Elsevier

Neuropharmacology

Volume 134, Part B, 15 May 2018, Pages 208-217
Neuropharmacology

Invited review
Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery

https://doi.org/10.1016/j.neuropharm.2017.11.011Get rights and content

Highlights

  • Stroke elicits robust DNA damage pro-death cascades in multiple neuronal cell types.

  • Multiple DNA repair mechanisms are initiated after stroke.

  • Boosting DNA repair may be a promising treatment strategy for stroke patients.

Abstract

The past two decades have witnessed remarkable advances in oxidative stress research, particularly in the context of ischemic brain injury. Oxidative stress in ischemic tissues compromises the integrity of the genome, resulting in DNA lesions, cell death in neurons, glial cells, and vascular cells, and impairments in neurological recovery after stroke. As DNA is particularly vulnerable to oxidative attack, cells have evolved the ability to induce multiple DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER) and non-homogenous endpoint jointing (NHEJ). Defective DNA repair is tightly correlated with worse neurological outcomes after stroke, whereas upregulation of DNA repair enzymes, such as APE1, OGG1, and XRCC1, improves long-term functional recovery following stroke. Indeed, DNA damage and repair are now known to play critical roles in fundamental aspects of stroke recovery, such as neurogenesis, white matter recovery, and neurovascular unit remodeling. Several DNA repair enzymes are essential for comprehensive neural repair mechanisms after stroke, including Polβ and NEIL3 for neurogenesis, APE1 for white matter repair, Gadd45b for axonal regeneration, and DNA-PKs for neurovascular remodeling. This review discusses the emerging role of DNA damage and repair in functional recovery after stroke and highlights the contribution of DNA repair to regenerative elements after stroke.

This article is part of the Special Issue entitled ‘Cerebral Ischemia’.

Introduction

Cerebral ischemic stroke is a leading cause of long-term disability and mortality, posing an enormous burden on patients and their communities (Feigin et al., 2014). According to the Centers for Disease Control and Prevention, stroke kills approximately 140,000 Americans each year (Yang et al., 2017), costing the United States an estimated $34 billion per annum (Benjamin et al., 2017). Intravenous tissue plasminogen activator and endovascular thrombectomy are the only currently available stroke treatments approved by the FDA. However, both treatments are limited by a narrow therapeutic window and must be administered within 4.5 and 12 h post-stroke, respectively (Gori et al., 2017). These limitations leave the vast majority of stroke patients inadequately treated and at risk for severe neurological deficits. Therefore, enhancing functional recovery after ischemic stroke remains an important priority for stroke researchers and clinicians (Etherton et al., 2017).

Oxidative stress is a hallmark of cerebral ischemic stroke. It is induced by elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which cause damage to all components of the cell, including proteins, lipids, and DNA (Zhao et al., 2016). Oxidative DNA damage is one of the most detrimental consequences of increased oxidative stress in cerebral ischemic stroke (Cui et al., 2000, Li et al., 2011). When left unrepaired, DNA damage triggers multiple pro-death signaling pathways that induce cell apoptosis and jeopardize functional recovery following stroke (Li et al., 2011). However, cells also combat the accumulation of DNA damage by induction of endogenous DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER) and non-homologous endpoint jointing (NHEJ). Oxidative DNA damage and repair transpire within minutes after cerebral ischemic stroke (Cui et al., 2000, Li et al., 2011), and may also persist even to six months after stroke (Pascotini et al., 2015). Recent studies highlight the important role of DNA repair as a critical element of the endogenous brain repair process during stroke recovery (Li et al., 2006, Liu et al., 2011). DNA repair has a profound impact on a wide range of recovery efforts, including neurogenesis (Jalland et al., 2016, Shimada et al., 2015), angiogenesis (Liu et al., 2015b), axonal outgrowth (Liu et al., 2015a), and remyelination (Stetler et al., 2016), all of which work in concert to orchestrate neurological recovery. Targeting DNA damage and endogenous DNA repair mechanisms after stroke holds promise for accelerating brain tissue repair and functional recovery. In this review, we provide an update on new insights into DNA damage and repair in the context of ischemic stroke and discuss novel targets that might be therapeutically modulated to improve functional recovery.

