{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:01:08Z","timestamp":1793275268568,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,5,27]],"date-time":"2013-05-27T00:00:00Z","timestamp":1369612800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,6]]},"abstract":"Background and Purpose<\/jats:title>H<\/jats:styled-content>untington's disease (HD<\/jats:styled-content>) 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<\/jats:styled-content>) is altered in a mouse model of HD<\/jats:styled-content>. Although mGluR5<\/jats:styled-content>\u2010dependent protective pathways are more activated in HD<\/jats:styled-content> neurons, intracellular Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5<\/jats:styled-content> positive allosteric modulators (PAMs<\/jats:styled-content>) could activate protective pathways without triggering high levels of Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> release and be neuroprotective in HD<\/jats:styled-content>.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We performed a neuronal cell death assay to determine which drugs are neuroprotective, W<\/jats:styled-content>estern blot and Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD<\/jats:styled-content> memory deficit.<\/jats:p><\/jats:sec>Key Results<\/jats:title>We find that mGluR5 PAMs<\/jats:styled-content> can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA<\/jats:styled-content>. mGluR5 PAMs<\/jats:styled-content> are capable of activating Akt<\/jats:styled-content> without triggering increased intracellular Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> concentration ([Ca2+<\/jats:sup>]i<\/jats:sub>); and Akt<\/jats:styled-content> blockage leads to loss of PAM<\/jats:styled-content>\u2010mediated neuroprotection. Importantly, PAMs<\/jats:styled-content>' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs<\/jats:styled-content> on striatal neurons from a mouse model of HD<\/jats:styled-content>, BACHD<\/jats:styled-content>. Moreover, mGluR5 PAMs<\/jats:styled-content> can activate neuroprotective pathways more robustly in BACHD<\/jats:styled-content> mice and ameliorate HD<\/jats:styled-content> memory deficit.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>mGluR5 PAMs<\/jats:styled-content> are potential drugs that may be used to treat neurodegenerative diseases, especially HD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12164","type":"journal-article","created":{"date-parts":[[2013,3,14]],"date-time":"2013-03-14T02:21:47Z","timestamp":1363227707000},"page":"909-921","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of H<\/scp>untington's disease"],"prefix":"10.1111","volume":"169","author":[{"given":"JG","family":"Doria","sequence":"first","affiliation":[{"name":"Departamento de Bioquimica e Imunologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"FR","family":"Silva","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica e Imunologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JM","family":"de Souza","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica e Imunologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LB","family":"Vieira","sequence":"additional","affiliation":[{"name":"INCT de Medicina Molecular Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TG","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica e Imunologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HJ","family":"Reis","sequence":"additional","affiliation":[{"name":"Departamento de Farmacologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GS","family":"Pereira","sequence":"additional","affiliation":[{"name":"Nucleo de Neurociencias Departamento de Fisiologia e Biofisica ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Dobransky","sequence":"additional","affiliation":[{"name":"DB Biotech Kosice Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"FM","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica e Imunologia ICB Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,5,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-21-07871.2000"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0380493"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2005.04.029"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.059170"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0953-816x.2001.01541.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1999.7092"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-011-0691-z"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2008.10.006"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.22.2905"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(90)90111-M"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00889.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(88)90157-X"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309348200"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920112800784817"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0857-08.2008"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0995-04.2004"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00188-0"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1999.4690"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2011.10.003"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2004.01.008"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00873.x"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4360-04.2005"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(96)20019-0"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1150"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.2174\/187152710793361612"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4974-09.2010"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-010-8153-1"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2005.pto_156.x"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.067207"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1134"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2004.06.005"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4286-09.2009"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.02.003"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00366-0"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409402102"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199805000-00001"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2008.09.007"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17742"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2000.0909"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00615-3"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.090308"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.12164","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.12164","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.12164","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.12164","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T15:53:38Z","timestamp":1694447618000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.12164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,27]]},"references-count":44,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2013,6]]}},"alternative-id":["10.1111\/bph.12164"],"URL":"https:\/\/doi.org\/10.1111\/bph.12164","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,5,27]]},"assertion":[{"value":"2012-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-02-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-05-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}