RESUMEN
The cyclopentenone prostaglandins (CyPGs) are a small group compounds that are a subset of the eicosanoid superfamily, which are metabolites of arachidonic acid as well as other polyunsaturated fatty acids. The CyPGs are defined by a structural feature, namely, a five-membered carbocyclic ring containing an alfa-beta unsaturated keto group. The two most studied members are PGA2 and 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2); other less studied members are PGA1, Δ12-PGJ2, and PGJ2. They are involved in a number of biological activities including the ability to resolve chronic inflammation and the growth and survival of cells, particularly those of cancerous or neurological origin. Also, they can activate the prostaglandin DP2 receptor as well as the ligand-dependent transcription factor PPAR-gamma. Their ability to promote the resolution of chronic inflammation makes it of particular interest to have a good understanding of their actions. Since their discovery, the literature on the CyPGs has greatly expanded both in size and in scope; these reports are covered in the current review.
Asunto(s)
Inflamación/prevención & control , Neoplasias/prevención & control , Prostaglandinas/química , Prostaglandinas/farmacología , Animales , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Interactions between cannabinoids and eicosanoids have been observed for the last several decades and account for a variety of cannabinoid actions. These were seen both in vitro and in vivo and may provide a molecular basis for these actions. Some of the topics included in this review are; effects on adenylate cyclase activity, alteration of behavioral responses, reduction of pain sensation, reduction and resolution of inflammation, hypotensive and vasorelaxant responses, anti-cancer and anti-metastatic activities, reduction of intraocular pressure and others. The most widely studied cannabinoids so far are tetrahydrocannabinol and cannabidiol. However, synthetic agents such as CP55,940, ajulemic acid, JWH-133 and WIN-55,212-2 were also investigated for interaction with eicosanoids. The endocannabinoids anandamide and 2-arachidonoylglycerol have been examined as well. Among the eicosanoids mediating cannabinoid actions are PGE2, 15-deoxy-Δ12,14-prostaglandin-J2, lipoxin A4, lipoxin B4, and leukotriene B4. Enzyme activities involved include monoacylglycerylipase, adenylatecyclase, phospholipase A2, cyclooxygenases-1, 2 and 5, lipoxygenases-12 and 15. Receptors involved include CB1, CB2 and the EP3 and EP3 prostanoid receptors. While not all cannabinoid activities can be accounted for, many are best explained by eicosanoid participation. The recent surge in interest in "medical marijuana" makes understanding mechanisms of cannabinoid actions particularly important.
Asunto(s)
Cannabinoides/química , Cannabinoides/uso terapéutico , Eicosanoides/uso terapéutico , Cannabinoides/farmacología , Eicosanoides/farmacología , HumanosRESUMEN
Ajulemic acid (AJA, CT-3, IP-751, JBT-101, anabasum) is a first-in-class, synthetic, orally active, cannabinoid-derived drug that preferentially binds to the CB2 receptor and is nonpsychoactive. In preclinical studies, and in Phase 1 and 2 clinical trials, AJA showed a favorable safety, tolerability, and pharmacokinetic profile. It also demonstrated significant efficacy in preclinical models of inflammation and fibrosis. It suppresses tissue scarring and stimulates endogenous eicosanoids that resolve chronic inflammation and fibrosis without causing immunosuppression. AJA is currently being developed for use in 4 separate but related indications including systemic sclerosis (SSc), cystic fibrosis, dermatomyositis (DM), and systemic lupus erythematosus. Phase 2 clinical trials in the first 3 targets demonstrated that it is safe, is a potential treatment for these orphan diseases and appears to be a potent inflammation-resolving drug with a unique mechanism of action, distinct from the nonsteroidal anti-inflammatory drug (NSAID), and will be useful for treating a wide range of chronic inflammatory diseases. It may be considered to be a disease-modifying drug unlike most NSAIDs that only provide symptomatic relief. AJA is currently being evaluated in 24-month open-label extension studies in SSc and in skin-predominant DM. A Phase 3 multicenter trial to demonstrate safety and efficacy in SSc has recently been initiated.
