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Oxidative stress and neurodegenerative disorders

oxidative stress and neurodegenerative disorders

The Fat metabolism boosters Disease Cooperative Study. Inhibition neurodegeneragive the neurodegenerativee interaction between β-amyloid peptide and membranes prevents β-amyloid-induced toxicity. Ion channel oxidxtive oxidative stress and neurodegenerative disorders differentiated by their primary structure, distribution, and functional properties Zheng and Trudeau, Regarding Tregs, some works using animal AD models have pointed out that these cells can critically regulate the response of Th cells, both in physiological and pathological environments Baruch et al. Neurotoxicology —8;

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The role of oxidative stress in Alzheimer’s disease

Oxidative stress and neurodegenerative disorders -

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Gerontology 41 suppl 2 —; Download references. Department of Pharmacology, University of Missouri, , Columbia, MO, USA. You can also search for this author in PubMed Google Scholar. Reprints and permissions. Sun, A. Oxidative stress and neurodegenerative disorders.

J Biomed Sci 5 , — Download citation. Received : 11 May Accepted : 18 May Issue Date : November Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Abstract Oxidative insults, whether over-excitation, excessive release of glutamate or ATP caused by stroke, ischemia or inflammation, exposure to ionizing radiation, heavy-metal ions or oxidized lipoproteins may initiate various signaling cascades leading to apoptotic cell death and neurodegenerative disorders.

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Ion channels are predominantly responsible for maintaining this regularity Raman and Bean, ; Braga Neto et al. TABLE 3. Summary of some ion channels involved in oxidative stress-related neurodegenerative disorders.

Enzymatic antioxidants, such as superoxide dismutase, glutathione peroxidases, and catalase, along with non-enzymatic antioxidants like GSH and vitamins A, C, and E, counteract various types of oxidative stress Irato and Santovito, These antioxidants, whether endogenous or exogenous, reduce oxidative stress and scavenge ROS in ICAs, which could pave the way for a new ICA treatment Pandolfo, ; Lew et al.

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The dopamine secretion by these neurons is crucial for controlling movement ease and balance. The etiologies of PD are still questionable. Leucine-rich repeat kinase 2 LRRK2 Mutations are one of the causative genetic variants that account for several autosomal, dominantly inherited PD Blauwendraat et al.

It has also been discovered that other genes, including ATP13A2, SNCA, PINK, GIGYF2, HTRA2, and DJ1, can cause familiar and early-onset PD.

Among their functions are the degradation of ubiquitin proteins, the response to oxidative stress, apoptosis, cell survival, and mitochondrial function Maiti et al.

Oxidative stress significantly promotes the erosion of dopaminergic neurons in PD Dias et al. Oxygen is essential for brain function, and a large amount of oxygen is converted into ROS. Oxidative stress is closely related to other components of the degenerative process, like excitotoxicity, nitric oxide toxicity, and mitochondrial dysfunction Jenner, ; Henchcliffe and Beal, Several genes associated with familial PD, including parkin, alpha-synuclein, LRRK2, DJ-1, and PINK-1, have been identified, providing important understandings of the molecular pathways underlying the disease pathogenesis, as well as highlighting earlier mysterious mechanisms where oxidative stress plays a role in the disease Dias et al.

As oxidative stress leads to programmed cell death, the mitochondrial condition of GSH has gained recognition as a significant indicator of this occurrence Chang and Chen, Targeting ion channels provides an intriguing mechanistic strategy to address the progression of PD and other neurodegenerative disorders because of their important roles in neuronal activities Braga Neto et al.

As a result, there have been numerous efforts to address these pathways in order to provide neuroprotection Daniel et al. While several of these drugs in preclinical studies have demonstrated positive outcomes, none of these interventions have effectively transitioned into clinical application Jenner, In the field of ion channel drug discovery, a significant challenge is preventing side effects arising from both target and off-target mechanisms.

Additionally, subtype selectivity is challenging when various homologous members belong to the same subfamily Brown et al.

Ion channel malfunction is a common factor in neurological disorders, even when various genes are implicated as the root causes of these diseases.

The malfunction of ion channels can result from changes in the intracellular redox environment, which alter how these channels function.

