Impact of trichostatin A and sodium valproate treatment on post-stroke neurogenesis and behavioral outcomes in immature mice

Abstract

Stroke in the neonatal brain frequently results in neurologic impairments including cognitive disability. We investigated the effect of long-term sodium valproate (valproate) and trichostatin A (TSA) treatment upon post-stroke neurogenesis in the dentate gyrus (DG) of stroke-injured immature mice. Decreased or abnormal integration of newborn DG neurons into hippocampal circuits can result in impaired visual-spatial function, abnormal modulation of mood-related behaviors, and the development of post-stroke epilepsy. Unilateral carotid ligation of P12 CD1 mice was followed by treatment with valproate, TSA, or vehicle for 2 weeks, bromodeoxyuridine (BrdU) administration for measurement of neurogenesis, and perfusion at P42 or P60. Behavior testing was conducted from P38–42. No detrimental effects on behavior testing were noted with TSA treatment, but mildly impaired cognitive function was noted with valproate-treated injured animals compared to normal animals. Significant increases in DG neurogenesis with both TSA and valproate treatment were noted with later administration of BrdU. Increased mortality and impaired weight gain was noted in the valproate-treated ligated animals, but not in the TSA-treated animals. In summary, the impact of histone deacetylase (HDAC) inhibition upon post-stroke subgranular zone neurogenesis is likely to depend on the age of the animal at the time point when neurogenesis is assessed, duration of HDAC inhibition before BrdU labeling, and/or the stage in the evolution of the injury.

Sodium Butyrate, a Histone Deacetylase Inhibitor, Exhibits Neuroprotective/Neurogenic Effects in a Rat Model of Neonatal Hypoxia-Ischemia

“…Thus, it follows, that in our experimental conditions, the expected SB-induced regenerative capacity fails as a source of meaningful compensation for lost neuronal circuits. According to the results of the detailed elegant study performed by George et al [ 29 ], the impact of HDAC inhibitors upon post-stroke neurogenesis is likely to depend on many factors, including the age of the animal at the time where neurogenesis is assayed, duration of HDAC inhibition before the BrdU labeling, and/or stage of the evolution of injury. Our results remain in disagreement with reports indicating that SB, as well as other inhibitor treatments, induced neuronal cell differentiation in brain areas injured by ischemia and may contribute to long-term beneficial effects in adult rodents [ 13 , 16 ].…”

Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery

“…Ischemia alters the expression of multiple HDAC proteins (Baltan et al, 2011), and these have become popular targets for preclinical neuroprotection studies in stroke. Several studies now have demonstrated protective effects of HDAC inhibition in animal models of stroke with various compounds including valproic acid, trichostatin A, and sodium butyrate (Kim et al, 2007; Wang et al, 2012; George et al, 2013). The action of HDAC enzymes is complex, with some subtypes exhibiting protective effects while others may promote cell death (Langley et al, 2008; Chuang et al, 2009).…”

Comparison between single and combined post-treatment with S-Methyl-N,N-diethylthiolcarbamate sulfoxide and taurine following transient focal cerebral ischemia in rat brain

“…Therefore, there is an urgent need for developing safer therapies that can be offered to a higher percentage of patients. Although some pharmacological agents exist (Zivin, 2009;Turner and Vink, 2012;George et al, 2013;Gharibani et al, 2013;Modi et al, 2014;Mohammad-Gharibani et al, 2014;Venna et al, 2014;Xu et al, 2015), it is very important to establish how these agents could be neuroprotective in poststroke individually or in a combined manner. Following stroke, the ischemic core and the peri-infarct zone (ischemic penumbra) suffer from different degrees of cellular damage and it is widely accepted that cell death in the ischemic core is triggered by necrosis while that which occurs in the penumbra is predominantly mediated by apoptosis (Kiewert et al, 2010).…”