RESUMO
Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.
Assuntos
Azóis/química , Azóis/metabolismo , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Animais , Células CHO , Canabinoides/química , Canabinoides/metabolismo , Cricetinae , Cricetulus , HumanosRESUMO
BIM-46187 (7-[2-amino-1-oxo-3-thio-propyl]-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine dimer, hydrochloride) is an inhibitor of the heterotrimeric G-protein complex signalling. Since many mediators of pain act through G-protein coupled receptors, the anti-hyperalgesic effects of BIM-46187 were assessed on experimental models of pain. In addition since opioids are widely used in pain management and act through specific G-protein-coupled receptors, the effects of BIM-46187 on the analgesic properties of morphine have also been investigated. BIM-46187 elicited a dose dependent analgesic effect in the models of carrageenan-induced hyperalgesia (0.1-1 mg/kg; i.v.) and chronic constriction injury (0.3-3 mg/kg; i.v.) in rats. BIM-46187, however, up to 10 mg/kg did not modify the paw oedema induced by carrageenan excluding an anti-inflammatory effect. In addition, at these doses, the compound was not sedative as shown by the lack of effect on the motor performance in the rotarod test. The combination of BIM-46187 and morphine (ratio 1/1) resulted in an unexpected synergistic effect in the model of carrageenan-induced hyperalgesia and in the chronic constriction injury model in rats when evaluated by isobolographic analysis. This synergy allowed a reduction of at least 20 fold in the dose of each compound. Conversely, the drug combination did not increase the side effects of morphine as assessed in the rotarod test. In conclusion, BIM-46187 elicits a potent anti-hyperalgesic effect and strongly synergizes with morphine. This work highlights the role of heterotrimeric G-protein complexes in pain and supports further investigations of the use of BIM-46187 alone, or in combination with low doses of morphine, in the management of pain.
Assuntos
Analgésicos não Narcóticos/farmacologia , Analgésicos Opioides/farmacologia , Cicloexanos/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores , Hiperalgesia/tratamento farmacológico , Morfina/farmacologia , Pirazinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina , Constrição Patológica/patologia , Sinergismo Farmacológico , Edema/induzido quimicamente , Edema/patologia , Hiperalgesia/induzido quimicamente , Masculino , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/psicologia , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Minocycline has been reported to exert neuroprotection through inhibition of inflammatory processes and of mitochondrial cell death pathway. To further characterize the neuroprotective effect of minocycline, we determined its efficacy in different neuronal damage paradigms involving inflammation or mitochondrial dysfunction. In transient global ischaemia in gerbils, minocycline reduced hippocampal neuronal damage measured by peripheral type benzodiazepine binding sites density, a marker of microglial activation. The antiinflammatory properties of minocycline were confirmed on the model of carrageenan-induced paw oedema in rats. The use of two experimental animal models involving administration of mitochondrial toxins inhibiting a different complex of the mitochondrial respiratory chain permitted the exploration of the mitochondrial impact of minocycline. Although minocycline exhibited a marked efficacy in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP; complex I inhibitor)-induced neurotoxicity in mice, it was ineffective in malonate (complex II inhibitor)-induced striatal lesion in rats. In vitro investigations on energized mitochondria isolated from rat liver showed that minocycline (1 microM) did not inhibit the swelling induced by MPP+(1-methyl-4-phenylpyridinium). Moreover, higher concentrations of minocycline induced swelling. From these experiments, the neuroprotective activity of minocycline appears more related to its antiinflammatory activity than to a direct beneficial action on mitochondria.
Assuntos
Minociclina/farmacologia , Dilatação Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevenção & controle , Carragenina , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/prevenção & controle , Gerbillinae , Membro Posterior , Isoquinolinas/metabolismo , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , Masculino , Malonatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , TrítioRESUMO
The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson's disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Antiparkinsonianos/farmacologia , Discinesias/metabolismo , Levodopa/metabolismo , Doença de Parkinson/tratamento farmacológico , Tiazóis/farmacologia , Amantadina/farmacologia , Animais , Antioxidantes/farmacologia , Comportamento Animal , Cromatografia Líquida de Alta Pressão , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Imuno-Histoquímica , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Neurônios/efeitos dos fármacos , Estresse Oxidativo , Tomografia por Emissão de PósitronsRESUMO
A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.