Despite recent advancements, the precise mechanisms of reactive oxygen species ROS -mediated neurodegenerative diseases remain partially understood. The role of ion channels in neurodegenerative disorders associated with oxidative stress has now been recognized, as they experience functional adjustments in such conditions.

However, the significance of targeting ion channels therapeutically varies depending on the disease and the tissues in which these channels are active. Ultimately, neurodegenerative diseases may be effectively treated with a combination of ion channel-modulating therapy and antioxidant medication.

More research on the function of ion channels in oxidative stress may provide a platform for exploring new therapeutic approaches for treating many neurodegenerative diseases associated with oxidative stress.

RO: Visualization, Writing—original draft. AA: Writing—review and editing. RSO: Visualization, Writing—original draft. LL: Writing—review and editing.

NC: Writing—review and editing. AMA: Writing—review and editing. Y-WN: Supervision, Writing—review and editing. MZ: Conceptualization, Supervision, Writing—review and editing. The study was supported by a 23AIREA grant from the American Heart Association and a 4R33NS grant from NIH awarded to MZ.

We thank King Fahad Medical City Writing Center for revising the manuscript. Thanks to Rahaf and Raghad Alabdulsalam for their technical Support. The figures were created with BioRender and published with permission.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Neurodegenerahive of the chronic neurodegenerative pathologies of the Oxidative stress and neurodegenerative disorders Organic stress adaptogens some common features, such oxdative oxidative stress, inflammation, synapse dysfunctions, protein misfolding and defective autophagia. Disordders can involve the activation of mast cells, contributing to oxidative stress, neurodevenerative addition strrss other sources of reactive oxygen species. Antioxidants can powerfully neutralize reactive oxygen species and free radicals, decreasing oxidative damage. Antioxidant genes, like the manganese superoxide dismutase enzyme, can undergo epigenetic changes that reduce their expression, thus increasing oxidative stress in tissue. Alternatively, DNA can be altered by free radical damage. The epigenetic landscape of these genes can change antioxidant function and may result in neurodegenerative disease. This imbalance of free radical production and antioxidant function increases the reactive oxygen species that cause cell damage in neurons and is often observed as an age-related event. oxidative stress and neurodegenerative disorders

Oxidative stress and neurodegenerative disorders -

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Brain Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume 6. Article Contents Abstract. ROS, OS and neurodegenerative diseases. Superoxide dismutase.

SOD2 as a pharmacological agent. Immunology of NDG. Motor neuron disease. Epigenetic landscape and effects of aging on antioxidant mechanisms. Competing interests. Data availability.

Journal Article. Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. Annwyne Houldsworth Annwyne Houldsworth.

University of Exeter Medical School. However, these studies came to opposite conclusions with respect for the correlation between 8-OHG levels and disease duration. In the CSF of living PD patients, enhanced levels of HNE and MDA have been shown as well [ — ], but different results were obtained by Shukla et al.

Moreover, markers of oxidative damage in PD patients were also detected in the serum and urine [ — ], but their use as indicators of the course of the disease is far from being useful for clinical practice because the existing data are contradictory [ — ].

As has been suggested [ — ], these differences may be due to the variability in methods used to measure OS markers. The results of many studies have demonstrated the presence of OS in the brain, CSF, serum, and urine of PD patients; however, none of the OS markers has been established as a specific biomarker for PD disease or as a marker for PD disease progression.

This decrease is one of the earliest biochemical changes that has been observed in the disease [ — ], and it results in a selective drop in mitochondrial complex I activity, another hallmark of PD [ ].

On the other hand, a substantial rise in SOD levels has been observed in the SN and basal ganglia in PD patients [ ], while no change in activities of CAT, GPx, and GR was found compared to age-matched controls [ ].

Another study showed some deficiency in GPx in the SN in Parkinsonian patients [ ], but the weak ca. This suggests that PD medications may play a disadvantageous role that leads to enhanced peripheral oxidative stress; however, the small sample size excludes a final conclusion [ ].

One of the possible strategies was to supplement GSH. As shown by Sechi et al. infusion [ ]. Unfortunately, no results concerning the clinical status of PD patients have been described.

