Abstract
Hypoxia-ischemia (HI) in the neonatal brain frequently results in neurologic impairments, including cognitive disability. Unfortunately, there are currently no known treatment options to minimize ischemia-induced neural damage. We previously showed the neuroprotective/neurogenic potential of a histone deacetylase inhibitor (HDACi), sodium butyrate (SB), in a neonatal HI rat pup model. The aim of the present study was to examine the capacity of another HDACi—Trichostatin A (TSA)—to stimulate neurogenesis in the subgranular zone of the hippocampus. We also assessed some of the cellular/molecular processes that could be involved in the action of TSA, including the expression of neurotrophic factors (glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF)) as well as the TrkB receptor and its downstream signalling substrate— cAMP response element-binding protein (CREB). Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 1 h. TSA was administered directly after the insult (0.2 mg/kg body weight). The study demonstrated that treatment with TSA restored the reduced by hypoxia-ischemia number of immature neurons (neuroblasts, BrdU/DCX-positive) as well as the number of oligodendrocyte progenitors (BrdU/NG2+) in the dentate gyrus of the ipsilateral damaged hemisphere. However, new generated cells did not develop the more mature phenotypes. Moreover, the administration of TSA stimulated the expression of BDNF and increased the activation of the TrkB receptor. These results suggest that BDNF-TrkB signalling pathways may contribute to the effects of TSA after neonatal hypoxic-ischemic injury.
Highlights
Neonatal hypoxia-ischemia (HI) insults due to perinatal asphyxia remain the main cause of neurological injury resulting from birth complications
Analysis of the Western Blot data clearly shows that the treatment with Trichostatin A (TSA) did not change the level of acetylated histone H3 estimated in rat brain hemispheres at 1, 3, and 7 days after HI (Figure 1A,B)
To investigate the molecular mechanism by which TSA enhanced the generation of neuroblasts and oligodendrocyte precursor cells (OPCs) after neonatal hypoxia-ischemia, we evaluated the expression of neurotrophic growth factors that are involved in neuronal survival and neurogenesis stimulation
Summary
Neonatal hypoxia-ischemia (HI) insults due to perinatal asphyxia remain the main cause of neurological injury resulting from birth complications. They are caused by the restriction of blood supply and, as a consequence, the deficiency of oxygen and glucose in the brain. Brain damage following hypoxic-ischemic insults is a process that evolves over several hours to days and it provides a possibility for therapeutic intervention in the HI-induced cascade of intracellular events. Until this point, the treatment and prevention options have been limited. A major challenge in this field is overcoming the redundancy of the multiple pathways activated in response to injury using a single intervention that will provide an efficient stimulation of brain neurogenesis [6]
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