trichostatin-a and Brain-Injuries

Trichostatin A (TSA), a pan-histone deacetylase inhibitor, exerts multiple neuroprotective properties. This study aims to examine whether TSA could enhance autophagy, thereby reduce neuronal apoptosis and ultimately attenuate early brain injury (EBI) following subarachnoid hemorrhage (SAH). SAH was performed through endovascular perforation method, and mortality, neurological score, and brain water content were evaluated at 24 h after surgery. Western blot were used for quantification of acetylated histone H3, LC3-II, LC3-I, Beclin-1, cytochrome c, Bax, and cleaved caspase-3 expression. Immunofluorescence was performed for colocalization of Beclin-1 and neuronal nuclei (NeuN). Apoptotic cell death of neurons was quantified with double staining of terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) and NeuN. The autophagy inhibitor 3-methyladenine (3-MA) was used to manipulate the proposed pathway. Our results demonstrated that TSA reduced brain edema and alleviated neurological deficits at 24 h after SAH. TSA significantly increased acetylated histone H3, the LC3-II/LC3-I ratio, and Beclin-1 while decreased Bax and cleaved caspase-3 in the cortex. Beclin-1 and NeuN, TUNEL, and NeuN, respectively, were colocalized in cortical cells. Neuronal apoptosis in the ipsilateral basal cortex was significantly inhibited after TSA treatment. Conversely, 3-MA reversed the beneficial effects of TSA. These results proposed that TSA administration enhanced autophagy, which contributes to alleviation of neuronal apoptosis, improvement of neurological function, and attenuation of EBI following SAH.

Topics: Animals; Apoptosis; Autophagy; Brain Injuries; Disease Models, Animal; Histone Deacetylase Inhibitors; Hydroxamic Acids; Male; Neurons; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

Hundreds of previous studies demonstrated the cytoprotective effect of trichostatin-A (TSA), a kind of histone deacetylases inhibitors (HDACIs), against cerebral ischemia/reperfusion insult. Meanwhile, phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is a well-known, important signaling pathway that mediates neuroprotection. However, it should be remains unclear whether the neuroprotective capabilities of TSA against cerebral ischemia/reperfusion is mediated by activation of the PI3K/Akt signaling pathway.. Five groups rats (n = 12 each), with middle cerebral artery occlusion (MCAO) except sham group, were used to investigate the neuroprotective effect of certain concentration (0.05 mg/kg) of TSA, and whether the neuroprotective effect of TSA is associated with activation of the PI3K/Akt signaling pathway through using of wortmannin (0.25 mg/kg).. TSA significantly increased the expression of p-Akt protein, reduced infarct volume, and attenuated neurological deficit in rats with transient MCAO, wortmannin weakened such effect of TSA dramatically.. TSA could significantly decrease the neurological deficit scores and reduce the cerebral infarct volume during cerebral ischemia/reperfusion injury, which was achieved partly by activation of the PI3K/Akt signaling pathway via upgrading of p-Akt protein.

Topics: Analysis of Variance; Androstadienes; Animals; Brain Injuries; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydroxamic Acids; Male; Nervous System Diseases; Neuroprotective Agents; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Wortmannin

To explore the effect of whole brain irradiation (WBI) on neurogenesis in hippocampus and its relationship with histone acetylation.. A signal dose of 30Gy 4MeV electron beam was offered to male Sprague-Dawley rats (150 - 200 g). At Days 7 and 30, immunohistochemistry and Western blot were used to analyze the effects of WBI on neurogenesis and the expression of acetyl-H3 and histone deacetylase 1 (HDAC1) in hippocampus. Finally trichostatin A (TSA), a HDAC1 inhibitor, was used to verify whether H3 acetylation was associated with neurogenesis impairment.. Immunofluorescence showed that, at Day 7 post-irradiation, the number of BrdU + NeuN + cells reduced by 67% (P < 0. 01) and it approached zero at Day 30 (P < 0. 01). Meanwhile, a significant decrease of HDAC1-dependent H3 acetylation was observed. Western blot showed 30% (P <0. 05) and 61% (P < 0. 01) reductions in H3 acetylation at Days 7 and 30 post-irradiation respectively. These results were further confirmed by immunofluorescent staining. Also HDAC1 levels significantly increased in a time-dependent manner at Days 7 and 30 post-irradiation. And TSA rescued neurogenesis impairment after WBI.. Radiation-induced HDAC1-dependent H3 acetylation decline is associated with long-term neurogenesis impairment in dentate gyrus.

Topics: Acetylation; Animals; Brain Injuries; Hippocampus; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Male; Neurogenesis; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley

Acetylation/deactylation of histones is an important mechanism to regulate gene expression and chromatin remodeling. We have previously demonstrated that the HDAC inhibitor trichostatin A (TSA) protects cortical neurons from oxygen/glucose deprivation in vitro which is mediated--at least in part--via the up regulation of gelsolin expression. Here, we demonstrate that TSA treatment dose-dependently enhances histone acetylation in brains of wildtype mice as evidenced by immunoblots of total brain lysates and immunocytochemical staining. Along with increased histone acetylation dose-dependent up regulation of gelsolin protein was observed. Levels of filamentous actin were largely decreased by TSA pre-treatment in brain of wildtype but not gelsolin-deficient mice. When exposed to 1 h filamentous occlusion of the middle cerebral artery followed by reperfusion TSA pre-treated wildtype mice developed significantly smaller cerebral lesion volumes and tended to have improved neurological deficit scores compared to vehicle-treated mice. These protective effects could not be explained by apparent changes in physiological parameters. In contrast to wildtype mice, TSA pre-treatment did not protect gelsolin-deficient mice against MCAo/reperfusion suggesting that enhanced gelsolin expression is an important mechanism by which TSA protects against ischemic brain injury. Our results suggest that HDAC inhibitors such as TSA are a promising therapeutic strategy for reducing brain injury following cerebral ischemia.

Topics: Acetylation; Animals; Brain Injuries; Brain Ischemia; Calcium; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Gelsolin; Glucose; Histones; Hydroxamic Acids; Hypoxia; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphopyruvate Hydratase; Rats