Asunto(s)
Dronabinol/análogos & derivados , Inflamación/tratamiento farmacológico , Animales , Enfermedad Crónica , Ensayos Clínicos como Asunto , Dronabinol/administración & dosificación , Dronabinol/farmacocinética , Dronabinol/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Inflamación/etiología , Resultado del TratamientoRESUMEN
The subject of N-acyl amino acid conjugates has been rapidly growing in recent years, especially with regard to their analgesic and anti-inflammatory actions. The field comprises a large family of lipid signaling molecules whose importance is only now being fully realized. The most widely studied member is N-arachidonoyl glycine (NAGly), which differs structurally from the endocannabinoid anandamide (N-arachidonoyl ethanolamide) by a single oxygen atom even as the two are metabolically related. Topics that are covered in this minireview are: biosynthetic pathways for N-acyl amino acids, receptors for N-acyl amino acids, physiologic actions of N-acyl amino acids, pharmacological effects of N-acyl amino acids, and molecular mechanisms believed to be responsible for their effects. On the subject of mechanisms, we propose several possibilities whose basis is the currently available information. Four putative pathways can be suggested: 1) inhibition of fatty acid amide hydrolase-induced increases in anandamide or 2-arachidonoyl glycerol (2-AG) levels, resulting in analgesic activity; 2) binding to GPR18, initiating the production of anti-inflammatory eicosanoids (specifically, the data suggest roles for 15-deoxy-Δ12,14-prostaglandin-J2 and lipoxin A4, both of which are potent inflammation-resolving molecules); 3) inactivation of T-type Cav3 channels; and 4) inhibition of the GLYT2 glycine transporter. Each pathway would produce analgesic effects. Also, the N-acyl amino acids do not bind to either cannabinoid or opioid receptors, thus reducing adverse actions and making them good templates for novel drug candidate molecules.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Endocannabinoides/metabolismo , Glicina/análogos & derivados , Alcamidas Poliinsaturadas/metabolismo , Analgésicos/química , Analgésicos/metabolismo , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Ácidos Araquidónicos/química , Vías Biosintéticas , Endocannabinoides/química , Glicina/química , Glicina/metabolismo , Humanos , Alcamidas Poliinsaturadas/química , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.-Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios/uso terapéutico , Cannabinoides/uso terapéutico , Endocannabinoides/metabolismo , Fibrosis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Humanos , Inflamación/metabolismoRESUMEN
We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis.
Asunto(s)
Ependimoma/patología , Carcinomatosis Meníngea/patología , Neoplasias de la Médula Espinal/patología , Vértebras Cervicales/patología , Ependimoma/radioterapia , Ependimoma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Carcinomatosis Meníngea/radioterapia , Carcinomatosis Meníngea/cirugía , Procedimientos Neuroquirúrgicos , Radioterapia Adyuvante , Neoplasias de la Médula Espinal/radioterapia , Neoplasias de la Médula Espinal/cirugía , Adulto JovenRESUMEN
Ajulemic acid, a side-chain analog of Δ(8)-THC-11-oic acid, was designed as a potent therapeutic agent free of the psychotropic adverse effects typical of most cannabinoids. Subsequent studies of ajulemic acid have yielded widely divergent findings on the occurrence of these adverse effects. To help resolve these discrepancies, we have prepared highly purified ajulemic acid using a different synthetic method than previously reported in the literature and compared its cannabinoid receptor binding constants with those obtained using several other preparations from different sources. Whereas CB2 binding did not vary greatly among all of the samples, the CB1 binding showed a wide range of affinities. The highly purified product (JBT-101) reported here had the weakest affinity for CB1 while the original preparation (HU-239) showed the strongest affinity for CB1. The CB1/CB2 ratio of affinities was 12.3 for JBT-101 whereas that for HU-239 was 0.19, a 65-fold difference. Functional responses such as catalepsy and hypothermia using JBT-101 versus HU-239 displayed reduced CB1 activity in keeping with the receptor binding data. Thus, earlier conclusions on the limited therapeutic index for ajulemic acid need to be reconsidered in the light of the data now obtained using JBT-101.
