title: Epigenetic modifications by inhibiting histone deacetylases reverse memory impairment in insulin resistance induced cognitive deficit in mice.
abstract: Insulin resistance has been reported as a strong risk factor for Alzheimer's disease. However the molecular mechanisms of association between these still remain elusive. Various studies have highlighted the involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits. Thus, the present study was designed to investigate the possible neuroprotective role of HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) in insulin resistance induced cognitive impairment in mice. Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. HFD fed mice were treated with SAHA at 25 and 50 mg/kg i.p. once daily for 2 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured. A battery of behavioral parameters was performed to assess cognitive functions. Level of tumour necrosis factor (TNF-α) was measured in hippocampus to assess neuroinflammation. To further explore the molecular mechanisms we measured the histone H3 acetylation and brain derived neurotrophic factor (BDNF) level. HFD fed mice exhibit characteristic features of insulin resistance. These mice also showed a severe deficit in learning and memory along with reduced histone H3 acetylation and BDNF levels. In contrast, the mice treated with SAHA showed significant and dose dependent improvement in insulin resistant condition. These mice also showed improved learning and memory performance. SAHA treatment ameliorates the HFD induced reduction in histone H3 acetylation and BDNF levels. Based upon these results, it could be suggested that HDAC inhibitors exert neuroprotective effects by increasing H3 acetylation and subsequently BDNF level.
authors.affiliation: Neuropharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India.
authors.forename: Sorabh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Neuropharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India. Electronic address: taliyanraja@gmail.com.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Taliyan
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics*; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat
keywords: Alzheimer's disease; Cognitive deficit; Histone deacetylases; Insulin resistance; Suberoylanilide hydroxamic acid