage in a diabetic subject.
  • Diabetes mellitus is a heterogeneous metabolic disorder characterized by chromic hyperglycemia due to a deficiency (type 1) or resistance (type 2) to insulin (Zimmet et al., 2001).
  • type 1 chromic hyperglycemia due to a deficiency
  • type 2 resistance
  • type 2 type 2 to insulin
  • DN central nervous system neuropathy
  • DN diabetic encephalopathy
  • cannabinoids exert neuroprotective effects in animals as well as in vitro models of various forms of acute neuronal injury, such as cerebral ischaemia, traumatic brain injury, neurodegenerative diseases, and Huntington's disease (Grundy et al., 2001 ; Baker et al., 2003). Recently, the neuroprotective actions of cannabidiol and other cannabinoids were shown in cultured cortical neurons to be mediated by a potent antioxidative effect which was receptor independent (Hampson et al., 1998). Studies in animal models of focal cerebral ischemia suggest that the antioxidative effect of cannabinoids was at least as effective in vivo as found in vitro (Hampson et al., 2000).
  • the present invention is based on the finding of neuroprotective effects of cannabinoids in experimental models of diabetes - in vivo and in vitro.
  • the synthetic cannabinoid agonist HU-210 which is the f+)-1 ,1-dimethylheptyl analog of 7-hydroxy- de/ta-6-tetrahydrocannabinol of the formula:
  • the present invention is based on the finding that the synthetic cannabinoid, HU-210 was capable of alleviating the oxidative damage and cognitive impairment, in streptozotocin (STZ)-induced diabetic mice, without affecting glycemic parameters.
  • the present invention is further based on the finding that HU-210 was able to alleviate hyperglycemia -induced oxidative stress and cellular injuries in PC 12 cells.
  • the present invention is further based on the finding that isolated THC was able to improve brain function in diabetic mice.
  • the present invention is directed to the use of an effective amount of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) and HU-210 for the manufacture of a pharmaceutical composition for alleviating neuronal damage due to hyperglycemia, wherein HU-210 is the (+)-1 ,1-dimethylheptyl analog of 7-hydroxy-de/t ⁇ -6-tetrahydrocannabinol of the formula:
  • the present invention further concerns the use of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) and HU-210 for alleviating neuronal damage due to hyperglycemia, wherein HU-210 is the (+M ,1-dimethylheptyl analog of 7-hydroxy-de/t ⁇ -6-tetrahydrocannabinol of the formula
  • the present invention is also directed to the use of an effective amount of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) and HU-210 for the manufacture of a pharmaceutical composition for treating neuronal damage in a diabetic subject, wherein HU-210 is the (+)-1,1-dimethylheptyl analog of 7-hydroxy-cfe/t ⁇ -6-tetrahydrocannabinol of the formula:
  • the present invention further concerns the use of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) HU-210 for treating neuronal damage in a diabetic subject, wherein HU-210 is the (+)-1 ,1- dimethylheptyl analog of 7-hydroxy-de/fa-6-tetrahydrocannabinol of the formula
  • a method for alleviating neuronal damage due to hyperglycemia comprising: administering an effective amount of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) and HU-210 wherein HU-210 is the (+)-1 ,1-dimethylheptyl analog of T-hydroxy-cfe/fa- ⁇ -tetrahydrocannabinol of the formula:
  • the present invention also provides a method for treating neuronal damage in a diabetic subject the method comprising: administering to a subject in need of the treatment a therapeutically effective amount of at least one cannabinoid selected from the group consisting of isolated Tetrahydrocannabinol (THC) and HU-210 and Tetrahydrocannabinol (THC), wherein HU-210 is the (+J-1,1-dimethylheptyl analog of 7- hydroxy-de/t ⁇ -6-tetrahydrocannabinol of the formula:
  • hypoglycemia refers to elevated glucose levels, as compared to the levels neurons are exposed to under normal physiological conditions
  • the hyperglycemia is the result of diabetic mellitus type 1
  • the hyperglycemia is the result of diabetic mellitus type 2.
  • the "neuronal damage” may be central (diabetic encephalopathy) and is mainly measured by electrophysiological and structural changes and limitations in the cognitive functioning of the subject.