Asunto(s)
Dronabinol/análogos & derivados , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Animales , Conducta Animal/efectos de los fármacos , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Dronabinol/química , Dronabinol/farmacología , Femenino , Células HL-60 , Humanos , Ratones , Conformación Molecular , Dimensión del Dolor/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
The cannabinoid acids are a structurally heterogeneous group of compounds some of which are endogenous molecules and others that are metabolites of phytocannabinoids. The prototypic endogenous substance is N-arachidonoyl glycine (NAgly) that is closely related in structure to the cannabinoid agonist anandamide. The most studied phytocannabinoid is Δ(9)-THC-11-oic acid, the principal metabolite of Δ(9)-THC. Both types of acids have in common several biological actions such as low affinity for CB1 anti-inflammatory activity and analgesic properties. This suggests that there may be similarities in their mechanism of action, a point that is discussed in this review. Also presented are reports on analogs of the acids that provide opportunities for the development of novel therapeutic agents, such as ajulemic acid.
Asunto(s)
Cannabinoides/química , Cannabinoides/farmacología , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacología , Animales , Cannabinoides/metabolismo , Dronabinol/análogos & derivados , Dronabinol/farmacología , Endocannabinoides/química , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Humanos , Estructura MolecularRESUMEN
Ajulemic acid is a synthetic analog of Δ(8)-THC-11-oic acid, the terminal metabolite of Δ(8)-THC. Unlike Δ(9)-THC, the psychoactive principle of Cannabis, it shows potent anti-inflammatory action and has minimal CNS cannabimimetic activity. Its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. Five metabolites, M1 to M5, were observed in human hepatocyte incubations. One metabolite, M5, a glucuronide, was observed in the chromatogram of canine hepatocyte incubations. In monkey hepatocyte incubations, M5 was observed in the chromatograms of both the 120 and 240 min samples, trace metabolite M1 (side-chain hydroxyl) was observed in the 120 min samples, and trace metabolite M4 (side-chain dehydrogenation) was observed in the 240 min samples. No metabolites were found in the rat hepatocyte incubations. Unchanged amounts of ajulemic acid detected after the 2-h incubation were 103%, 90%, 86%, and 83% for rat, dog, monkey, and human hepatocytes, respectively. Additional studies were done to ascertain if ajulemic acid can inhibit the activities of five principal human cytochrome P450 isozymes; CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. In contrast to the phytocannabinoids Δ(9)-THC and CBD, no significant inhibition of cytochrome activity was observed. These data further support the conclusions reached in earlier reports on ajulemic acid's high margin of safety and suggest that it undergoes minimal metabolism and is not likely to interfere with the normal metabolism of drugs or endogenous substances.
RESUMEN
N-arachidonoylglycine (NAgly) is an endogenous signaling lipid that is a member of the eicosanoid super family and is related to anandamide. It shows anti-inflammatory activity in vivo in the mouse peritonitis model where it reduces migration of inflammatory leukocytes following injection of pro-inflammatory agents into the peritoneal cavity. Using cell culture models, including GPR18 transfected HEK-293 cells, evidence is presented that the orphan receptor GPR18 is involved in this action. Increases in free arachidonic acid, and robust stimulation of anti-inflammatory eicosanoids were observed at low micromolar concentrations. These included 15-deoxy-delta-13,14-PGJ(2) and lipoxin A(4) both of which are believed to mediate the resolution stage of inflammation. It was further shown that NAgly might act via GPR18 activation in promoting the number of Trypan Blue stained cells, a possible indicator of programmed cell death. Thus, we hypothesize that NAgly induces the death of inflammatory cells, a process that is considered to be important for the resolution of inflammation.
