Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease.

التفاصيل البيبلوغرافية
العنوان:	Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease.
المؤلفون:	Doria, JG, Silva, FR, Souza, JM, Vieira, LB, Carvalho, TG, Reis, HJ, Pereira, GS, Dobransky, T, Ribeiro, FM
المصدر:	British Journal of Pharmacology; Jun2013, Vol. 169 Issue 4, p909-921, 13p, 9 Graphs
مصطلحات موضوعية:	GLUTAMATE receptors, ALLOSTERIC regulation, NEUROPROTECTIVE agents, HUNTINGTON disease, NEURODEGENERATION, GENETIC disorders, LABORATORY mice
مستخلص:	Background and Purpose Huntington's disease ( HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 ( mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca²⁺ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators ( PAMs) could activate protective pathways without triggering high levels of Ca²⁺ release and be neuroprotective in HD. Experimental Approach We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca²⁺ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit. Key Results We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca²⁺ concentration ([Ca²⁺]i); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit. Conclusions and Implications mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD. [ABSTRACT FROM AUTHOR]
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قاعدة البيانات:	Complementary Index

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