  • the neuronal damage may also be peripheral (diabetic neuropathy), affecting the peripheral nerves, and is manifested by numbness, pain, tingling in the feet, double vision or drooping eyelids, or weakness and atrophy of the thigh muscles.
  • diabetic neuropathy may lead to problems in the digestive tract and sexual organs, which can cause indigestion, diarrhea or constipation, dizziness, bladder infections, and impotence.
  • the loss of sensation in the feet may increase the possibility of foot injuries going unnoticed, and which then would develop into ulcers or lesions that become infected.
  • the neuronal damage is for motor weakness which is equivalent to NSS but affecting both sides of the body, and which condition is determined by placement tests to test for proprioception and position.
  • the neuronal damage may also be evident by instability in blood pressure and heart rate.
  • treating refers the any one of the following: improving at least one undesired symptom of neuronal damage (peripheral or central as defined above); halting the deterioration in the neuronal function as compared to an untreated control; slowing down the rate of deterioration in the neuronal damage as compared to an untreated control; preventing the deterioration of some manifestation of the neuronal damage before it occurs.
  • THCJ Tetrahydrocannabinol
  • compositions of the present invention can be provided in any form known in the art, for example in a form suitable for oral administration (e.g., a solution, a suspension, a syrup, an emulsion, a dispersion, a suspension, a tablet, a pill, a capsule, a pellet, granules and a powder), for parenteral administration (e.g., intravenous, intramuscular, intraarterial, transdermal, subcutaneous or intraperitoneal), for topical administration (e.g., an ointment, a gel, a cream), for administration by inhalation or for administration via suppository.
  • oral administration e.g., a solution, a suspension, a syrup, an emulsion, a dispersion, a suspension, a tablet, a pill, a capsule, a pellet, granules and a powder
  • parenteral administration e.g., intravenous, intramuscular, intraarterial, transdermal
  • the preferred mode of administration is sublingual, preferably by administering 5 mg THC twice a day sublingually in an olive oil solution (5 mg in 0.2 ml oil).
  • mice were injected i.p. with 200 mg/kg STZ. 8 weeks later, 0.1 mg/kg HU-210 was administered daily for 5 days.
  • A Performance in an eight arm maze was recorded every day after the HU-210 treatment.
  • B Neurological score was evaluated after the HU-210 treatment.
  • C Performance in an eight arm maze after co-administration with 0.1 mg/kg HU-210 and 5 mg/kg SR141716A.
  • D Neurological score evaluation after co-administration with 0.1 mg/kg HU-210 and 5 mg/kg SR141716A.
  • the figures represent 3 independent experiments. Values were calculated as described in Materials and Methods.
  • PC12 cells (2x10 4 ) were seeded in a medium containing 8% FBS+ 8% HS. The cells were exposed to 27 g/L glucose and treated with vehicle or 5-20 ⁇ M HU-210 for up to 72 h. WST-1 was supplemented to the medium for 2 h. Absorbance was determined at the respective wavelength with an ELISA reader. The figures are averages of five independent experiments. Figure 5. Effect of HU-210 on the hyperglycemia pro-apoptotic activity.
  • PC12 cells (1x10 5 ) were seeded in a medium containing 8% FBS and 8% HS, exposed to 27 g/L glucose and treated with the indicated concentrations of HU-210. After 48 h, the cells were co-stained with annexin V antibodies and propidium iodide and were then analyzed by flow-cytometry.
  • A FACS analysis of PC12 cells exposed to 27 g/l glucose and treated with vehicle or 20 ⁇ M HU210. Apoptotic cells are represented by the two right hand rectangles in each panel and calculated as such.
  • B Apoptotic rates of PC12 cells exposed to 27 g/L glucose and treated with the indicated dosage of HU-210. The figures are averages of three independent experiments.
  • Figure 6. The cell cycle profile of PC12 is modulated by hyperglycemia and HU- 210.
  • PC12 cells (1x10 5 ) were seeded in a medium containing 8% FBS and 8% HS, exposed to 27 g/L glucose and treated with the indicated concentrations of HU-210. At 24 h, the cells were stained with propidium iodide and subjected to cell cycle profiling by flow-cytometry. The figures are averages of five independent experiments.
