Elsevier

Progress in Neurobiology

Volume 75, Issue 3, February 2005, Pages 207-246
Progress in Neurobiology

Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease

https://doi.org/10.1016/j.pneurobio.2005.02.004Get rights and content

Abstract

Despite our present knowledge of some of the cellular pathways that modulate central nervous system injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. The cellular mechanisms that precipitate these diseases are more involved than initially believed. As a result, identification of novel therapeutic targets for the treatment of cellular injury would be extremely beneficial to reduce or eliminate disability from nervous system disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we discuss novel pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Current work has identified exciting pathways, such as the Wnt pathway and the serine–threonine kinase Akt, as central modulators that oversee cellular apoptosis and their downstream substrates that include Forkhead transcription factors, glycogen synthase kinase-3β, mitochondrial dysfunction, Bad, and Bcl-xL. Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation. New therapeutic avenues that are just open to exploration, such as with brain temperature regulation, nicotinamide adenine dinucleotide modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat a variety of disorders that include stroke, Alzheimer's disease, and traumatic brain injury.

Introduction

At present, over 23 million people in the United States suffer from central nervous system (CNS) disorders. Globally, this number reaches a level of 368 million people. These disorders predominantly consist of neurodegenerative diseases that include presenile dementia, Alzheimer's disease (AD), and Parkinson's disease (PD). Intimately linked to the development of CNS degeneration are also a variety of injuries associated with traumatic brain injury (TBI). For example, both penetrating head injuries and blast injuries without direct head trauma have been shown to result in subsequent neurotrauma as a result of potential elevations in nervous system oxidative stress and free radical levels (Cernak et al., 2000). In addition to direct head trauma, diffuse neuronal degeneration can ensue as a result of an increased load of kinetic energy from the original insult (Carey et al., 1984). Furthermore, tangential cranial injuries are susceptible to acute ischemic neuronal injury with intracerebral hemorrhage (Elron et al., 1998). Finally, environmental toxin exposure also may foster oxidative neuronal and vascular damage (Miller et al., 2002) (Table 1).

In the general population, the cost of physician services, hospital and nursing home care, and medications continues to rise dramatically. In addition, these medical costs for neurodegenerative disease parallel a progressive loss of economic productivity with rising morbidity and mortality, ultimately resulting in an annual deficit to the economy that is greater than $ 380 billion. Interestingly, the most significant portion of this economic loss is composed of only a few neurodegenerative disease entities, such as ischemic disease and AD. The annual cost per patient with AD is estimated at $ 174,000 with an annual population aggregate cost of $ 100 billion (McCormick et al., 2001, Mendiondo et al., 2001).

Despite our present knowledge of some of the cellular pathways that modulate CNS injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. As a result, identification of novel therapeutic targets for the treatment of neuronal injury would be extremely beneficial to reduce or eliminate disability from CNS disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we describe the unique capacity of intrinsic cellular mechanisms that may offer novel therapy for a variety of acute and chronic disorders in both neuronal and vascular systems. Oxidative stress leads to apoptotic injury that involves early loss of cellular membrane asymmetry as well as the eventual destruction of genomic DNA. These dynamic stages of apoptosis can be associated with an ill-fated attempt to enter the cell cycle, particularly in post-mitotic neurons. Subsequent cellular pathways can originate from the proto-oncogene Wnt and the serine–threonine kinase Akt and involve mechanisms linked to inflammatory activation of microglia, Forkhead transcription factors, glycogen synthase kinase-3β activation, loss of mitochondrial membrane permeability, and the eventual induction of caspases and calpains. Understanding these processes may ultimately serve to elucidate robust therapeutic strategies linked to brain temperature, cellular metabolism, genomic DNA repair, metabotropic glutamate modulation, and cytokine regulation that allow future clinical strategies to mature from “bench side prediction” to “daily practice”.

Oxidative stress occurs when oxygen free radicals are generated in excess through the reduction of oxygen. Reactive oxygen species (ROS) consist of oxygen free radicals and associated entities that include superoxide free radicals, hydrogen peroxide, singlet oxygen, nitric oxide (NO), and peroxynitrite. Several of these species are produced at low levels during normal physiological conditions and are scavenged by endogenous antioxidant systems that include superoxide dismutase (SOD), glutathione peroxidase, catalase, and small molecule substances such as Vitamins C and E. Superoxide radical is the most commonly occurring oxygen free radical that produces hydrogen peroxide by dismutation. Hydroxyl radical is the most active oxygen free radical and is generated from hydrogen peroxide through the Haber–Weiss reaction in the presence of ferrous iron. Hydroxyl radical alternatively may be formed through an interaction between superoxide radical and NO (Fubini and Hubbard, 2003). NO interacts with superoxide radical to form peroxynitrite that can further lead to the generation of peroxynitrous acid. Hydroxyl radical is produced from the spontaneous decomposition of peroxynitrous acid. NO itself and peroxynitrite are also recognized as active oxygen free radicals. In addition to directly altering cellular function, NO may work through peroxynitrite that is potentially considered a more potent radical than NO itself (Pfeiffer et al., 2001).