Asunto(s)
Glicina/análogos & derivados , Inflamación/tratamiento farmacológico , Animales , Secuencia de Bases , Línea Celular , Células Cultivadas , Cartilla de ADN , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Ratones , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Moduladores de Receptores de Cannabinoides/uso terapéutico , Cannabinoides/uso terapéutico , Endocannabinoides , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Ácidos Araquidónicos/farmacología , Ácidos Araquidónicos/uso terapéutico , Moduladores de Receptores de Cannabinoides/farmacología , Cannabinoides/síntesis química , Cannabinoides/farmacología , Cannabis/química , Modelos Animales de Enfermedad , Dronabinol/análogos & derivados , Dronabinol/farmacología , Dronabinol/uso terapéutico , Evaluación Preclínica de Medicamentos , Eicosanoides/biosíntesis , Eicosanoides/fisiología , Fibromialgia/tratamiento farmacológico , Glicina/análogos & derivados , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Inflamación/fisiopatología , Ratones , Aceites de Plantas/química , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Receptores de Cannabinoides/efectos de los fármacos , Receptores de Cannabinoides/fisiologíaRESUMEN
AIMS: To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS). MAIN METHODS: FLS isolated from tissue obtained at joint replacement surgery or cultured from synovial fluid were treated for 60 min with AjA (10-30 microM), then stimulated with tumor necrosis factor alpha (TNFalpha). COX2 mRNA was measured by hybridization/colorimetric assay of whole cell lysates collected 4 h after stimulation. To determine effects on arachidonic acid release, FLS were incubated with (14)C-arachidonic acid for 20 h then treated with AjA (8-32 microM). Arachidonic acid release was measured by scintillation counting. Prostaglandins (PG) were measured by enzyme linked immunosorbent assay (ELISA) in cell supernatants collected 4 and 24 h after stimulation. KEY FINDINGS: AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly. SIGNIFICANCE: The capacity of AjA to increase selectively and markedly 15d-PGJ(2), an eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation.
Asunto(s)
Antiinflamatorios , Dronabinol/análogos & derivados , Eicosanoides/metabolismo , Membrana Sinovial/citología , Membrana Sinovial/metabolismo , Ácido Araquidónico/biosíntesis , Artritis Psoriásica/patología , Artritis Reumatoide/patología , Ciclooxigenasa 2/biosíntesis , Dronabinol/farmacología , Humanos , Prostaglandinas/biosíntesis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Líquido Sinovial/citología , Líquido Sinovial/efectos de los fármacos , Líquido Sinovial/metabolismo , Membrana Sinovial/efectos de los fármacosRESUMEN
Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.
Asunto(s)
Cannabinoides/metabolismo , Dronabinol/análogos & derivados , PPAR gamma/metabolismo , Analgésicos/farmacología , Cannabis/metabolismo , Cristalografía por Rayos X , Dronabinol/farmacología , Diseño de Fármacos , Humanos , Ligandos , Modelos Químicos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de Cannabinoides/metabolismoRESUMEN
A library of amino acid-fatty acid conjugates (elmiric acids) was synthesized and evaluated for activity as potential anti-inflammatory agents. The compounds were tested in vitro for their effects on cell proliferation and prostaglandin production, and compared with their effects on in vivo models of inflammation. LPS stimulated RAW 267.4 mouse macrophage cells were the in vitro model and phorbol ester-induced mouse ear edema served as the principal in vivo model. The prostaglandin responses were found to be strongly dependent on the nature of the fatty acid part of the molecule. Polyunsaturated acid conjugates produced a marked increase in media levels of i15-deoxy-PGJ(2) with minimal effects on PGE production. It is reported in the literature that prostaglandin ratios in which the J series predominates over the E series promote the resolution of inflammatory conditions. Several of the elmiric acids tested here produced such favorable ratios suggesting that their potential anti-inflammatory activity occurs via a novel mechanism of action. The ear edema assay results were generally in agreement with the prostaglandin assay findings indicating a connection between them.