  • PC12 cells (2x10 4 ) were maintained in a medium containing 1% FBS, 1% HS and 50 ng/ml NGF.
  • A Representative phase-contrast images showing neurite outgrowth in PC 12 cells exposed to 27 g/L glucose and treated with vehicle or 20 ⁇ M HU210. Panels were randomly selected and are representative fields.
  • B Graph comparing neurite length in PC12 cells treated with the indicated dosage of HU-210 under normal or 27 g/L medium glucose. The figures are averages of three independent experiments.
  • Figure 8 Effect of HU-210 on hyperglycemia-induced hyper dopamine levels in PC12 cells.
  • PC 12 cells (1x10 6 ) were seeded in a medium containing 8% FBS and 8% HS 1 exposed to 27 g/L glucose and treated with vehicle or 20 ⁇ M HU-210 for 6 h. Cells were harvested and analyzed by HPLC. The figures represent 5 independent experiments.
  • Figure 9 PC12 intracellular ROS formation in response hyperglycemic conditions and HU-210 treatment.
  • mice were injected i.p. with 200 mg/kg STZ. 8 saline, THC (0.1mg/kg) or THC+SR144528 (0.1 mg/kg) were administered intraperitoneally for 1 day, 1 h before the maze testing was carried out and results are shown in the graph .
  • THC 0.1mg/kg
  • THC+SR144528 0.1 mg/kg
  • PC 12 cells were kindly provided by O. Meyuhas, Dept. of Biochem., Faculty of Medicine, Jerusalem. These cells were grown either in Dulbecco's modifed Eagle's medium (DMEM) supplemented with 8% horse serum (HS), 8% fetal bovine serum (FBS), glutamine, and gentamicin or with 1% HS, in the presence of nerve growth factor (NGF) (50 ng/ml), which causes the cells to differentiate.
  • DMEM Dulbecco's modifed Eagle's medium
  • HS horse serum
  • FBS 8% fetal bovine serum
  • glutamine glutamine
  • gentamicin gentamicin
  • HU-210 was provided by Prof. Raphael Mechoulam. Mice
  • mice Eight- to 10-week old female Sabra mice (29-32g) were assigned at random to different groups of 10 mice per cage and were used in all experiments. All cages contained wood-chip bedding and were placed in a temperature-controlled room at 22 0 C, on a 12 h light/dark cycle (lights on at 07.00 a.m.). The mice had free access to water 24 h a day. The food provided was Purina chow and the animals were maintained in the animal facility (SPF unit) of the Hebrew University Hadassah Medical School, Jerusalem.
  • mice were made diabetic by intraperitoneal (i.p.) injection of 200 mg/kg of body weight STZ (Sigma) in 0.05M citrate buffer (pH 4.5). Mice receiving an injection of citrate buffer were used as controls. Hyperglycemia was determined 4 days after injection by blood glucose analysis. Mice with blood glucose levels >300 mg/dl were considered to have diabetes. Mice were divided into four groups: control mice treated with saline, control mice treated with HU-210, diabetic mice treated with saline, and diabetic mice treated with HU-210. HU-210 or saline were administered i.p. daily. Glucose assay
  • TAA-RS Thiobarbituric acid-reactive substances
  • TBA-RS was determined according to the method of Esterbauer and Cheeseman (Esterbauer and Cheeseman., 1990). Briefly, 30O uL of cold 10% trichloroacetic acid were added to 150 uL of brain supernatant and centrifuged at 300 g for 10 min. Three hundred microlitres of the supernatant were transferred to a Pyrex tube and incubated with 30O uL of 0.67% thiobarbituric acid (TBA) in 7.1% sodium sulphate in boiling water bath for 25 min. The mixture was allowed to cool on running tap water for 5 min. The resulting pink-stained TBA-RS was determined in a spectrophotometer at 532 nm. A calibration curve was performed using 1 ,1 ,3,3- tetramethoxypropane. Each curve point was subjected to the same treatment as supernatants. TBARS was calculated as nmol TBARS/mg protein.
