title: The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats.
abstract: Sodium butyrate (NaB) is a histone deacetylase (HDAC) inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of stroke as well as a myocardial ischemia model. Although clinical evidence shows that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of NaB either in females or in older animals.
  
  
  
  To determine the effects of NaB on stroke in older females, acyclic middle-aged Sprague-Dawley female rats (9-11 months old, constant diestrus) were subject to middle cerebral artery occlusion (MCAo) by intracerebral injection of recombinant endothelin-1. Rats were treated with NaB (300 mg/kg, i.p.) at 6 and 30 h following ET-1 injection. Animals were sacrificed at the early (2 days) or late (5 days) acute phase after MCAo. Serum and tissue lysates were collected for biochemical analyses.
  
  
  
  NaB treatment reduced infarct volume and ameliorated sensory motor impairment in middle-aged female rats, when measured at 2 and 5 days post MCAo. At the early acute phase (2 days post stroke), NaB treatment decreased brain lipid peroxides, and reduced serum levels of GFAP, a surrogate marker of blood-brain barrier (BBB) permeability. NaB also reduced expression of the inflammatory cytokine IL-1beta in circulation and IL-18 in the ischemic hemisphere. At the late acute phase (5 days post stroke), NaB treatment further suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates (cortex and striatum) from the ischemic hemisphere, and decreased ischemia-induced upregulation of IL-1beta and IL-18 in circulation, indicating a potent anti-inflammatory effect of the HDAC inhibitor. Moreover, NaB treatment also increased expression of IGF-1, a known neuroprotectant, in peripheral tissue including serum, liver, and spleen at the late acute phase.
  
  
  
  These data provide the first evidence that delayed (>6 h) NaB treatment post-stroke is neuroprotective in older female rats. Additionally, these data also show that in addition to its well-known anti-inflammatory actions, NaB may exert a biphasic effect after stroke, operating initially to reduce BBB permeability and oxidative stress in the brain, and later, elevating IGF-1 expression in peripheral tissues.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, College of Medicine, Texas A&M University Health Science Center, 8447 State Highway 47, Bryan, TX, 77807, USA.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, College of Medicine, Texas A&M University Health Science Center, 8447 State Highway 47, Bryan, TX, 77807, USA. Sohrabji@medicine.tamhsc.edu.
authors.forename: Farida
authors.initials: F
authors.lastname: Sohrabji
mesh_terms: D000367:Age Factors; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D020148:Butyric Acid / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D020148:Butyric Acid
keywords: Cytokines; Histone deacetylase inhibitor; Inflammation; Insulin-like growth factor-1; Ischemic stroke; Middle-aged female; Oxidative stress; Sodium butyrate