Asunto(s)
Antiinflamatorios , Alanina/química , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Cromatografía en Capa Delgada , Evaluación Preclínica de Medicamentos , Edema/inducido químicamente , Edema/prevención & control , Ácidos Grasos/química , Glicina/química , Indicadores y Reactivos , Macrófagos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ésteres del Forbol , Antagonistas de Prostaglandina/síntesis química , Antagonistas de Prostaglandina/farmacología , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.
Asunto(s)
Antirreumáticos/uso terapéutico , Dronabinol/análogos & derivados , Inhibidores de la Metaloproteinasa de la Matriz , PPAR gamma/metabolismo , Animales , Antirreumáticos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Cartílago/metabolismo , Cartílago/patología , Células Cultivadas , Modelos Animales de Enfermedad , Dronabinol/farmacología , Dronabinol/uso terapéutico , Embrión de Mamíferos , Fibroblastos/metabolismo , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/fisiología , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Noqueados , PPAR gamma/genética , Ratas , Líquido Sinovial/citología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Usage of glyphosate [N-(phosphonomethyl)-glycine] and glufosinate [2-amino-4-(hydroxy-methylphosphinyl)butanoic acid] may reduce the environmental impact of agriculture because they are more strongly sorbed to soil and may be less toxic than many of the residual herbicides they replace. Preferential flow complicates the picture, because due to this process, even strongly sorbed chemicals can move quickly to ground water. Therefore, four monolith lysimeters (8.1 m(2) by 2.4 m deep) were used to investigate leaching of contact and residual herbicides under a worst-case scenario. Glufosinate, atrazine (6-chloro-N(2)-ethyl-N(4)-isopropyl-1,3,5-triazine-2,4-diamine), alachlor [2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl) acetamide], and linuron (3-3,4-dichlorophenyl-1-methoxy-1-methylurea) were applied in 1999 before corn (Zea mays L.) planting and glyphosate, alachlor, and metribuzin [4-amino-6-(1,1-dimethylethyl)-3-(methylthio)-1,2,4-triazin-5(4H)-one] were applied in 2000 before soybean [Glycine max (L.) Merr.] planting. A high-intensity rainfall was applied shortly after herbicide application both years. Most alachlor, metribuzin, atrazine, and linuron losses occurred within 1.1 d of rainfall initiation and the peak concentration of the herbicides coincided (within 0.1 d of rainfall initiation in 2000). More of the applied metribuzin leached compared with alachlor during the first 1.1 d after rainfall initiation (2.2% vs. 0.035%, P < 0.05). In 1999, 10 of 24 discrete samples contained atrazine above the maximum contaminant level (atrazine maximum contaminant level [MCL] = 3 mug L(-1)) while only one discrete sample contained glufosinate (19 mug L(-1), estimated MCL = 150 mug L(-1)). The results indicate that because of preferential flow, the breakthrough time of herbicides was independent of their sorptive properties but the transport amount was dependent on the herbicide properties. Even with preferential flow, glyphosate and glufosinate were not transported to 2.4 m at concentrations approaching environmental concern.
