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Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

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ABSTRACT

Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC) is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia-induced neurodegenerative changes as well as intracellular signaling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL-positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK) protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke.

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Proposed mechanisms leading to homocysteine neurotoxicity and the protection induced by ischemic preconditioning (IPC) in hyperhomocysteinemic conditions (hHCy). (+): increased number of cells and/or activity, (−): decreased number of cells and/or activity. Homocysteine induced neurotoxicity includes dysregulation in redox balance, lipoperoxidation and protein oxidation, Ca2+ pump dysfunction and activation of MAPKp38 which is detected in vulnerable cells by increased Fluoro-Jade C staining (+) and TUNEL positive cells (+). Ischemic preconditioning suppresses oxidative dysregulation and activates MAPK-ERK which leads to reduced Fluoro Jade C and TUNEL positivity in sensitive cells (Pavlikova et al., 2011; Petras et al., 2014; Kovalska et al., 2015; Lehotsky et al., 2015; Škovierová et al., 2015). Adapted from Lehotsky et al. (2015).
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Figure 3: Proposed mechanisms leading to homocysteine neurotoxicity and the protection induced by ischemic preconditioning (IPC) in hyperhomocysteinemic conditions (hHCy). (+): increased number of cells and/or activity, (−): decreased number of cells and/or activity. Homocysteine induced neurotoxicity includes dysregulation in redox balance, lipoperoxidation and protein oxidation, Ca2+ pump dysfunction and activation of MAPKp38 which is detected in vulnerable cells by increased Fluoro-Jade C staining (+) and TUNEL positive cells (+). Ischemic preconditioning suppresses oxidative dysregulation and activates MAPK-ERK which leads to reduced Fluoro Jade C and TUNEL positivity in sensitive cells (Pavlikova et al., 2011; Petras et al., 2014; Kovalska et al., 2015; Lehotsky et al., 2015; Škovierová et al., 2015). Adapted from Lehotsky et al. (2015).

Mentions: Taken together, documented responses of neuronal cells to hHcy, IRI and preischemic challenge in the hHcy model in rats (Figure 3) might suggest a correlation of several ethiological factors such as antioxidant defense (Borowczyk et al., 2012; Petras et al., 2014), alterations in the mechanisms of Ca2+ transport (Pavlíková et al., 2009) and likely newly explored epigenetic mechanisms, such as DNA methylation and chromatin remodeling in the phenomenon of ischemic damage and ischemic tolerance (Dirnagl et al., 2009; Lehotský et al., 2009a; Kalani et al., 2013; Thompson et al., 2013; Stetler et al., 2014).


Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance
Proposed mechanisms leading to homocysteine neurotoxicity and the protection induced by ischemic preconditioning (IPC) in hyperhomocysteinemic conditions (hHCy). (+): increased number of cells and/or activity, (−): decreased number of cells and/or activity. Homocysteine induced neurotoxicity includes dysregulation in redox balance, lipoperoxidation and protein oxidation, Ca2+ pump dysfunction and activation of MAPKp38 which is detected in vulnerable cells by increased Fluoro-Jade C staining (+) and TUNEL positive cells (+). Ischemic preconditioning suppresses oxidative dysregulation and activates MAPK-ERK which leads to reduced Fluoro Jade C and TUNEL positivity in sensitive cells (Pavlikova et al., 2011; Petras et al., 2014; Kovalska et al., 2015; Lehotsky et al., 2015; Škovierová et al., 2015). Adapted from Lehotsky et al. (2015).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120102&req=5

Figure 3: Proposed mechanisms leading to homocysteine neurotoxicity and the protection induced by ischemic preconditioning (IPC) in hyperhomocysteinemic conditions (hHCy). (+): increased number of cells and/or activity, (−): decreased number of cells and/or activity. Homocysteine induced neurotoxicity includes dysregulation in redox balance, lipoperoxidation and protein oxidation, Ca2+ pump dysfunction and activation of MAPKp38 which is detected in vulnerable cells by increased Fluoro-Jade C staining (+) and TUNEL positive cells (+). Ischemic preconditioning suppresses oxidative dysregulation and activates MAPK-ERK which leads to reduced Fluoro Jade C and TUNEL positivity in sensitive cells (Pavlikova et al., 2011; Petras et al., 2014; Kovalska et al., 2015; Lehotsky et al., 2015; Škovierová et al., 2015). Adapted from Lehotsky et al. (2015).
Mentions: Taken together, documented responses of neuronal cells to hHcy, IRI and preischemic challenge in the hHcy model in rats (Figure 3) might suggest a correlation of several ethiological factors such as antioxidant defense (Borowczyk et al., 2012; Petras et al., 2014), alterations in the mechanisms of Ca2+ transport (Pavlíková et al., 2009) and likely newly explored epigenetic mechanisms, such as DNA methylation and chromatin remodeling in the phenomenon of ischemic damage and ischemic tolerance (Dirnagl et al., 2009; Lehotský et al., 2009a; Kalani et al., 2013; Thompson et al., 2013; Stetler et al., 2014).

View Article: PubMed Central - PubMed

ABSTRACT

Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC) is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia-induced neurodegenerative changes as well as intracellular signaling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL-positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK) protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke.

No MeSH data available.


Related in: MedlinePlus