RESUMO
Huntington's disease (HD) is the most common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approaches may open the door to new and more targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2 mice, a widely used HD animal model. Chronic administration of low-dose (0.1 mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2 mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HD mice from the classic progressive motor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5 may be also seen as an effective approach to target brain vasculature defects in the disease.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Proteína Huntingtina/genética , Doença de Huntington/tratamento farmacológico , Agregação Patológica de Proteínas/tratamento farmacológico , Receptores de Lisoesfingolipídeo/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Agregação Patológica de Proteínas/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Lisoesfingolipídeo/agonistasRESUMO
We have recently reported that the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates acquisition of conditioned place preference (CPP) induced by heroin and ketamine. The present study investigated to what extent this effect of MPEP can be generalized to other classes of drugs, such as the stimulants nicotine and cocaine, and to drugs that produce CPP in the rat despite a lack of abuse potential in humans, such as buspirone and clonidine. Adult male Sprague Dawley rats were subjected to a standard unbiased CPP protocol (six conditioning sessions lasting 20 minutes for nicotine and 40 minutes for the other compounds). Rats were conditioned with either nicotine (0.05-0.2 mg/kg, subcutaneously), cocaine [1-10 mg/kg, intraperitoneally (i.p.)], buspirone (0.3-3 mg/kg, i.p.) or clonidine (0.2-0.6 mg/kg, i.p.) in combination with MPEP (0 or 10 mg/kg, i.p.). For nicotine and cocaine, the minimal effective dose to induce CPP was lowered by pre-treatment with MPEP. While buspirone and clonidine did not induce CPP when given alone (i.e. combined with MPEP vehicle), both compounds induced CPP after pre-treatment with MPEP. It is concluded that MPEP consistently potentiates acquisition of drug-induced reward, independent of the mechanism of action of the co-administered drug. We suggest that the proposed anti-abuse effect of MPEP may be due to a substitution-like effect.