Magnetic resonance imaging MRI studies showed a rise in iron concentrations in the SN in PD patients [ ]. Because iron can lead to ROS production in PD patients, an iron-binding compound, deferiprone, has been tested in a pilot study in PD patients FAIRPARK trial, registered as ClinicalTrials.

gov NCT The earlier therapy start diminished SN iron deposits to a greater extent than the delayed-start paradigm and improved motor performance vs. placebo and vs. Moreover, in deferiprone-treated patients, GPx and SOD activity in the CSF increased, which supports the connection between the chelator treatment and the antioxidant response.

Vitamin E α-tocopherol was also suggested as a way to diminish the OS and to reduce clinical symptoms in PD. It is of note that no analysis of OS biomarkers was performed in that trial [ , ]. Since DATATOP, no clinical trials using vitamin E as a potential PD medication have been conducted. In fact, vitamin E was only used in PD clinical trials as a supplement for coenzyme Q10 or as a placebo [ ] or a control [ ].

Another potent antioxidant, coenzyme Q10 mg a day , in the first reported multicenter, randomized, placebo-controlled, and double-blind trial slowed functional declines compared to placebo [ ].

Lower doses or different formulations of coenzyme Q10 displayed no symptomatic effects on midstage PD [ ]. In September , the NINDS discontinued the NET-PD LS-1 study phase III clinical trial with a total of 1, planned participants, ClinicalTrials.

gov identifier: NCT that started in because the results obtained from a study of creatine used for the treatment of early stage PD did not demonstrate a statistically significant difference between the active substance and placebo [ ].

In conclusion, although evidence for the link between OS and damage in PD is overwhelming, suggesting the potential efficacy of antioxidant drugs, most clinical trials have so far failed to support this statement.

Administration of zonisamide, an anticonvulsant drug prescribed to treat resting tremor in PD, inhibited the rise of 8-OHdG levels in the urine of PD patients.

As the 8-OHdG rise correlates with disease progression and aging, it can be presumed that zonisamide could be helpful in defending against OS-evoked DNA modifications in PD patients.

Other drugs used for treatment of PD i. Interesting findings were reported in a study that measured GSH levels in venous blood in PD subjects who were on- and off-medication while performing acute physical exercises, because we know that this type of physical activity leads to GSH depletion and GSSG rise [ ].

Surprisingly, the off-medication patients had a lower drop in GSH level than the on-medication group. This finding suggests that patients in the off-medication state handled acute stress better than those in the on-medication state, indicating that medication may impede the ability to tolerate acute OS [ ].

Similar conclusions were obtained in a very recent study by Nikolova et al. The most popular animal models of PD include pharmacological 6-hydroxydopamine 6-OHDA , 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP , rotenone, and paraquat as well as several genetic with mutations in the α-synuclein, PINK1, Parkin, or LRRK2 genes models [ ].

The 6-OHDA model Table 5 , wherein the toxin is injected directly into the SNpc, medial forebrain bundle, or striatum, was the first animal model of PD associated with dopaminergic neuronal death within the SNpc [ ]. Another PD model utilizes MPTP, a highly lipophilic molecule that rapidly crosses the blood—brain barrier, leading to an irreversible and selective loss of dopaminergic neurons in the SN in non-human primates [ , ] and in rodents [ , ], although the latter species was less sensitive to MPTP than primates [ ].

Other chemical models are based on an insecticide, rotenone, or paraquat, an herbicide. Rotenone, when given i. in a low dose to rats, produces selective degeneration of SN dopaminergic neurons that is accompanied by α synuclein-positive LB-like inclusions [ ]. Paraquat is used less widely than MPTP, rotenone, or 6-OHDA models and is used instead as an addition to other toxic agents, such as the fungicide maneb [ ].

It was reported to cause selective degeneration of nigrostriatal dopaminergic neurons in mice [ ]. As has been demonstrated in numerous studies, OS is widely present in all of these toxin-based models see Table 5. Similarly, in the MPTP and in the rotenone models, elevated levels of lipid peroxidation products [ — ] and oxidatively modified proteins [ , ] were observed in various parts of the brain striatum, cortex, SN, hippocampus, cerebellum, and midbrain.

