Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke
Section snippets
Production of reactive oxygen species
Oxidative stress is characterized by the excess production of reactive oxygen species (ROS), which may cause irreversible damage to cellular components. Although neural cell damage during stroke is partially triggered by hypoxia, oxidative stress plays an instrumental role during the initial and later phases of ischemic stroke pathophysiology. During the initial phase of injury, energy failure interferes with the activity of ATP-dependent ion channels and the maintenance of the electrochemical
Glutathione metabolism
Under physiological and pathophysiological conditions, several enzymes are responsible for regulating redox balance in neurons. Some of these enzymes protect neurons from oxidative stress by maintaining adequate expression levels of the antioxidant glutathione. Glutathione, an oligopeptide containing a cysteine residue, acts as a nucleophile by donating electrons to break the disulfide bonds of oxidized proteins. Once reduced, these proteins are unable to react with other cellular components
Sex-specific antioxidant expression
Preclinical and clinical studies indicate that high levels of estrogen protect younger females against the risk of ischemic stroke. In addition to decreasing inflammation, estrogen increases the expression and activity of several antioxidant enzymes in the brain. In a study by Borras et al., female rats were less prone to mitochondrial damage compared to male rats due to higher basal expression of GSH-PX and SOD2 (Borrás et al., 2003). Strehlow et al. showed that 17β-estradiol administration
Human umbilical cord blood cells
Although these therapies contain mesenchymal stem cells, cells isolated from autologous peripheral and umbilical cord blood also contain a large fraction of mononuclear cells, which consist of monocytes/macrophages, lymphocytes, and neutrophils. Similar to NSCs, these cell populations have been shown to exert protective effects via released factors that activate survival signaling. HUCB treatment 48 h after stroke increases PI3K/Akt signaling and induces the expression of antioxidant enzymes.
Antioxidant enzymes upregulated by LIF
Since LIF is among the factors produced by HUCB cell (Seo et al., 2011), LIF does promote antioxidant expression and reduce white matter damage after permanent FCI in a manner similar to HUCB therapy. Rats were administered either LIF or PBS at 6, 24, and 48 h after undergoing permanent MCAO and euthanized at 72 h. According to the results of this study, LIF treatment increased motor skill recovery and reduced stroke volume at 72 h post-MCAO. White matter showed considerably lower levels of
Antioxidant effects of other IL-6 family cytokines
Despite the failures of exogenous agents, focusing research efforts on drugs that confer long-lasting changes in antioxidant expression have shown great potential in treating animal models of stroke. Anti-inflammatory cytokines provide a unique benefit to stroke patients: they exert their signaling quickly before being cleared from the body, thus lessening the potential for adverse side effects. However, the downstream effects of these signaling pathways confer long-lasting protection by
Conclusion
One of the current shortcomings of clinical stroke treatments stems from the inability to address both phases of stroke pathophysiology. Increased expression of enzymes such as Prdx4, Mt3, and SOD3 would not only protect neural cells against ROS that are generated during the acute cytotoxic phase of damage, but also against ROS produced by activated microglia and peripheral leukocytes. Moreover, these antioxidant enzymes can be modified (polyethylene glycol) to increase their stability thus
Funding
This study was funded by project #7R01NS091146-02 from the National Institute of Neurological Disorders and Stroke.
Conflict of interest
Stephanie M. Davis declares that she has no conflict of interest. Keith R. Pennypacker declares that he has no conflict of interest.
References (115)
- et al.
Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons
Mol. Cell. Neurosci.
(2001) - et al.
The structure of human extracellular copper–zinc superoxide dismutase at 1.7 Å resolution: insights into heparin and collagen binding
J. Mol. Bio
(2009) - et al.
Leukemia inhibitory factor can mediate Ras/Raf/MEK/ERK-induced growth inhibitory signaling in medullary thyroid cancer cells
Cancer Lett.
(2010) - et al.
Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis
Brain Res.
(2001) - et al.
Polymorphonuclear neutrophils contribute to infarction and oxidative stress in the cortex but not in the striatum after ischemia–reperfusion in rats
Brain Res.
(2003) - et al.
Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males
Free Radic. Biol. Med.
(2003) Tissue-specific functions of individual glutathione peroxidases
Free Radic. Biol. Med.
(1999)- et al.
Crystal structure of reduced and of oxidized peroxiredoxin IV enzyme reveals a stable oxidized decamer and a non-disulfide-bonded intermediate in the catalytic cycle
J. Biol. Chem.
(2011) - et al.
Age-related changes in antioxidant enzyme activities are region and organ, as well as sex, selective in the rat
Mech. ageing Dev.
(1992) - et al.
Cloning, sequencing, and mutation of thiol-specific antioxidant gene of Saccharomyces cerevisiae
J. Bio Chem.
(1993)