  • Neurological function was assessed by a 10 point scale based on reflexes and task performance (Chen et al., 1996): exit from a circle 1 meter in diameter in less than 1 minute; seeking; walking a straight line; startle reflex; grasping reflex; righting reflex; placing reflex; corneal reflex; maintaining balance on a beam 3, 2 and 1 cm in width; and climbing onto a square and a round pole. For each task failed or abnormal reflex reaction, a score of 1 was assigned. Thus, a higher score indicates poorer neurological function. The neurological score was assessed one day after TAA induction (day 2). The mice were then divided between treatment groups so that each group had a similar baseline neurological score before STZ administration. 2',7'-dihydrodichlorofluorescein (DCFH) oxidation.
  • DCFH 2',7'-dihydrodichlorofluorescein
  • Reactive species production was assessed according to LeBeI et al.,1992 by using 2',7'-dihydrodichlorofluorescein diacetate (DCF-DA).
  • DCF-DA prepared in 20 mM sodium phosphate buffer, pH 7.4, containing 140 mM KCI, was incubated with pre- treated cerebral cortex supernatants during 30 min at 37 0 C.
  • DCF-DA is enzymatically hydrolyzed by intracellular esterases to form non-fluorescent DCFH, which is then rapidly oxidized to form highly fluorescent 2',7'-dichlorofluorescein (DCF) in the presence of reactive species (RS).
  • RS reactive species
  • Cell viability was evaluated in control and hyperglycemic conditions treated with HU-210 for 24-72h.
  • the assay was performed using the Cell proliferation Reagent WST-1 kit, based on the cleavage of the tetrazolium salt WST-1 (Berridge M.V.,1996), according to the manufacturer's instruction (Roche Applied Science, Germany). Values are presented as percent of control. Cell cycle analysis and annexin V staining
  • Cells were grown in 60 mm plate, exposed to 27 g/L glucose and treated with HU-210 as before. Both attached and floating cells were collected after 24 h and centrifuged at 5000xg for 5 min. The cell pellet was fixed with 1 ml 70% ethanol (1 ml), centrifuged and re-suspended in 1 ml PBS containing RNase A and propidium iodide (50 mg/ml each). Stained cells were analyzed for relative DNA content by a Coulter FACSort flow cytometer (Becton Dickinson).
  • Apoptosis was evaluated in cells exposed to 27 g/l glucose and treated with HU- 210 for 48 h using the Annexin V FITC Detection Kit according to the manufacturer's instruction (Oncogene Research Products, Cambridge MA). Briefly, both attached and floating cells were collected, washed with cold PBS, re-suspended at a density of 5x10 5 /ml in 0.5 ml DMEM 1 stained for annexin V and analyzed by flow cytometry. Measurement of neurite extension
  • PC12 cells were grown in the presence of NGF (50 ng/ml) and assayed by measurement of the number of cells bearing at least one extended neurite (>2 mm). Neurites were counted in 100 cells per field in four separated fields per well. Triplicate wells were used routinely for each experimental condition or treatment. Catecholamine measurements
  • Catecholamines were measured as described previously (Dagon et al., 2005). 12x10 6 cells were collected, washed with cold PBS and re-suspended for each analysis. The assay for dopamine was performed by HPLC separation and detection using HPLC-ECD. Values are presented as a concentration of ng per 1 g of re- suspended cells. Statistics
  • Cannabinoids have been shown to protect the brain from various insults and to improve several neurodegenerative diseases (Grundy et al., 2001). However, their direct effect on diabetic encephalopathy has not been demonstrated.
  • the effect of the synthetic cannabinoid HU-210 was tested on STZ-induced brain dysfunction. Mice were assigned randomly to saline or STZ treatment groups. After 8 weeks of diabetes, control and STZ administered mice were treated daily with HU-210 0.1 mg/kg and tested in the eight arm maze. Diabetic mice demonstrated a progressive decline in performances throughout the 5 days of testing. HU-210 treatment did not significantly affect performance in the control group. However, performance of the diabetic mice was significantly improved by HU-210 treatment (Fig.1A).