In addition to lipid damage, increased 3-NT levels were also detected following the use of MPTP in the SN, striatum, and ventral midbrain [ , ]. MPTP or rotenone-treated animals also showed oxidatively modified RNA or DNA in the SN or striatum [ , , ].

In the paraquat and maneb PD models, enhanced lipid peroxidation in the nigrostriatal areas of animal brains was also shown [ ] Table 5. A very recent report from Kumar et al. This interesting result regarding α-synuclein radical formation was obtained by using the immuno-spin trapping method in combination with immunoprecipitation [ ].

Moreover, it was noted that protein radicals such as α-synuclein radical may trigger protein aggregation, which plays a causal role in dopaminergic neuronal death [ ]. For review of genetic models and OS, see the excellent paper [ ].

All toxin-based models share common characteristics, including the ability to produce ROS and further oxidative damage, which causes death in dopaminergic neurons and reflects part of the pathology observed in PD.

Although all of those models have drawbacks, they are useful for testing neuroprotective therapies. A characteristic shared feature observed in all toxin-based models is a drop in GSH level in key PD structures [ , — , — ] Table 5. Importantly, lower GSH levels make nigrostriatal neurons more susceptible to oxidative damage and further degeneration.

Studies using 6-OHDA also showed a reduction in activity by SOD, CAT, and glutathione S -transferase GST in striatum and SN [ , , ]. On the other hand, results from the MPTP model are inconclusive regarding SOD and CAT activity. Moreover, some of the MPTP studies showed increased SOD activity in the SN [ ] and striatum [ ], while others reported diminished SOD activity in these regions [ , ].

These differences may have resulted from the use of different doses of the toxin, varied routes of drug administration intracranial versus i.

Similar to SOD activity, CAT activity cannot be considered a biomarker of OS in rodent PD models as its activity was both diminished [ , , , , , ] and enhanced [ ]. Moreover, GPx activity was diminished in striatum in an MPTP model [ ], while GST activity was found to be elevated in a maneb and paraquat PD animal model [ ] Table 5.

All of these reports on the enhanced activities of SOD, CAT, and GST suggest the presence of mechanisms in brain areas that defend against exposure to PD toxin models. On the other hand, diminished activities or levels of antioxidant enzymes may indicate that these defense mechanisms were overcome and that the degeneration process had begun.

Several agents, such as valproic acid [ ] and melatonin [ ], effectively reversed changes in antioxidant defense biomarkers and oxidative damage in the 6-OHDA rat model of PD Table 6. There are also data in the literature showing that other agents and drugs have antioxidant activity i. Ibuprofen a non-steroidal anti-inflammatory drug [ ] , acetyl- l -carnitine a natural compound reported to prevent mitochondrial injury deriving from oxidative damage in vivo , α-lipoic acid given alone or in combination with acetyl- l -carnitine [ ] , and centrophenoxine a potent nootropic agent that acts as an antioxidant [ ] were demonstrated to enhance GSH levels and CAT and SOD activity and to decrease lipid peroxidation in investigated brain regions in a rat rotenone model Table 6.

Prevention of oxidative damage and the presence of antioxidant defense biomarkers have been documented following treatment with natural compounds, such as lycopene [ ], aqueous extract of tomato seeds TSE [ ], and melatonin [ ].

Many different agents may improve antioxidant brain status in different PD models. However, it should be noted that most of these agents were given before or concomitantly with rotenone, MPTP, or other PD-causing toxins. To definitively answer whether these agents can also show efficacy in reducing the consequences of exposure to prior administration of PD-inducing toxins, further studies are required.

This is especially true because the latter type of drug administration would be a better model for evaluating any pharmacological strategy for reducing OS in PD patients. Most anti-parkinsonian drugs may improve brain antioxidant status in PD preclinical tests Table 7. Ropinirole, a second-generation, non-ergoline dopamine receptor agonist with D2-like receptor selectivity and a chemical structure similar to that of dopamine was found to enhance GSH levels and CAT [ ] activity and to diminish nitrate levels [ ] in the striatum in MPTP-lesioned animals.

