Pages October More article options. Oxidative stress in neurological diseases: Cause or effect?. Download PDF. Corresponding author. This item has received. Article information. Further studies are needed in order to identify mechanisms of selective neuronal vulnerability to ROS in different brain regions, and to determine how effective antioxidant therapy may be for treating these diseases. Du, H.
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Damage to dopaminergic neurons by oxidative stress in Parkinson's disease (Review)
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Bandala, L. Carmona-Aparicio, et al. Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. Iron promotes the generation of highly reactive oxygen species, resulting in further oxidative damage, particularly for nigral dopaminergic neurons that appear to exhibit increased sensitivity to iron-induced oxidative stress. Studies in postmortem brains of PD patients have shown higher levels of iron in the SN compared with that in controls 41 , The link of oxidative iron dysregulation with the neurodegenerative process is also supported by PD animal models, where increased levels of iron and hyroxyl radicals could be detected in the SN Administration of desferrioxamine, an iron chelator, significantly decreases the levels of iron in the brain and protects against neurodegeneration induced by iron and MPTP in PD mouse models 44 , further supporting the contribution of iron in the neurodegenerative process of PD.
Furthermore, the brain is enriched in lipids that participate in membrane fluidity and permeability, and mediate the inflammatory processes and apoptotic signals The lipids are susceptible to ROS-mediated damage, particularly polyunsaturated fatty acids, which are the most prone to lipid peroxidation, resulting in the structural damage of membranes, consequent neuronal damage and ultimately, mortality Oxidative stress-mediated death mechanism has been underlied in the pathogenesis of PD Higher levels of malondialdehyde, a production of polyunsaturated fatty acid peroxidation in oxidative conditions, have also been reported in SN compared with that in other brain regions in PD The lipid peroxidation marker, cholesterol lipid hydroperoxide, is also detected as significantly increased in PD brains compared with that in control subjects The reinforcement of peroxidation of polyunsaturated fatty acids to oxidative damage of dopaminergic neurons is also supported by the elevated levels of HNE detected in the SN and the cerebrospinal fluid of PD patients 5 , HNE is a lipid peroxidation product contributing to apoptotic cell death via the activation of the caspase cascade and the subsequent induction of DNA fragmentation Additionally, other causal factors that are associated with the vulnerabilities of dopaminergic neurons to oxidative stress have been well documented Taken together, these results indicate that the dopaminergic neurons are more vulnerable to oxidative attack.
Although the mechanisms of oxidative damage in response to oxidative stress causing the progressive degeneration of dopaminergic neurons in PD is unclear, events such as mitochondrial dysfunction, the opening of the mitochondrial permeability transition pore mPTP , neuroinflammation and oxidative DNA damage induced by oxidative stress may serve crucial roles in the process of neurodegeneration.
The interaction between these various mechanisms forms a positive feedback loop that drives uncontrolled pathogenesis conditions, resulting in the development of PD Fig. ROS trigger a cascade of events leading to the degeneration of neurons. Oxidative stress serves a central role in the neurodegenerative process by triggering the cascade events, including mitochondrial dysfunction, impairment of nuclear and mitochondrial DNA, and neuroinflammation, which in turn cause more ROS production, thus forming a vicious cycle.
These vicious cycles generate an uncontrolled pathogenesis conndition that drives the progressive degeneration of dopaminergic neurons in Parkinson's disease.
The Role of Oxidative Stress in Neuronal Death
Mitochondria are the primary intracellular source of ROS, and for this reason the organelles are frequently exposed to oxidative stress 51 , Consequently, the vicious cycle between the defects in the ETC and the subsequent production of ROS drive the uncontrolled oxidative stress that may play a central role in the progressive degeneration of dopaminergic neurons and have been underlied in PD pathogenesis 3. The proteins of the ETC complex are encoded by mitochondrial and nuclear genomes.
The damage to mtDNA and subsequent defects in the production of these proteins could induce mitochondrial dysfunctions that are implicated in a multitude of diseases or pathological conditions The accumulation of defects in mtDNA has been detected in nigral dopaminergic neurons of elderly individuals and sporadic PD subjects 56 — Inhibition of mtDNA expression leads to dysfunction in the respiratory chain in dopaminergic neurons accompanied by progressive parkinsonism in mouse models These studies suggest that oxidative ETC and mtDNA damage may be involved in the degeneration of dopaminergic neurons in oxidative conditions.
This has particularly importance in dopaminergic neurons with exposure to frequent influxes of calcium The opening of the mPTP has been reported to serve a crucial role in the pathogenesis of neurodegenerative disorders, including PD 73 , Generally, CyPD is a mitochondrial matrix protein. These proteins are located in the cytosol, but translocate and oligomerize into the OMM in response to oxidative stress.
The release of mitochondrial apoptogenic proteins from the opening pore into the cytosol serves a crucial role in mPTP-mediated cell death, of which cytochrome c is the most potent apoptotic inducer 79 , The released cytochrome c triggers the activation of caspase-9 via the interaction with apoptotic protease-activating factor 1 Apaf1 Apaf1 is a cytoplasmic protein that contains several domains associated with its functional and regulatory role The binding of cytochrome c with the special domain of Apaf1 results in the protein forming an oligomeric apoptosome that is required for the activation of pro-caspase Caspase-9 cleaves pro-caspase-3 resulting in its activation and the subsequent cleavage of DNA, the irreversible step toward apoptotic cell death 79 , Apoptosis-inducing factor AIF is another apoptotic factor released from the mitochondria into the cytosol triggering caspase-independent apoptosis The contribution of other apoptotic mediators released from the opening of the mPTP to apoptosis has been well documented 53 , Several mechanisms have been revealed to antagonize the opening of the mPTP.