  • HU-210 mice Diabetic mice also exhibited reduced neurological score. This effect was overcome by HU-210 treatment (Fig. 1B). Recent studies have claimed that much of the cannabinoid neuroprotective effect is mediated through the cerebral CB-1 receptor signaling (Van der Stelt et al, 2005). To study this pathway, STZ administrated mice were co-treated daily with the CB-1 antagonist SR141716A alone and together with HU-210 0.1 mg/kg. Mice were subjected to the eight arm maze as before. SR141716A treatment did not significantly affect the progressive decline in performance demonstrated by the diabetic mice or the improvement following HU-210 treatment (Fig.1C).
  • HU-210 Blood glucose levels were recorded in control and STZ administrated STZ mice daily treated with 0.1 mg/kg HU-210 for 5 days.
  • HU-210 treatment had no significant effect on the hyperglycemic index in diabetic animals or on normal levels in the treated controls (Fig. 2A).
  • HU-210 did not affect the animal's weights (Fig. 2B).
  • HU-210 attenuates cerebral oxidative stress in diabetic mice.
  • HU-210 treatment increased cell viability during the incubation periods in a dose dependent manner (Fig. 4). These results established a direct effect of HU-210 on neuronal targets and implied a neuroprotective effect of HU-210 on hyperglycemic PC12 cells.
  • HU-210 counteracts hyperglycemia-induced apoptotic cell death.
  • HU-210 overcomes hyperglycemia-induced cell cycle arrest.
  • HU-210 improves hyperglycemia-induced impaired neuritogenesis.
  • PC 12 cells synthesize and store the catecholamine neurotransmitters dopamine and norepinephrine (Greene et al., 1976). The effect of hyperglycemia on catecholamines levels was studied. Exposure of the cells to hyperglycemia promptly enhanced dopamine levels after 3h (and longer). Treatment of these cells with 20 ⁇ M HU-210 restored elevated dopamine levels to control levels (Fig. 8). HU-210 blocks cellular oxidative stress in PC12 exposed to hyperglycemic conditions.
  • T-maze is a 'two-trial' phenomena in which an animal is said to alternate if its choice on the second trial of testing is opposite from that of the first trial.
  • the method was based on that described by Henderson (1970) with modifications (Zahalka et al.. 1995).
  • the apparatus consisted of a T-shaped maze made of opaque Plexiglas® and a transparent cover. The width and the height of the T-maze were 4*4 cm.
  • THC was found also to act through a mechanism other than CB1 Receptor.
  • HU-210 overcomes hyperglycemia-induced proliferation arrest and inhibition of differentiation, suggests that in addition to preventing neural cell loss, cognitive improvement resulted from stimulating cell regeneration (As seen in Fig 7A).
  • DN is one of the most common complications of diabetes, severely interfering with the quality of life of patients.
  • improvement of glycemic control remains the principal therapeutic strategy to prevent or delay its onset or progression (Zochdne .,1999).
  • a vast effort is invested in searching for therapies based on superior antioxidative properties for the prevention of neuropathy in diabetic patients.
  • HU-210 administration ameliorated the neural insults of diabetes, both in vivo and in vitro.

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Abstract

La présente invention concerne l'utilisation d'une quantité effective d'au moins un cannabinoïde sélectionné dans un groupe consistant de HU-210 et de tétrahydrocannabinol (THC) pour la fabrication d'une composition pharmaceutique pour l'atténuation de la lésion neuronale due à l'hyperglycémie, ou pour le traitement de la lésion neuronale chez un sujet diabétique, dans laquelle HU-210 est l'analogue (+)-1,1-diméthylheptyl du 7-hydroxy-delta-6- tétrahydrocannabinol de formule :
PCT/IL2008/000477 2007-04-19 2008-04-06 Cannabinoïde pour le traitement des lésions neuronales chez les patients diabétiques Ceased WO2008129529A2 (fr)

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US91272007P 2007-04-19 2007-04-19
US60/912,720 2007-04-19
IL190531A IL190531A0 (en) 2008-03-31 2008-03-31 Cannabinoid for the treatment of neuronal damage in diabetic patients
IL190531 2008-03-31

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