Electroconvulsive shock ameliorates disease processes and extends survival in huntingtin mutant mice.

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin (Htt) protein. Mutant Htt may damage and kill striatal neurons by a mechanism involving reduced production of brain-derived neurotrophic factor (BDNF) and increased oxidative and metabolic stress. Because electroconvulsive shock (ECS) can stimulate the production of BDNF and protect neurons against stress, we determined whether ECS treatment would modify the disease process and provide a therapeutic benefit in a mouse model of HD. ECS (50 mA for 0.2 s) or sham treatment was administered once weekly to male N171-82Q Htt mutant mice beginning at 2 months of age. Endpoints measured included motor function, striatal and cortical pathology, and levels of protein chaperones and BDNF. ECS treatment delayed the onset of motor symptoms and body weight loss and extended the survival of HD mice. Striatal neurodegeneration was attenuated and levels of protein chaperones (Hsp70 and Hsp40) and BDNF were elevated in striatal neurons of ECS-treated compared with sham-treated HD mice. Our findings demonstrate that ECS can increase the resistance of neurons to mutant Htt resulting in improved functional outcome and extended survival. The potential of ECS as an intervention in subjects that inherit the mutant Htt gene merits further consideration.

• Authors: Mohamed R Mughal, Akanksha Baharani, Srinivasulu Chigurupati, Tae Gen Son, Edmund Chen, Peter Yang, Eitan Okun, Thiruma Arumugam, Sic L Chan, Mark P Mattson
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 20 Issue 4 Pg. 659-69 (Feb 15 2011) ISSN: 1460-2083 [Electronic] England
• PMID: 21106706 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Brain-Derived Neurotrophic Factor
• Cyclic AMP Response Element-Binding Protein
• Heat-Shock Proteins
• Serotonin Plasma Membrane Transport Proteins
• Slc6a4 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Disease Progression
• Electroshock
• Gene Expression Regulation
• Heat-Shock Proteins (genetics, metabolism)
• Huntington Disease (genetics, pathology, therapy)
• Male
• Mice
• Mice, Transgenic
• Mutation (genetics)
• Nerve Degeneration (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Serotonin Plasma Membrane Transport Proteins (genetics, metabolism)
• Signal Transduction
• Survival Analysis