1,721,023 research outputs found
HU 210: A potent tool for investigations of the cannabinoid system
No full textThe synthetic compound HU 210 displays a multiplicity of biochemical, pharmacological, and behavioral effects, most of which have been demonstrated to be dependent on a selective agonistic activity at CB1 and CB2 cannabinoid receptors and to involve the main neurotransmitter systems. Results obtained in various studies suggest a potential clinical application of this highly potent drug (e.g., as antipyretic, antiinflammatory, analgesic, antiemetic, and antipsychotic agent) as well as its usefulness in research aimed to develop a better understanding of the involvement of the endogenous cannabinoid system in a number of physiopathological functions
Cannabimimetic activity in rats and pigeons of HU 210, a potent antiemetic drug
No full textPreliminary behavioral experiments in rats with thecannabinoid agonist HU 210 (12.5–100mg/kg IP) showed that it has a potent cannabimimetic profile similar to that ofD9THC;the drug dose dependently depressed locomotor activity, rearing, and grooming and elicited vocalization and circling at thehighest doses. In subsequent studies on pigeons, HU 210 (12.5–50mg/kg SC) confirmed its sedative effects; it also affordedprotection against vomiting induced by cisplatin (7.5 mg/kg IV) and emetine (20 mg/kg SC) and emetine-induced headshake
Effect of the cannabinoid receptor agonist, HU 210, on body weight and feeding behaviour of rats
No full textThe effect of the synthetic cannabinoid receptor agonist, y.11-hydroxy-D8-tetrahydrocannabinol-dymethylheptylHU 210., on ratbody weight and eating and drinking behaviour was examined. In Experiment 1, the drug25, 50 or 100 mgrkg., sub-chronicallyadministered for 4 days, produced a dose- and time-dependent loss of body weight that, at the highest dose, was not regained by 7 daysafter the drug was stopped, and remained markedly below that of vehicle-treated animals. In Experiment 2, food and water intakes, whichwere evaluated in fasted rats, tested as in Experiment 1, were significantly inhibited only by the dose of 100 mgrkg, and this effect wasstill present 7 days after the last injection of the drug. The possibility that the effects observed are not directly dependent on the control ofappetite and might be ascribable to stress-related phenomena is discussed
Dual acting anti-inflammatory drugs
No full textDrugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB4) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins
THE CANNABINOID AGONIST HU 210 MODIFIES RAT BEHAVIOURAL RESPONSES TO NOVELTY AND STRESS
No full textExperiments were performed on groups of rats after acute and sub-chronic treatment (once daily for 9 days) with the cannabinoid agonist HU 210 (25-100 μg kg(-1), i.p.) as well as 24 h and 7 days after the last drug injection. The animals underwent three behavioural tests in novel environments. In the observation cages (Test 1), rat locomotor activity was found to be dose-dependently reduced after acute and sub-chronic treatment at all doses and virtually unchanged during abstinence; grooming was potently inhibited by acute treatment but potentiated by the sub-chronic one at doses of 50 and 100 μg kg(-1), the effect of the higher dose persisting after 24 h and 7 days abstinence. Vocalization in animals in response to a tactile stimulus was highest after HU 210 at 100 μg kg(-1)in all experimental modes except after 7 days abstinence. In the X-maze (Test 2), sub-chronic HU 210 dose- dependently enhanced rat natural aversion for open arms, and this behaviour persisted during abstinence after the highest dose. Grooming in the X-maze was completely absent in rats acutely injected with HU 210 but potentiated in those sub-chronically treated or abstinent. In the swimming test (Test 3) rats sub-chronically treated at 50 and 100 pg kg(-1)displayed relevant wall-hugging and the same occurred 24 h after last injection. On the whole, our results are indicative of an anxiogenic-like effect of sub-chronic HU 210 at high doses and reflect the persistence of enhanced emotional response to novel environments when the treatment is discontinued
Influence of sildenafil on central dopamine-mediated behaviour in male rats