Other anti-parkinsonian drugs, such as selegiline a selective irreversible MAO-B inhibitor [ ], deferoxamine [ ], and pramipexole a non-ergoline dopamine agonist [ ], increased GSH levels in the striatum, SN, or cortex. Deferoxamine also decreased a protein oxidative damage biomarker [ ] and enhanced SOD activity in the striatum, while selegiline reduced superoxide anion generation SAG and increased CAT activity in midbrain regions and the cortex [ ].

Interestingly, l -DOPA, the most commonly used drug in PD treatment, did not restore the reduced GSH levels in the SN in the MPTP mouse model [ ].

The above studies suggest that antiparkinsonian drugs, with the exception of l -DOPA, display some antioxidant properties, which may be considered as part of their mode of action and efficacy in PD treatment.

AD is the most common neurodegenerative disease and is characterized by memory loss, dysfunctions in cognitive abilities e. The pathogenesis of AD is not yet clearly understood. The aggregation of extracellular insoluble protein plaques composed of beta amyloid Aβ and intracellular neurofibrillary tangles NFTs, composed of tau protein are critical hallmarks of AD [ , ].

However, many ongoing pathological processes lead to regional neuron loss, beginning in the medial temporal lobe [ ] and following in other brain regions, such as the hippocampus and cerebral cortex [ ].

Many clinical trials and animal studies have recognized free radicals as mediators of injury in AD patients and AD models. The first report of the involvement of OS in AD pathology came from a paper by Martins et al. The latter increase was proposed to be a response to enhanced brain peroxide metabolism.

Other post-mortem studies on brains and CSF from AD patients showed ROS-mediated injuries. For instance, AD patients had increased levels of MDA and HNE, iso- and neuroprostanes, and acrolein compared to controls [ ]. It was suggested that these peroxidated lipids formed adducts with proteins and that they might thereby play a role in AD pathogenesis [ ].

In addition to lipids, protein damage due to OS has also been reported in AD. In fact, increased PC levels in the frontal and parietal cortices and the hippocampus were found in post-mortem studies of the brains of AD patients, while PC was absent in the cerebellum, where no AD pathology was present [ ].

Furthermore, evidence of oxidative DNA modification was found in AD patients as an increase in 8-OHG in human brain homogenates [ ]. In AD patients, ROS production seems to be enhanced; furthermore, increases in RNS were also detected.

Such evidence of RNS modification was identified both in astrocytes and in neurons in AD patient brains examined post-mortem [ ].

The changes in astrocytes were found to co-localize with an increase in iNOS, eNOS, and nNOS expression. The latter increases were noted specifically in cortical pyramidal cells [ ].

In another study, increased expression of iNOS and eNOS was observed to be directly associated with Aβ deposits, showing that beta amyloid might induce NOS to produce NO, which might lead to 3-NT formation [ ].

The presence of 3-NT was also reported in the cerebral blood vessels of AD patients post-mortem [ ]. These findings were associated with reduced NO bioavailability in plasma and further hypoperfusion in AD patients because NO promotes vascular smooth muscle relaxation and thereby regulates blood flow.

Another set of oxidative damage biomarkers, 8-OHdG and 8-OHG, were elevated in AD ventricular CSF [ ] and in brains in both mitochondrial and nuclear DNA compared with age-matched controls [ ].

Consistent data showing enhanced levels of MDA, HNE, iso- and neuroprostanes, acrolein, PC, 8-OHG, 8-OHdG, and 3-NT in the CNS of AD patients can be considered to be proof that OS and NOS are significant contributors to brain damage.

Pivotal antioxidant enzymes, including GPx, CAT, and SOD, display changed levels in the brains of AD patients [ , ]. However, the data are not consistent. For instance, elevated levels of antioxidant enzymes mainly SOD in the hippocampus and amygdala of AD patients have been reported [ ].

On the other hand, in AD patients, decreased levels of SOD, GPx, and CAT were found in the frontal and temporal cortex [ ], while decreases in GSH were observed in the brain and erythrocytes of AD patients [ , ]. Evidence in support of changes in antioxidant enzymes comes from a recent study that identified genetic polymorphisms in the GPx - 1 and GST genes that were positive risk factors for AD [ , ].

