Meclizine is neuroprotective in models of Huntington's disease.
Defects in cellular energy metabolism represent an early feature in a variety of human neurodegenerative diseases. Recent studies have shown that targeting energy metabolism can protect against neuronal cell death in such diseases. Here, we show that meclizine, a clinically used drug that we have recently shown to silence oxidative metabolism, suppresses apoptotic cell death in a murine cellular model of polyglutamine (polyQ) toxicity. We further show that this protective effect extends to neuronal dystrophy and cell death in Caenorhabditis elegans and Drosophila melanogaster models of polyQ toxicity. Meclizine's mechanism of action is not attributable to its anti-histaminergic or anti-muscarinic activity, but rather, strongly correlates with its ability to suppress mitochondrial respiration. Since meclizine is an approved drug that crosses the blood-brain barrier, it may hold therapeutic potential in the treatment of polyQ toxicity disorders, such as Huntington's disease.
Gohil
Vishal M
VM
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. vgohil@chgr.mgh.harvard.edu
Offner
Nicolas
N
Walker
James A
JA
Sheth
Sunil A
SA
Fossale
Elisa
E
Gusella
James F
JF
MacDonald
Marcy E
ME
Neri
Christian
C
Mootha
Vamsi K
VK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008468:Meclizine / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000009:adverse effects
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D008468:Meclizine