Assuntos
Amantadina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Purinas/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/toxicidade , Amantadina/farmacologia , Amantadina/toxicidade , Animais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacologia , Comportamento Animal , Benserazida/farmacologia , Bioensaio , Corpo Estriado , Dopamina/fisiologia , Dopaminérgicos/farmacologia , Dopaminérgicos/toxicidade , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Levodopa/efeitos adversos , Levodopa/farmacologia , Levodopa/toxicidade , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Placebos , Purinas/farmacologia , Purinas/toxicidade , Distribuição Aleatória , Ratos , Reprodutibilidade dos Testes , Rotação , Tamanho da Amostra , Método Simples-Cego , Simpatolíticos/toxicidadeRESUMO
The development of L-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD. Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of L-dopa over a further four-week period. Over the course of L-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia. In animals rendered dyskinetic by L-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of L-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of L-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
Assuntos
Corpo Estriado/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Tiazóis/uso terapêutico , Animais , Área Sob a Curva , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/metabolismo , Expressão Gênica , Masculino , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxidopamina/farmacologia , Transtornos Parkinsonianos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/metabolismo , Tiazóis/farmacologiaRESUMO
The standardized extract of Ginkgo biloba EGb 761 has been used to reduce cognitive dysfunction. The present study was designed to evaluate the effect of postischemic oral treatment with EGb 761 in a model of vascular dementia in gerbils. Daily oral posttreatment with EGb 761 led to a significant recovery of spatial memory assessed by the object location test, inhibited the decrease in plasma SOD activity and protected the hippocampal CA1 neurons, even when administered after the insult. These data provide further evidence for the therapeutic potential of EGb 761 in the treatment of vascular dementia.
Assuntos
Demência Vascular/tratamento farmacológico , Ginkgo biloba , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Demência Vascular/sangue , Demência Vascular/patologia , Modelos Animais de Doenças , Gerbillinae , Hipocampo/patologia , Memória/efeitos dos fármacos , Transtornos da Memória/sangue , Degeneração Neural/sangue , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Superóxido Dismutase/sangueRESUMO
In addition to inhibition of acetylcholine release in the neuromuscular junction botulinum toxin type A (BoNT-A) also inhibits the release of mediators involved in pain perception. We have investigated the effect of two types of BoNT-A on mechanical hyperalgesia in the rat models of carrageenan-induced hyperalgesia and of paclitaxel-induced peripheral neuropathy. A subplantar (s.p.) injection of BoNT-A in the ipsilateral hindpaw 3 days before carrageenan administration reduced hypersensitivity. Dysport and Botox elicited comparable antihyperalgesic effects. Dysport up to 30 U/kg and Botox up to 20 U/kg did not impair the rat withdrawal nociceptive reflex or the locomotor performance as assessed by the rotarod test. Intraperitoneal administration of the skeletal muscle relaxant dantrolene produced, in contrast to BoNT-A, more motor impairment than analgesia. Paclitaxel treatment resulted in a peripheral neuropathy that affected the two hindpaws. Injection of 20 U/kg (s.p.) Dysport produced a significant antihyperalgesic effect in the injected paw of neuropathic animals 3 days after administration. Unexpectedly, a similar analgesic effect was observed in the contralateral paw. The same results were also observed when Botox was used instead of Dysport. In contrast, a contralateral administration of Dysport in the carrageenan test was ineffective. We conclude that BoNT-A elicits antinociceptive effects independent of the effects on muscular relaxation. Our results suggest that different mechanisms of action are responsible for the effect of BoNT-A in inflammatory and peripheral polyneuropathic rat models.
Assuntos
Analgésicos/farmacologia , Toxinas Botulínicas Tipo A/farmacologia , Polineuropatias/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/uso terapêutico , Carragenina , Dantroleno/administração & dosagem , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Injeções , Masculino , Atividade Motora/efeitos dos fármacos , Paclitaxel , Polineuropatias/induzido quimicamente , Polineuropatias/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
BN82451 belongs to a new family of small molecules designated as multitargeting or hybrid molecules. BN82451 is orally active, has good central nervous system penetration, and elicits potent neuronal protection and antiinflammatory properties. Neuronal protection is due to Na+ channel blockade, antioxidant properties, and mitochondria-protecting activity, whereas inhibition of cyclooxygenases is mostly responsible for its antiinflammatory activity. BN82451 has been shown to exert a potent neuroprotective effect in various in vitro and in vivo animal models. BN82451 was found to exert a significant protection in experimental animal models mimicking aspects of cerebral ischemia, Parkinson disease, Huntington disease, and more particularly amyotrophic lateral sclerosis. Collectively, its pharmacological properties designate BN82451 as a promising neuroprotective agent.
Assuntos
Doenças do Sistema Nervoso/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fenóis/farmacologia , Animais , Modelos Animais de Doenças , Fenóis/química , Fenóis/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
A series of 4-arylimidazole carbamates was synthesized and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to the identification of compound 10, a potent Na+ channel blocker which was efficacious in pain models in vivo.
Assuntos
Carbamatos/síntese química , Carbamatos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Batraquiotoxinas , Ligação Competitiva/efeitos dos fármacos , Carragenina , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indicadores e Reagentes , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Ratos , Sódio/metabolismo , Relação Estrutura-Atividade , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Veratridina/farmacologiaRESUMO
The synthesis and biological activity of novel lipoic acid analogues are reported. Lipoic acid and structural homologues coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ácido Tióctico/análogos & derivados , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , Arginina/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citrulina/metabolismo , Desenho de Fármacos , Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidade , Glutationa/deficiência , Glutationa/metabolismo , Camundongos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase/toxicidade , Óxido Nítrico Sintase Tipo I , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/síntese química , Ácido Tióctico/farmacologiaRESUMO
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.