The GSH levels were reduced not only in AD but also in mild cognitive impairment MCI , which is considered to be a preclinical stage of AD [ ]. The plasma levels of antioxidants, such as albumin, bilirubin, uric acid, lycopene, vitamin A, vitamin C, and vitamin E, are decreased in AD patients [ , ], although there are some reports indicating the opposite direction of these changes [ ].

Differences in results might be caused by measurement of antioxidants at different disease stages fully developed disease vs. subclinical stage of the disease [ — ]. As OS is present in AD patients, some clinical studies have aimed to test the ability of antioxidant substances to diminish ROS production and to alleviate or to slow the course of the disorder Table 8.

Most studies on the effects of the administration of vitamins that possess antioxidant activity have provided inconclusive information showing that they diminished lipid peroxidation in CSF but had no positive effects on cognitive or functional aspects.

Although the latter study suggests that vitamin E can have a positive influence on AD, no OS biomarkers have been measured in parallel in the AD patients who participated in that trial, which limits the final conclusion.

Administration of other antioxidants, including coenzyme Q10 as well as its synthetic analogue, idebenone which possesses a better ability to pass the blood—brain barrier , in AD patients did not provide any positive results with regards to the volume of ROS-dependent tissue damage or cognitive function improvements [ , ].

Different results were reported in a recent study, where month ω-3 fatty acid supplementation caused a delay in progression of functional impairment in AD patients, while combined supplementation of ω-3 and α-lipoic acid resulted in slowing global cognitive declines MMSE [ ].

Although positive cognitive outcomes were obtained, no changes after ω-3 or ω-3 plus α-lipoic acid supplementation were observed in OS biomarkers, suggesting a different mechanism for their actions that lead to improved cognitive and functional measures [ ].

Curcumin, which is a natural polyphenolic compound and an in vitro blocker of Aβ aggregation, did not diminish the enhancement of F2-isoprostane levels in the CSF [ ] or plasma [ ], or the Aβ 1—40 level in plasma [ ], and it did not ameliorate neuropsychological test results in AD patients [ , ].

As suggested by Ringman et al. There is some hope that curcumin efficacy can be improved through the use of its lipidated forms, which are predicted to have better uptake compared to the nonlipidated form [ ].

More promising results came from a study using resveratrol. The Copenhagen City Heart Study reported that monthly or weekly consumption of red wine was associated with a lower risk of dementia [ ]. gov record accessed 15 May , the study has been completed, but no results have yet been published.

Acetylcholinesterase AChE inhibitors donepezil, rivastigmine, galantamine, and tacrine and the NMDA receptor antagonist memantine are the most commonly used drugs in AD pharmacotherapy. Only some clinical studies that have investigated the influence of these drugs on oxidative balance in AD patients are currently available see Table 9.

One of them showed no positive effects of AChE inhibitors on OS parameters CAT and GR levels in the blood of AD patients compared with AD drug-naïve patients [ ]. In another study, donepezil enhanced GSH levels, while rivastigmine diminished advanced glycation end products AGEs in the plasma of AD patients.

However, other examined parameters, namely total antioxidant capacity TAC and PC, have not been improved by those drugs [ ]. Combined therapy with memantine and donepezil failed to improve GSH, TAC, PC, or AGEs [ ].

A very recent study revealed that 6-month treatment with memantine decreased the oxidation rate of plasma lipids in AD patients compared with untreated patients [ ]. The above clinical trials included small sample sizes and should initiate future examinations evaluating the effect of different types of AD medications on OS markers in AD patients.

AD can be modeled by several procedures in animal. Injection with scopolamine i. For detailed descriptions of AD animal models, see [ — ].

In both pharmacological and genetic models of AD, disordered OS biomarkers are present in animal brains Table Oxidative modification of proteins has also been demonstrated in the cortex and whole brain homogenate of transgenic AD mice [ , ] and in the cerebral cortex and hippocampus of an Aβ mouse model [ ].

In addition to OS due to oxygen, there is also proof of the presence of NS in whole brain lysates from the APP23 transgenic AD mouse model [ ].