No full textTwo experiments were performed to evaluate the effects of sildenafil on spontaneous or dopamine agonist-induced behaviour in male rats. Data obtained in experiment 1 show that oral administration of the drug, at 1 mg/kg, significantly increased the occurrence of penile erections, anogenital self-grooming and homosexual mounting in grouped sexually-experienced, but not inexperienced, animals. In experiment 2, pre-treatment with sildenafil (0.5, 1 or 10 mg/kg) dose-dependently modified several behavioural signs, centrally evoked by the D-2/D-3 dopamine agonists, 7-OH-DPAT or B-HT 920 (both at 0.1 mg/ka), in experimentally naive male rats. While sildenafil at 1 mg/kg significantly increased the number of penile erection and stretching-yawning episodes induced by 7-OH-DPAT or B-HT 920, at 10 mg/kg it elicited low stereotyped behaviour, antagonizing stretching-yawning and sedation in 7-OH-DPAT treated rats. Discussion centres on the modulatory activity of sildenafil on central dopaminergic pathways and, possibly, on nitric oxide production. (C) 2002 Elsevier Science Inc. All rights reserved
Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: Critical remarks
No full textNon steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAlDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, expecially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient's compliance. Also incorporation of a nitric oxide (NO)generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti - inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Finally, recent data strongly suggest that dual inhibitors may have specific protective activity also in neurodegeneration
Modulatory activity of sildenafil on copulatory behaviour of both intact and castrated male rats
No full textThe first experiment of the present study investigates the effects induced by sildenafil (1 or 10 mg/kg po) on the copulatory behaviour of intact male rats, categorized, on the basis of seven consecutive mating pretests, as sluggish or normal ejaculators (SE or NE, respectively). The data obtained show that sildenafil modifies both sexual arousal and the ejaculatory mechanisms of copulation, diminishing ejaculation latency in both categories and increasing copulatory efficacy in SE rats; in addition, it reduced the inter-intromission interval in both SE and NE animals and the post-ejaculatory interval only in SE animals. The second experiment, conducted on rats 3 weeks after their castration, shows that sildenafil alone (1 or 10 mg/kg) did not modify copulatory failure. However, 3 months after castration, and 24 h after the last injection of testosterone (25 microg/kg sc) given twice weekly for 4 weeks, sildenafil (1 or 10 mg/kg) ameliorated rat copulatory performance
Rat cognitive function during and after treatment with the cannabinoid agonist, HU 210
No full textTo ascertain whether the cannabinoidagonist HU 210 (25, 50, or 100mg/kg, IP) influences rat spatial learning, water-maze performance was examined in theplace (hidden platform)—and cue (visible platform)—versions of the Morris water maze. In addition, other unlearned behaviorswere examined, namely, vocalization and wall hugging during the place task, and motor abilities during a motor test battery.The results obtained show that HU 210 at 50 or 100mg/kg (once daily for 4 days, 60 min before a daily session) impairedlearning in the place version but not in the cue one; wall hugging and enhanced vocalization were also displayed by the animalsin the fourth session. Motor activity was compromised by the same treatment schedule. When the drug was discontinued,the effects produced by HU 210 at 50mg/kg reversed in 3 days, while disruption of acquisition and vocalization caused byHU 210 at 100mg/kg remained after 7 days’ abstinence. Discussion centers on the possible specific cognitive mechanisms affectedby the drug and on aspecific factors (i.e., anxiety-like state), which may contribute to the impairment of spatial learning
Influence of the cannabinoid agonist HU 210 on cocaine- and CQP 201-403-induced behavioural effects in rat
No full textAcute injection of the cannabinoid agonist HU 210 (6.25-100 mu g/kg, i.p.) dose-dependently inhibited rat locomotor activity and rearing, while subchronic treatment with the drug (once daily for 7 days) at the same doses only diminished locomotion. Acute but not subchronic administration of HU 210 (12.5-50 mu g/kg, i.p.) potently counteracted acute and subchronic cocaine (15 mg/kg, i.p.)- induced hyperlocomotion and enhanced rearing. The acute cannabinoid (6.25-100 mu g/kg, i.p.) also inhibited locomotor activity, stereotyped behaviour and shaking elicited by the D-1/D-2 agonist CQP 201-403 (500 mu g/kg, i.p.). On the contrary, subchronic treatment's with HU 210 enhanced CQP 201-403-induced locomotor activity and potently stimulated escape attempts. Discussion centers on the influence of cannabinoids on experimental models of psychosis
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