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Alpha-lipoic acid and neuroprotection

Alpha-lipoic acid and neuroprotection

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Alpha-lipoic acid and neuroprotection -

P53 was originally identified as a tumor suppressor gene, and has been considered to be a key contributor in neuronal cell death and dopaminergic neuron degeneration 34 , The pharmacologic inhibition of p53 has been shown to preserve dopamine neurons against the neurotoxic effects of MPTP and other neuronal toxins that induce PD-like pathology in in vivo and in vitro models of PD 23 , 36 — The classical trigger for p53 activation is oxidative stress, and pdependent apoptosis in neuronal cells is predominantly mediated by DNA damage 34 , P53 is an upstream inducer of PCNA, and a higher concentration of wild-type p53 inhibits the PCNA promoter and reduces the production of PCNA 20 , Previous studies have shown that ALA has anti-inflmmatory and anti-oxidative properties in a range of cell types and tissues 40 — 43 , which may be beneficial in neurodegenerative conditions.

Preclinical and clinical data have indicated that ALA is bioavailable and safe in moderate doses 8. Further investigations are required to fully elucidate the mechanisms responsible for the protective effects of ALA in neurodegenerative conditions, which may provide a potential effective neuroprotection strategy for the treatment of PD by targeting DNA damage-mediated neuronal degeneration.

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J Surg Res — Packer L, Tritschler HJ, Wessel K Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Panigrahi M, Sadguna Y, Shivakumar BR, Kolluri SV, Roy S, Packer L, Ravindranath V alpha-Lipoic acid protects against reperfusion injury following cerebral ischemia in rats.

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There are no recommendations for daily LA intake in humans. has been reported Packer et al. placebo Shay et al. In spite of that, the exact doses that could induce adverse human health effect are still to be set up.

Neurodegenerative diseases are a heterogeneous group of disorders described by progressive and selective neuronal death with degeneration of specific brain regions Arivazhagan and Panneerselvam, ; Lin and Beal, ; Savitha and Panneerselvam, , often associated with abnormal deposits of proteins in neurons or extracellularly Chen et al.

Neurodegeneration is characterized by its insidious and chronic progressive onset and aging has been considered the main risk factor Lin and Beal, ; Chen et al. During aging, deleterious changes accumulate, causing the gradual decline of the biochemical and physiological functions Arivazhagan and Panneerselvam, ; Kumaran et al.

Moreover, aging individuals are susceptible to degeneration of selective brain regions Aliev et al. Over the last decades, a wide range of studies have shown that progression of neurodegeneration is associated with increased DNA damage partly is attributed to an imbalance between antioxidant and prooxidant factors; Chen et al.

In addition, mitochondrial decline, leading to cognitive dysfunction Liu, ; Aliev et al. Oxidative stress and mitochondrial dysfunction are interrelated mechanisms that play a central role in aging brain Santos et al.

Although the exact mechanisms underlying the effects of unbalanced redox signaling are not completely elucidated, studies suggest that it plays a role in the pathogenesis of neurodegenerative disorders Liu et al. Brain aging has been related to structural alterations and inflammation, accompanied by cognitive and memory dysfunctions Bagh et al.

With the aging of the world population and the increasing life expectancy, the risk of developing neurodegenerative diseases is higher than ever, as they are affecting millions of people each year in epidemic proportions Santos et al.

As a result, an inevitable socioeconomic burden on our health care systems will occur. Effective prophylactic and therapeutic treatments are urgent for this group of seemingly inexorable diseases. In this review we will focus on discussing the ameliorating effects of LA on cognitive deficits observed in animal models of aging and neurodegenerative disorders.

Alzheimer's disease AD is the most common neurodegenerative disorder that causes dementia and affects middle to old-aged individuals Hager et al.

AD is characterized by progressive loss of cognitive functions, including memory, language, and reasoning Di Domenico et al. Studies have investigated the effects of LA in experimental AD models Jesudason et al. For instance, Quinn et al.

LA treatment was shown to reduce hippocampal-dependent memory deficits, significantly improving learning and memory in the Morris water maze in comparison to Tg mice that did not receive LA.

However, no significant differences in β-amyloid levels were found between Tg mice that received LA in comparison to the ones that did not receive LA, indicating that chronic LA supplementation in the diet can ameliorate hippocampal memory impairments in Tg mice without any effect on β-amyloid levels or plaque deposition.

Another study assessed the effects of LA in senescence-accelerated mouse prone 8 SAMP8 mice, associated to learning and memory impairments, and showed that LA can improve memory, in different paradigms Farr et al.

In object recognition, results indicated that mice that received LA presented a higher memory index than vehicle-treated mice. On the other hand, Siedlak et al. The authors concluded that, although oxidative stress has been proposed to mediate amyloid pathology and cognitive decline in aging, long-term LA administered within tolerable nutritional levels, presented limited benefit.