Antioxidant defense biomarkers have been found to be changed in AD models see Table Diminished levels of GSH in the cerebral cortex or hippocampus or in whole brain lysates have been demonstrated in pharmacologically induced AD animal models [ , , , , , , , ].

Furthermore, the activities of enzymes connected with GSH metabolism, such as GPx and GR, and the enzymes involved in antioxidant defense SOD and CAT were reduced in the hippocampus and cerebral cortex in pharmacological and genetic models [ , , , , , — ].

It should be noted that some studies demonstrated no change in CAT and SOD activity in whole brain lysates in Wistar rats in the streptozotocin model [ ], while enhanced SOD, GPx, and GR were observed in the mouse cerebral cortex and hippocampus following i.

Aβ injection [ ]. It is also important to mention that in transgenic models, the changes depend on animal age. Several preclinical studies on AD have shown that many antioxidants can both diminish OS and improve cognitive impairments Table Among different compounds of special interest are vitamin E, vitamin C, and α-lipoic acid.

Vitamin E given 7 days before Aβ decreased MDA and protein carbonyls in the mouse hippocampus and cortex [ ]. Similarly, α-lipoic acid enrichment decreased HNE levels in AbPP Tg mouse brains but did not decrease 3-NT levels [ ]. In AbPP Tg mice that overexpress a mutant form of APP beta amyloid βA , an A4 precursor protein and show impaired learning, an R-α-lipoic acid-enriched diet, administered for 10 months, decreased HNE levels in total brain homogenates and also attenuated HNE protein adducts that accumulated around amyloid deposits in the hippocampal and cortical region, but it had little effect on cognitive performance and brain Aβ load.

This latter study seems to suggest that a long-term antioxidant therapy that reduced oxidative modifications provided a limited benefit [ ]. The lack of effect of vitamin C on Aβ plaque deposits seems to result from the late introduction of medication in this test because Aβ plaques, considered an end point in the disease process, are detectable in these mice at 4—5 months, which was before the beginning of the test [ ].

It is also possible that ascorbate had an effect on soluble Aβ [ ]. This latter observation led to the conclusion that vitamin C may not be an anti-OS medication per se, but its deficiency in AD patients may lead to oxidative damage.

Interestingly, another study showed that the long-lasting incretin hormone analogue d -Ala 2 GIP glucose-dependent insulinotropic polypeptide was able to decrease OS biomarkers i.

Many natural compounds that possess antioxidant properties have been tested in animal models as AD treatments. Imperatorin and hesperidin diminished brain damage due to OS, and most of them enhanced the power of oxidative defenses [ — , ].

Moreover, meloxicam an anti-inflammatory drug and selegiline, given alone or in combination, inhibited lipid peroxidation, prevented a decrease in CAT activity, and showed memory-enhancing capacity in a scopolamine AD model [ ].

Another compound, S -allyl cysteine, which is a sulfur-containing amino acid that was reported to have antioxidant and neurotrophic activity, prevented cognitive and neurobehavioral impairments, prevented ROS damage in the hippocampus, and augmented endogenous antioxidant enzymes in a streptozocin AD model [ ].

Similar results were obtained when melatonin was given chronically to a genetic AD mouse model, as the drug alleviated OS and enhanced GSH levels [ , ]. Moreover, results from Feng et al. As shown above, results from animal AD models that have used various pharmacological compounds to reduce OS and to alleviate memory deficits in AD are promising but do not yet parallel the results obtained in clinical trials.

For example, tacrine, the first anticholinesterase inhibitor approved by the Food and Drug Administration FDA , was shown to suppress OS in an animal AD model [ ]. The effect of tacrine may therefore be considered to be positive when this drug is used in doses that stimulate the antioxidant system without inducing oxidative damage in brain tissue [ ].

However, donepezil, when given in a similar dose of 2. Those contradictory results come from studies using non-transgenic and transgenic animal AD models, which means that the multiple adaptations developed for use in these transgenic animals could be the reason for the observed difference in outcomes.

Another medication used in AD treatment is rivastigmine. This drug neither attenuated lipid peroxidation nor restored GSH depletion in the brains of rats in an AD model [ ], although an older study indicated antioxidant properties for rivastigmine when AD was induced in rats by aluminum chloride administration [ ].

