Histone Hyperacetylation as a Response to Global Brain Ischemia Associated with Hyperhomocysteinemia in Rats

Abstract

Epigenetic regulations play an important role in both normal and pathological conditions of an organism, and are influenced by various exogenous and endogenous factors. Hyperhomocysteinemia (hHcy), as a risk factor for several pathological conditions affecting the central nervous system, is supposed to alter the epigenetic signature of the given tissue, which therefore worsens the subsequent damage. To investigate the effect of hHcy in combination with ischemia-reperfusion injury (IRI) and histone acetylation, we used the hHcy animal model of global forebrain ischemia in rats. Cresyl violet staining showed massive neural disintegration in the M1 (primary motor cortex) region as well as in the CA1 (cornu ammonis 1) area of the hippocampus induced by IRI. Neural loss was significantly higher in the group with induced hHcy. Moreover, immunohistochemistry and Western blot analysis of the brain cortex showed prominent changes in the acetylation of histones H3 and H4, at lysine 9 and 12, respectively, as a result of IRI and induced hHcy. It seems that the differences in histone acetylation patterns in the cortical region have a preferred role in pathological processes induced by IRI associated with hHcy and could be considered in therapeutic strategies.

Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus

“…(a,b) Bar = 500 µm; (c,d) Bar = 50 µm; n = 5/group. Schematic coronal rat brain section (e), redrawn according to Tothova et al [12] representing hippocampus (blue rectangle) and smaller (red rectangle) detects CA1 area of rat hippocampus.…”

“…This hHcy condition resulted in the disintegration of neuronal tissue in the cerebral cortex as well as the hippocampus. Moreover, Tóthová et al [12] have shown that hHcy on the same rat model also triggers remarkable epigenetic changes with the impairment in histone acetylation, likely within the context of hHcy-initiated DNA hypomethylation in vulnerable brain areas [9].…”

“…Our previous works documented that subcutaneous administration of Hcy in rats led to the development of mild hHcy [10][11][12]. This hHcy condition resulted in the disintegration of neuronal tissue in the cerebral cortex as well as the hippocampus.…”

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

“…In our previous work on the rat hHcy model induced by a Met-enriched diet [ 20 ], we have revealed considerable cerebral dysregulations: (i) on the level of cerebral metabolites, and (ii) histologically detected acceleration of the hippocampal neurodegeneration. Previous papers from our laboratory [ 21 , 22 , 23 , 24 ] documented that the combination of hHcy induced by direct Hcy injection with the subsequent ischemia-reperfusion insult (IRI), aggravates neurodegenerative processes and might eventually lead to the development of AD-like pathology [ 22 , 23 ]. Using a novel methodological approach, we demonstrate here that the rats with the Met-enriched diet (inducing hHcy) were subject to the IRI manifested exacerbated patterns of hippocampal neurodegeneration.…”

Hydroalcoholic Extract of Anchusa Italica Protects Global Cerebral Ischemia-Reperfusion Injury Via a Nitrergic Mechanism

“…In contrast, overexpressed eNOS in transgenic mice renders them resistant to stress-induced hypotension, inflammation, and stroke ( Beck & Plate, 2009 ). It is well established that global ischemia, caused by reduced cerebral blood flow, initiates a cascade of mechanisms, including elevated levels of ROS, excitotoxicity, mitochondrial dysfunction and neuronal apoptosis ( Tóthová, Kovalská, Kalenská, Tomašcová, & Lehotský 2018 ). Accordingly, eNOS has a neuroprotective role by increasing blood flow in the very early stages of cerebral ischemia ( Hashiguchi et al, 2004 ).…”