Parkinson's disease PD is the second most frequent neurodegenerative disorder in aging individuals and features motor symptoms related to dopaminergic neuronal loss in the substantia nigra , which results in decreased striatal dopaminergic terminals Beal, ; De Araujo et al.

Studies have shown that, in addition to rescuing cognitive deficits, LA is also able to ameliorate motor impairment related to PD. The effects of LA were examined in a rat model of PD induced by rotenone. was evaluated after the administration of rotenone in the open-field and square bridge tests.

The authors reported that LA improved rotenone-induced behavioral deficits. In the open-field test, LA significantly increased the ambulation frequency, increased the number of stops, elevated the activity index and lessened the inactive sittings, but did not increase the rearing frequency in comparison to the group that received rotenone.

In the Square bridge test, treatment with LA protected the rats from falling as compared to rotenone group Zaitone et al. The effects of LA in lipolysaccharide LPS -induced inflammatory PD model were also evaluated Li et al.

No significant recovery was observed in dyskinesia in PD mice that received LA. However, a significant amelioration was observed in the adhesive removal test, in which LA treatment significantly decreased the reaction time in comparison to the LPS group. Huntington's disease HD is a chronic neurodegenerative disease and a hereditary autosomal-dominant disorder of the central nervous system caused by a single genetic mutation Ross et al.

This disorder is classically characterized by motor symptoms and cognitive and behavioral features Ross et al. A HD model that has been easily replicated in animals is based on the treatment with 3-nitropropionic acid 3-NP , which promotes development of mitochondrial dysfunctions leading to bioenergetic failure energy impairment, oxidative stress, and excitotoxicity.

A study by Mehrotra et al. Administration of LA improved spatial memory acquisition and retrieval assessed using the Morris water maze. Analysis of time taken and distance traveled to find the platform in the target quadrant revealed that LA supplementation for 21 days to 3-NP—treated animals resulted in a lower latency and the distance traveled was also reduced.

In addition, the average number of platform crossings in the probe trial was increased in 3-NP treated animals that received LA. Thus, the authors demonstrated that LA supplementation improved spatial memory by ameliorating the iron- and copper-induced oxidative injury observed in age-related disorders.

In the Y-maze test, animals display a preference to explore the novel arm of the maze, making fewer entrances in the previously explored arm, due to spontaneous alternation. The authors showed that 3-NP—treated animals traveled a significantly lower distance, assessed by the number of entries in the novel arm, and that supplementation with LA reversed these deficits.

Consistent evidence indicate that memory is affected by aging in rodents as well as in humans. A study by Liu et al. Results showed that LA supplementation alone or combined with another mitochondrial metabolite, acetyl-l-carnitine, improved both spatial and temporal memory.

In month old SAMP-8 mice, chronic LA administration improved cognition in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific locomotor effects Farr et al.

LA has also been reported to improve behavior of aged mice in an open-field memory test Stoll et al. LA also and ameliorated acquisition and retrieval in a dose-dependent manner, in old female NMRI mice, in the active avoidance learning test Stoll et al.

Cui et al. Another study reported the neuroprotective effects of LA in neurotoxicity model induced by AlCl 3 administration to mice Mahboob et al. LA enhanced fear memory and social novelty preference in comparison to the AlCl 3 -treated group.

In summary, current evidence indicates that LA is able to improve memory, reversing impairments associated to a variety of experimental models of neurodegenerative disorders, and exposure to neurotoxicants, as well as normal aging.

Table 1 summarizes in vivo studies investigating the neuroprotective effects of LA on behavioral parameters. Furthermore, LA was also shown to act as a memory-improving molecule in different learning and memory paradigms, including aversive, spatial, and recognition memory.

Table 1. Summary of studies testing the effects of LA on behavioral parameters in animal models. LA has been tested in humans, in studies by Hager and coworkers Hager et al.

The authors examined the effect of LA for 24 and 48 months and observed that the treatment lead to a stabilization of cognitive function, verified by unchangeable records in two neuropsychological tests, mini-mental state examination MMSE and the AD assessment score, cognitive subscale ADAScog.

In vivo as well as in vitro studies have been performed in order to characterize cellular and molecular effects of LA underlying its memory-ameliorating activities Table 2. The effects of LA on oxidative markers in various brain regions have been discussed in different studies in animals models of aging and neurodegenerative diseases Cui et al.

LA administration decreases lipid peroxidation evaluated by MDA Arivazhagan and Panneerselvam, ; Arivazhagan et al. Moreover, administration of LA reversed the augmentation of protein carbonyls levels in a radiation-induced cognitive dysfunction model Manda et al.

Table 2. Summary of in vivo studies testing cellular and molecular effects of LA. A study by Zaitone et al. In reserpine-treated rats, LA enhanced the amount of GSH, while diminishing GSSG levels in the striatum.

Moreover, LA decreased NO concentrations in striatum and pre-frontal cortex, without significantly affecting S-nitrosothiol levels. LA also increased enzymatic activities of GPx and GST in the striatum Bilska et al.