Oxidative stress in the brain occurs when the generation of ROS overrides the ability of the endogenous antioxidant system to remove excess ROS subsequently leading to cellular damage. Several cellular features of the brain suggest that it is highly sensitive to oxidative stress. For example, the brain is known to possess the highest oxygen metabolic rate of any organ in the body (Maiese, 2002). The brain consumes approximately twenty percent of the total amount of oxygen in the body. This enhanced metabolic rate leads to an increased probability that excessive levels of ROS will be produced. In addition, the brain tissues contain increased amounts of unsaturated fatty acids that can be metabolized by oxygen free radicals. Finally, the brain contains high levels of iron which have been associated with free radical injury (Herbert et al., 1994). Liposoluble iron chelators have been reported to lead to a reduction in ROS and protect neurons from permanent focal cerebral ischemia (Demougeot et al., 2004). Yet, given the increased risk factors for the generation of elevated levels of ROS in the brain, it is interesting to note that the brain also may suffer from an inadequate defense system against oxidative stress. Catalase activity in the brain is significantly below other body organs. If one compares the catalase activity of the brain to the catalase activity in the liver, the brain has been shown to contain only 10% of the catalase activity present in the liver (Floyd and Carney, 1992).

Oxidative stress represents a significant pathway that leads to the destruction of both neuronal and vascular cells in the CNS. The production of ROS can lead to cell injury through cell membrane lipid destruction and cleavage of DNA (Vincent and Maiese, 1999b; Wang et al., 2003). ROS result in the peroxidation of cellular membrane lipids (Siu and To, 2002), peroxidation of docosahexaenoic acid, a precursor of neuroprotective docosanoids (Mukherjee et al., 2004), the cleavage of DNA during the hydroxylation of guanine and methylation of cytosine (Lee et al., 2002), and the oxidation of proteins that yield protein carbonyl derivatives and nitrotyrosine (Adams et al., 2001). In addition to the detrimental effects to cellular integrity, ROS can inhibit complex enzymes in the electron transport chain of the mitochondria resulting in the blockade of mitochondrial respiration (Yamamoto et al., 2002). In cerebral vascular system, the cellular effects of ROS may lead to the destruction of endothelial cell (EC) membranes and an increase in endothelial cell permeability (Sakamaki, 2004).

Section snippets

Acute

Oxidative brain damage is considered to be a significant contributor to ischemic brain injury (Chong et al., 2004b). During cerebral ischemia, ROS, such as superoxide radicals, are released in significant quantities and have been demonstrated at the interface of the cerebrovascular cell membrane (Yamato et al., 2003). Sources such as cyclooxygenase-2 (COX-2) and impaired mitochondrial function can lead to the release of ROS in the brain during cerebral ischemia and reperfusion (Bazan et al.,

Early and late apoptotic programs

Apoptosis, or PCD, is considered to be important for tissue re-modeling during development. Yet, this active process is recognized as a central pathway that can lead to a cell's demise in a variety of tissues and has recently been identified in organisms as diverse as plants (Hatsugai et al., 2004). PCD consists of two independent processes that involve membrane phosphatidylserine (PS) exposure and DNA fragmentation (Maiese et al., 2004). Apoptotic injury is believed to contribute significantly

Microglial activation and inflammation

Modulation of extrinsic cell homeostasis through microglial activation is as vital to cellular survival as the maintenance of cellular DNA integrity. Microglia are monocyte-derived immunocompetent cells that enter the CNS during embryonic development and function similar to peripheral macrophages for the phagocytic removal of apoptotic cells. Some studies identify the generation of annexin I and membrane PS exposure that appears to be necessary to connect an apoptotic cell with a phagocyte (

Attempted cell cycle induction in post-mitotic cells

The attempted reentrance into the cell cycle in post-mitotic neurons can trigger apoptosis (Becker and Bonni, 2004). In the CNS, post-mitotic neurons are incapable of differentiation, but they continue to possess the ability to enter into the cell cycle. During a cellular insult, deregulation of cell cycle proteins, such as cyclin, cyclin-dependent kinase (CDK), and the retinoblastoma protein, can ensue (Padmanabhan et al., 1999). The deficiency of several essential components for the complete

Induction of the Wnt pathway

Wnt proteins, named after the Drosophilia protein “wingless” and the mouse protein “Int-1”, represent a large family of secreted cysteine-rich glycosylated proteins. This novel family of proteins are intimately involved in cellular signaling pathways that play a role in a variety of processes that involve embryonic cell patterning, proliferation, differentiation, orientation, adhesion, survival, and apoptosis (Chong and Maiese, 2004, Nelson and Nusse, 2004, Patapoutian and Reichardt, 2000).

Activation and expression of Akt

Protein kinase B (PKB) is ubiquitously expressed in mammals but is initially present at low levels in the adult brain (Owada et al., 1997). Three family members of this serine/threonine kinase are now known to exist that were termed Akt after the molecular cloning of the oncogene v-Akt and two human homologs (Staal, 1987, Staal et al., 1988). They are PKBα or Akt1, PKBβ or Akt2, and PKBγ or Akt3 (Chong et al., 2005a). Akt is part of the AGC (cAMP-dependent kinase/protein kinase G/protein kinase

Downstream cellular targets

At this point of time, no definitive therapy for either acute or chronic neurodegenerative diseases is available. Yet, investigations into the cellular pathways that determine oxidative stress and apoptotic injury have begun to elucidate pathways that provide us with a clearer understanding of the mechanisms that determine a cell's ability to function and sustain itself during adverse environments. In the following sections, we discuss novel downstream cellular pathways that are linked to

Future directions

Therapeutic regimens for neurodegenerative disorders that seek to reduce or eliminate injury from ROS currently focus on a limited number of strategies. For example, prevention of N-methyl-d-aspartate (NMDA) receptor activity during memory loss associated with AD is considered to be one potential route for treatment. Although memantine, an antagonist of the NMDA receptor, can lead to cognitive improvement in patients with moderate to severe forms of AD (Reisberg et al., 2003), the mechanism of

Acknowledgments

This work was supported by the following grants (KM): American Heart Association (National), Janssen Neuroscience Award, Johnson and Johnson Focused Investigator Award, LEARN Foundation Award, MI Life Sciences Challenge Award, and NIH NIEHS (P30 ES06639).

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