The translocation and oligomerization of Bax and Bak into the OMM, for example, can be antagonized by the antiapoptotic proteins Bcl-2 and Bcl-xL via sequestration and inhibition of the activator proteins that are required for the activation of these pro-apoptosis proteins Overall, the oxidative stress-mediated opening of the mPTP is one of the pathways responsible for the apoptosis of dopaminergic neurons in PD, and understanding the mechanisms involved is essential to the development of effective therapies for neurodegenerative diseases.
The opening of the mPTP releases pro-apoptotic mediators, including cytochrome c, from the mitochondria into the cytosol.
The released cytochrome c triggers the activation of pro-caspase-9 via the interaction with Apaf1. Caspase-9 cleaves pro-caspase-3 resulting in its activation and subsequent DNA cleavage. Neuroinflammation is a protective mechanism of the CNS against infectious insults and injury by activation of the innate immune system in the brain to destroy and remove the detrimental agents and injured tissues However, uncontrolled inflammation can cause excessive cell and tissue damage, ultimately leading to chronic inflammation and progressive destruction of normal tissue.
The elevated levels of ROS production serve an important role in the activation of a strong proinflammatory response, and the link between oxidative stress and inflammation and tissue injury has been well documented The inflammatory damage has been underlied in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, multiple sclerosis and PD 99 — The inflammatory response is a complex process involved in a series of cellular and molecular processes, including the activation of immune cells, the induction of certain intracellular signaling pathways and the release of inflammatory mediators in the brain The activation of microglia is an initiator in inflammation-mediated neuronal injury.
Microglia are the resident immune cells of the brain that become activated in response to brain injury or immune challenge Inflammation-derived oxidative stress and cytokine-dependent toxicity have been suggested to be involved in the loss of dopaminergic neurons in PD — As one important cytokine, TNF serves a crucial role in inflammation-mediated neurodegeneration, since elavated levels of this cytokine can be persistently detected in the affected areas of the SN in PD In addition to the induction of proinflammatory signaling pathways resulting in cell damage 16 , TNF can promote the secretion of NO by increasing the expression of iNOS in microglia The dopaminergic neurons are particularly susceptible to microglia-mediated toxicity due to the highest density of microglial cells being distributed in the SN of the brain , Microglia activation promotes the production of proinflammatory cytokines, which cause dopaminergic nigrostriatal neuron degeneration in MPTP models of PD Animal models of PD have shown that suppression of the inflammatory response, results in the protection of neurons from the damage induced by neurotoxin , These data indicate a close association between microglial activation and the degeneration of dopaminergic neurons in PD pathogenesis.
Dopaminergic neuronal death releases noxious endogenous mediators, including oxidized proteins, lipids and DNA, in the extracellular space, which can also activate the microglia, resulting in the release of multiple proinflammatory cytokines. Proinflammatory factor prodcution subsequently exacerbates damage to the neurons via oxidative stress and cytokine toxicity 19 , causing the injured neurons to release further noxious endogenous mediators and resulting in a continuous inflammatory response This positive feedback loop between activated microglia and damaged neurons forms a neurotoxic vicious cycle and an uncontrolled, prolonged inflammatory process, and is hypothesized to be partially responsible for the gradual loss of dopaminergic neurons in PD , Thereby, inhibiting the inflammatory response generated by microglia activation may be show benefits in neurodegenerative conditions.
DNA integrity is required for cell survival. Under physiopathologycial conditions, DNA is often subjected to damage by endogenous and environmental toxic agents, and unrepaired DNA damage leads to genetic and protein instability, and subsequent cell death. The number of strand breaks in nuclear DNA have also been reported to be elevated in the SN compared with that in other areas of the brain, and evidence of alterations to DNA conformation and stability in the SN has also been documented Abasic sites were also shown in brain tissue from PD mouse models treated with the neuronal toxin rotenone, which causes oxidative stress by inhibiting the mitochondrial complex Abasic sites are DNA segments that have lost a purine or pyrimidine base, leading to the blockage of the polymerase during the replication and transcription of DNA These studies demonstrate that dopaminergic neuron injury could be ascribed to the oxidative damage of nuclear DNA and mtDNA, which alters its coding properties or interferes with normal metabolic function, and subsequently results in cell death Effective repair of damaged DNA is required to preserve its integrity and maintain the viability of the cell, particularly in dopaminergic neurons.
A number of cellular mechanisms are devoted to the repair of DNA A previous study determined an association between variants in DNA repair and an increased risk of PD As a critical regulatory protein for DNA repair, proliferating cell nuclear antigen PCNA serves a central role in the repair of damaged DNA in a variety of pathological conditions via the interaction with numerous enzymes and regulatory proteins , These results may provide a potential target for the reversal of oxidative DNA damage-mediated neuronal death in PD pathogenesis.
The pathogenesis and progression of PD are complex and involved in a series of diverse mechanisms that alone or together contribute to the damage and gradual loss of dopaminergic neurons. Oxidative stress appears to serve a central role in the neurodegenerative process, since dopaminergic neurons are frequently exposed to oxidative stress, which triggers a cascade of events, including mitochondrial dysfunction, impairment of nuclear DNA and mtDDA, and neuroinflammation, which in turn cause more ROS production.
The formation of this vicious cycle may serve a central role in the progressive degeneration of dopaminergic neurons in PD, therefore, the inhibition of the production of ROS and the blockage of the interactions in the signaling pathway may alleviate the severity and development of the disease. This require further elucidation. Mov Disord. Adv Pharmacol Sci.