The pathophysiology of cerebral ischemia involves multiple mechanisms including neuroinflammation mediated by activated microglia and infiltrating macrophages/monocytes. The present study employed a rat permanent middle cerebral artery occlusion (pMCAO) model to study effects of histone deacetylase (HDAC) inhibition on ischemia-induced brain infarction, neuroinflammation, gene expression, and neurological deficits. We found that post-pMCAO injections with HDAC inhibitors, valproic acid (VPA), sodium butyrate (SB), or trichostatin A (TSA), decreased brain infarct volume. Postinsult treatment with VPA or SB also suppressed microglial activation, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. The reduction in levels of acetylated histone H3 in the ischemic brain was prevented by treatment with VPA, SB, or TSA. Moreover, injections with HDAC inhibitors superinduced heat-shock protein 70 and blocked pMCAO-induced down-regulation of phospho-Akt, as well as ischemia-elicited up-regulation of p53, inducible nitric oxide synthase, and cyclooxygenase-2. The motor, sensory, and reflex performance of pMCAO rats was improved by VPA, SB, or TSA treatment. The beneficial effects of SB and VPA in reducing brain infarct volume and neurological deficits occurred when either drug was administrated at least 3 h after ischemic onset, and the behavioral improvement was long-lasting. Together, our results demonstrate robust neuroprotective effects of HDAC inhibitors against cerebral ischemia-induced brain injury. The neuroprotection probably involves multiple mechanisms including suppression of ischemia-induced cerebral inflammation. Given that there is no effective treatment for stroke, HDAC inhibitors, such as VPA, SB, and TSA, should be evaluated for their potential use for clinical trials in stroke patients.Stroke, also referred to as cerebral ischemia, is a pathological condition resulting from occlusion or hemorrhage of blood vessels supplying oxygen and essential nutrients to the brain. In all cases, stroke ultimately induces death and/or dysfunction of brain cells, as well as neurological impairments that reflect the location and size of the ischemic brain area. Mechanisms leading to cell death during cerebral ischemic injury are complex, including excitotoxicity, ionic imbalance, oxidative/nitrosative stress, and inflammation (for review, see Lo et al., 2003). It is increasingly recognized that cerebral inflammation mediated by activated microglia and infiltrating leukocytes, including monocytes/macrophages, also plays a key role in focal ischemia-induced neurodegeneration. Activated microglia and invading leukocytes exert a cytotoxic function by releasing proinflammatory cytokine factors (IL-1, IL-2, and TNF-␣), nitric oxide (NO), and reactive oxygen species, which contribute to brain infarction and excitotoxicity (Gregersen et al., 2000).Valproic acid (2-propylpentanoic acid sodium salt; VPA), a drug commonly used to treat seizures and bipolar mood disorder, has been...

In the healthy adult brain, neurogenesis normally occurs in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Cerebral ischemia enhances neurogenesis in neurogenic and non‐neurogenic regions of the ischemic brain of adult rodents. This study demonstrated that post‐insult treatment with a histone deacetylase inhibitor, sodium butyrate (SB), stimulated the incorporation of bromo‐2′‐deoxyuridine (BrdU) in the SVZ, DG, striatum, and frontal cortex in the ischemic brain of rats subjected to permanent cerebral ischemia. SB treatment also increased the number of cells expressing polysialic acid–neural cell adhesion molecule, nestin, glial fibrillary acidic protein, phospho‐cAMP response element‐binding protein (CREB), and brain‐derived neurotrophic factor (BDNF) in various brain regions after cerebral ischemia. Furthermore, extensive co‐localization of BrdU and polysialic acid–neural cell adhesion molecule was observed in multiple regions after ischemia, and SB treatment up‐regulated protein levels of BDNF, phospho‐CREB, and glial fibrillary acidic protein. Intraventricular injection of K252a, a tyrosine kinase B receptor antagonist, markedly reduced SB‐induced cell proliferation detected by BrdU and Ki67 in the ipsilateral SVZ, DG, and other brain regions, blocked SB‐induced nestin expression and CREB activation, and attenuated the long‐lasting behavioral benefits of SB. Together, these results suggest that histone deacetylase inhibitor‐induced cell proliferation, migration and differentiation require BDNF–tyrosine kinase B signaling and may contribute to long‐term beneficial effects of SB after ischemic injury.

One-third of the global population aged 15 years and older engages in insufficient physical activities, which affects health. However, the health risks posed by sedentary behaviors are not well known. The mean daily duration of sedentary behavior is 8.3 hours among the Korean population and 7.7 hours among the American adult population. Sedentary lifestyles are spreading worldwide because of a lack of available spaces for exercise, increased occupational sedentary behaviors such as office work, and the increased penetration of television and video devices. Consequently, the associated health problems are on the rise. A sedentary lifestyle affects the human body through various mechanisms. Sedentary behaviors reduce lipoprotein lipase activity, muscle glucose, protein transporter activities, impair lipid metabolism, and diminish carbohydrate metabolism. Furthermore, it decreases cardiac output and systemic blood flow while activating the sympathetic nervous system, ultimately reducing insulin sensitivity and vascular function. It also alters the insulin-like growth factor axis and the circulation levels of sex hormones, which elevates the incidence of hormone-related cancers. Increased sedentary time impairs the gravitostat, the body's weight homeostat, and weight gain, adiposity, and elevated chronic inflammation caused by sedentary behavior are risk factors for cancer. Sedentary behaviors have wide-ranging adverse impacts on the human body including increased all-cause mortality, cardiovascular disease mortality, cancer risk, and risks of metabolic disorders such as diabetes mellitus, hypertension, and dyslipidemia; musculoskeletal disorders such as arthralgia and osteoporosis; depression; and, cognitive impairment. Therefore, reducing sedentary behaviors and increasing physical activity are both important to promote public health.

PurposeThe purpose of the Korean Frailty and Aging Cohort Study (KFACS) is to initiate a nationwide, population-based prospective cohort study of older adults living in the community to assess their frailty status and explore transitions between frailty states over time in Korea.ParticipantsThe KFACS is a multicentre longitudinal study with the baseline survey conducted from May 2016 to November 2017. Each centre recruited participants using quota sampling stratified by age and sex. The number of participants recruited through 2 years of baseline study from 10 centres was 3014, with each site accounting for approximately 300 participants. The inclusion criteria were: having an age of 70–84 years, currently living in the community, having no plans to move out in the next 2 years, having no problems with communication and no prior dementia diagnosis.Findings to dateTo define physical frailty, the KFACS used a modified version of the Fried Frailty Phenotype (FFP) consisting of five components of frailty: unintended weight loss, weakness, self-reported exhaustion, slowness and low physical activity. In the baseline study of 2016–2017, 2907 of 3014 individuals fulfilled all five components of FFP. The results indicated that 7.8% of the participants (n=228) were frail, 47.0% (n=1366) were prefrail and 45.2% (n=1313) were robust. The prevalence of frailty increased with age in both sexes; in the group aged 70–74 years, 1.8% of men and 3.7% of women were frail, whereas in the 80–84 years age group, 14.9% of men and 16.7% of women were frail. Women tended to exhibit a higher prevalence of frailty than men in all age groups.Future plansThe KFACS plans to identify outcomes and risk factors associated with frailty by conducting a 10-year cohort study, with a follow-up every 2 years, using 3014 baseline participants.