Section snippets

Stroke elicits DNA damage in multiple neuronal cell types

Cerebral ischemia leads to a robust increase in oxidative stress followed by DNA damage and ischemic injury in gray and white matter (Basso and Ratan, 2013). Oxidative DNA damage occurs soon after ischemic stroke and is usually reversible (Chen et al., 1997, Cui et al., 2000, Lan et al., 2003). The latter feature is particularly important because it opens an avenue for therapeutic intervention. Therefore, oxidative DNA damage and repair have become primary foci of interest in stroke research.

Signaling cascades underlying DNA damage after stroke

In order to develop new therapies targeting DNA damage after stroke, one course of action centers on elucidation of signaling pathways that initiate DNA damage and its pro-death effects. Below we discuss four major cellular events related to DNA damage: 1) Phosphoinositide 3-kinase (PI3K)-related kinase (PIKK)-mediated DNA damage recognition, 2) poly (ADP-ribose) (PAR) polymerase-1 (PARP-1)-mediated AIF translocation, 3) MIF nucleus translocation, and 4) matrix metalloproteinase (MMP)-mediated

Endogenous DNA repair mechanisms after ischemic stroke

In order to reverse oxidative DNA damage and prevent subsequent cell death, cells possess multiple DNA repair capabilities. Decades of intense research efforts have greatly improved our understanding of DNA repair and identified three major DNA repair mechanisms: 1) direct reversal of DNA damage, 2) non-homologous endpoint jointing (NHEJ), and 3) DNA excision repair (Li et al., 2011). Direct reversal DNA repair includes three major mechanisms: 1) photolyases that reverse UV light-induced

Enhancing DNA repair capacity promotes functional recovery after ischemic brain injury

If cells display extensive DNA damage, simply inhibiting the pro-death pathways downstream of the DNA damage response is not likely to be an effective treatment strategy. Given the critical importance of genome integrity to survival, DNA itself must be repaired to achieve true and long-lasting protection. Thus, enhancing DNA repair capacity may be key to treating ischemic injury. For example, genetic or pharmacological upregulation of APE1 facilitates the repair of oxidative AP sites and

Promoting endogenous regenerative responses—the role of DNA damage and repair

DNA damage and repair are usually considered early events following cerebral ischemia and reperfusion. The contribution of oxidative stress and DNA damage to long-term stroke outcomes in the late phase of stroke (>6 months) is unclear. In the peripheral blood in stroke patients, markers of oxidative DNA damage and apoptosis are evident even 6 months after stroke (Pascotini et al., 2015). In the late phase of ischemic stroke, pleiotropic endogenous brain repair mechanisms orchestrate stroke

Concluding remarks

Recent studies have shed light on cerebral ischemia-induced DNA damage and its contribution to neuronal cell death and slowing of neurological recovery after stroke. The impact of DNA damage accumulation has now been extended to non-neuronal cells and likely extends beyond facilitation of post-ischemic cell death. Rather, DNA damage profoundly affects the repair and restoration of the neurovascular network of the post-ischemic brain. Although additional research is required to determine if the

Acknowledgements

This work was supported by NIH/NINDS grants NS036736 (to Jun Chen, Rehana K. Leak, and Michael V.L. Bennett), NS095671, NS089534 and NS45048 (to Jun Chen), and NS100803 (to R. Anne Stetler), VA merit grants I01BX002495 and I01RX000420 (to Jun Chen), the U.S. Department of Veterans Affairs Senior Research Career Scientist Award (to Jun Chen); and Shanghai Rising-Star Program 16QA1402600 (to Peiying Li), and Chinese Natural Science Foundation grants 81400956 and 81722017 (to Peiying Li).

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