Such differences in the effects of rivastigmine might be caused either by differences in the AD model used in the study aluminum chlorate p.

colchicine i. models or by differences in the rivastigmine dose regimen 0. for 28 days. Based on the above scant reports, it is too soon to either confirm or exclude rivastigmine as an effective OS scavenger in AD. A single report showed the ability of another AChE inhibitor, galantamine, to reduce OS.

In a cognitive impairment animal model, galantamine decreased lipid peroxidation, nitrate, and GSSG levels, enhanced SOD activity, and impaired GSH levels following kainic acid intrahippocampal injection, and it restored cognitive deficits as well [ ].

Memantine has also been widely studied in preclinical AD models. For example, it was shown that memantine reduced oxidative damage to proteins in the cortex and hippocampus but not in the striatum, resulting in the reversal of concomitant age-induced recognition memory deficits in aged rats [ ].

Other studies found that memantine diminished the level of inducible forms of NOS in an Αβ 25—35 AD model [ ] and ROS and nitrate levels in the hippocampus and cortex in a streptozotocin AD model [ ] and in a kainic acid-induced model of dementia [ ].

However, memantine was shown to have neuroprotective properties not only in AD models but also in 3-nitropropionic acid [ ], rotenone [ ], and diisopropylphosphorofluoridate DFP toxicity models [ ]. There is a wide range of evidence showing that several drugs used to treat AD have antioxidant properties, suggesting that at least part of their efficacy in animal models may come from that action.

In general, the presence of OS in the pathophysiology of many neurodegenerative disorders, including ALS, PD, and AD, is a well-recognized phenomenon. The results of many in vitro and in vivo preclinical and clinical studies have consistently demonstrated that OS is one of the crucial players in the degeneration that occurs in the nervous system.

The imbalance between OS and antioxidant defense systems seems to be a universal condition in neurodegeneration. However, what can be surprising is that the results of many studies often provide different results when trying to determine the exact mechanisms that underlie OS and to determine which of the markers of OS could be clinically useful.

What has been shown to be elevated in one study does not necessarily have to rise in another. In preclinical studies, these divergent results could be explained by the use of different models, different species, or different methodologies.

As for the clinical setting, it must be stressed that the number of patients available for study is usually small because they are in different stages of their diseases, there are often coexisting comorbidities, and, last but not least, they often take many other medications with different pro- or antioxidant properties.

The analysis of potential biomarkers under these conditions is extremely difficult. Therefore, assessing the real efficacy of potential antioxidant drugs is a challenge. However, there are some data, if even modest, that some of the existing drugs possess anti-oxidant properties and that they could slow down neurodegenerative processes and improve our understanding of the significance of OS in the pathobiology of these untreatable conditions.

The results of clinical and preclinical studies have demonstrated the presence of elevated levels of OS biomarkers as well as impairments to antioxidant defenses in the brain and peripheral tissues in PD, AD, and ALS.

As the currently available therapies for these neurodegenerative diseases are not sufficiently effective for treating disease symptoms, novel substances are searched for.

Most such drugs have so far failed to slow down the progression of the disease or to prolong the lives of patients. Some exceptions within these anti-neurodegenerative drugs exist, and they give hope and inspire further research.

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The Mental focus exercises nervous system CNS disordets oxidative stress and neurodegenerative disorders for strress and controls the physiological functions of the body. However, the biochemical characteristics oxiddative the CNS make it especially vulnerable to oxidative damage OS. This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death. OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. Oxidative stress OS has been proposed as neurkdegenerative factor that plays a potential role in the pathogenesis of neurodegenerative disordees. Clinical and preclinical studies neurodegeneartive that neurodegenerative oxidative stress and neurodegenerative disorders are characterized by Advanced recovery techniques levels neurodegenreative OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction. Martina Rekatsina, Antonella Paladini, … Giustino Varrassi.

Author: JoJora

2 thoughts on “Oxidative stress and neurodegenerative disorders

  1. Absolut ist mit Ihnen einverstanden. Darin ist etwas auch mich ich denke, dass es die ausgezeichnete Idee ist.

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