Asunto(s)
Herbicidas/análisis , Contaminantes del Suelo/análisis , Movimientos del Agua , Contaminantes Químicos del Agua/análisis , Adsorción , Monitoreo del Ambiente , Herbicidas/química , SueloRESUMEN
A long-standing goal in cannabinoid research has been the discovery of potent synthetic analogs of the natural substances that might be developed as clinically useful drugs. This requires, among other things, that they be free of the psychotropic effects that characterize the recreational use of Cannabis. An important driving force for this goal is the long history of the use of Cannabis as a medicinal agent especially in the treatment of pain and inflammation. While few compounds appear to have these properties, ajulemic acid (AJA), also known as CT-3 and IP-751, is a potential candidate that could achieve this goal. Its chemical structure was derived from that of the major metabolite of Delta9-THC, the principal psychotropic constituent of Cannabis. In preclinical studies it displayed many of the properties of non-steroidal anti-inflammatory drugs (NSAIDs); however, it seems to be free of undesirable side effects. The initial short-term trials in healthy human subjects, as well as in patients with chronic neuropathic pain, demonstrated a complete absence of psychotropic actions. Moreover, it proved to be more effective than placebo in reducing this type of pain as measured by the visual analog scale. Unlike the narcotic analgesics, signs of dependency were not observed after withdrawal of the drug at the end of the one-week treatment period. Data on its mechanism of action are not yet complete; however, the activation of PPAR-gamma, and regulation of eicosanoid and cytokine production, appear to be important for its potential therapeutic effects.
Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Cannabis/química , Dronabinol/análogos & derivados , Dronabinol/uso terapéutico , Dolor/tratamiento farmacológico , Dronabinol/química , Dronabinol/metabolismo , Diseño de Fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor gamma (PPARgamma), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARgamma at pharmacological concentrations. Activation of PPARgamma by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARgamma through the ligand-dependent AF-2 function. AJA binding consistently enables PPARgamma to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARgamma-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARgamma. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARgamma. Together, these data indicate that PPARgamma may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARgamma activation in multiple signaling pathways.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Dronabinol/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Adipocitos/citología , Adipocitos/efectos de los fármacos , Sitios de Unión , Células Cultivadas , Dronabinol/análogos & derivados , Humanos , Interleucina-8/genética , Regiones Promotoras Genéticas/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiologíaRESUMEN
Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, reduces joint tissue damage in rats with adjuvant arthritis. Because interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis, we investigated human monocyte IL-1beta and TNFalpha responses after the addition of AjA to cells in vitro. Peripheral blood and synovial fluid monocytes (PBM and SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AjA (0-30 microM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for mRNA, and supernatants were collected for cytokine assay. Addition of AjA to PBM and SFM in vitro reduced both steady-state levels of IL-1beta mRNA and secretion of IL-1beta in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 microM AjA (P<0.05 vs untreated controls, N=7). AjA did not influence TNFalpha gene expression in or secretion from PBM. Reduction of IL-1beta by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis. Development of nonpsychoactive therapeutically useful synthetic analogs of Cannabis constituents, such as AjA, may help resolve the ongoing debate about the use of marijuana as medicine.
Asunto(s)
Cannabinoides/farmacología , Dronabinol/farmacología , Interleucina-1/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Monocitos/efectos de los fármacos , Dronabinol/análogos & derivados , Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Interleucina-1/genética , Leucocitos Mononucleares/metabolismo , Monocitos/metabolismo , Estabilidad del ARN , Líquido Sinovial/citología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
N-arachidonylglycine (NAGly), the carboxylic analog of the endocannabinoid anandamide, occurs in rat and bovine brain as well as in peripheral sites and shows activity against tonic, formalin-induced pain. It was also observed, using cell membrane preparations, that it inhibits the hydrolytic activity of fatty acid amide hydrolase (FAAH) on anandamide (N-arachidonylethanolamide). These data suggested that it may serve as an endogenous regulator of tissue anandamide concentrations. In this report, we show findings derived from mass spectrometric analyses, indicating that blood levels of anandamide in rats given 10 mg/kg p.o. of NAGly were increased significantly by more than 9-fold when compared with vehicle-treated controls. In vitro evidence in RAW 264.7 cells using a deuterium-labeled NAGly demonstrated that it was not a precursor or source of arachidonic acid for the observed 50% rise in anandamide levels, suggesting that the increase was due to some effect other than increased biosynthesis of anandamide. Moreover, the findings presented here suggest that NAGly can serve as a model for the design of agents to provide pharmacological control of tissue anandamide concentrations.