Reserpine significantly decreased enzymatic activity of L-γ-glutamyl transpeptidase γ-GT , while pretreatment with LA was able to restore it.

The effects of LA on oxidative stress in rotenone parkinsonian rat brains were investigated, showing that LA can reduce lipid peroxidation and protein carbonylation Zaitone et al.

LA also lowered the levels of MDA and nitrite in the 6-OHDA-induced rat model of hemi-parkinsonism Jalali-Nadoushan and Roghani, Karunakaran et al.

R-LA induced significant reductions in markers of oxidative modifications in transgenic AD mice model, significantly decreasing HO-1 and protein-bound HNE levels Siedlak et al. Inman et al.

The results showed that after 4 and 11 months of dietary LA, respectively, LA treatment increased antioxidant genes and protein expression, protected retinal ganglion cell RGC , and improved retrograde transport.

Dietary therapy also reduced lipid peroxidation, protein nitrosylation, and DNA oxidation in a retina model of glaucoma. Accumulation of metal ions also has been associated with increased oxidative stress related with aging and neurodegenerative disorders.

Suh et al. However, Liu et al. There are multiple cell death mechanisms implicated in neurodegeneration. Apoptosis is a highly controlled cellular process that can be activated by two pathways: extrinsic, which is a receptor-mediated pathway, and intrinsic, which is mediated by signals from the mitochondria.

Both pathways culminate at cleavage-dependent activation of aspartate-specific effector caspases caspases-3, 6, and 7. Manda et al. They observed that pre-treatment with LA prevented radiation-induced decreases of total, nonprotein and protein-bound sulfhydryl T-SH, NP-SH, and PB-SH levels in the cerebellum.

Moreover, LA treatment also improved the cytoarchitecture of cerebellum, increasing the number of intact Purkinje cells and granular cells when compared to untreated irradiated mice. Mehrotra et al. The results showed that LA decreased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, and increased Mn-superoxide dismutase and CAT activity.

LA improved activity of enzymes from the mitochondrial respiratory chain, altered cytochrome levels, increased histochemical staining of complex-II and IV, increased in-gel activity of complex-I to V, and increased mRNA expression of respiratory chain complexes.

Stoll et al. The results showed that LA improved age-related NMDA receptor deficits B max. No changes were observed regarding muscarinic, benzodiazepine, and α 2 -adrenergic receptor deficiencies. Thus, the authors concluded that LA-induced memory improving effects may be related to partial reparation of NMDA receptor deficits that accompany aging.

A loss of dopaminergic neurons is particularly relevant to PD, in which genetic and environmental factors are involved Di Domenico et al. Jalali-Nadoushana and Roghania using a rat model of hemi-parkinsonism 6-OHDA found that LA prevented neuronal loss on the left side of the substantia nigra pars compacta SNpc Jalali-Nadoushan and Roghani, In a study using the LPS-induced inflammatory PD model, Li et al.

Zaitone et al. Li et al. Moreover, the authors showed that LA inhibited the stimulation of nuclear factor-κB NF-κB and expression of pro-inflammatory molecules in M1 microglia.

The results showed that LA significantly decreased rotenone-induced mtDNA damage. Liu et al. Dietary administration of LA significantly reduced oxidized RNA levels and reversed mitochondrial structural deterioration induced by aging in the hippocampus. Dwivedi et al. The results indicated that arsenic and dichlorvos induced oxidative stress and cholinergic dysfunction in brain, which was significantly protected by the supplementation with LA.

Seidman et al. Their results showed that mtDNA deletions associated with aging were reduced by LA and this effect appeared to be related to the mitochondrial capacity to protect and repair mtDNA against age-induced injury. Palaniappan and Dai investigated the effect of LA administration to aged rats and verified a reduction of mitochondrial lipid peroxidation, 8-oxo-dG and oxidized glutathione GSSG and increased GSH, ATP, and electron transport chain ETC complex activities in the brain.

The SAMP8 mouse strain is an experimental model that displays increased oxidative stress accompanied by memory decline associated to a rapid aging process. In order to determine the mechanisms underlying LA-induced reversion of memory deficits exhibited by SAMP8 mice, Poon et al.

The levels of three proteins neurofilament triplet L protein, a-enolase, and ubiquitous mitochondrial creatine kinase were significantly increased, while protein carbonylation was reduced in lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and a-enolase in aged SAMP8 mice that received LA, suggesting that, in addition to improving learning and memory, LA also can restore specific proteins in aged SAMP8 mouse brain.

Evidence indicates that deregulation in neurotransmitter systems, including decreased levels of neurotransmitters, decline in the number of receptors, and lower responsiveness to neurotransmitters can be key features of neurological disorders Payton et al.

Arivazhagan and Panneerselvam investigated the effect of LA on levels of neurotransmitters dopamine, serotonin, and norepinephrine , and showed that LA treatment can improve neurotransmitter function in models of neurodegenerative diseases.

Jesudason et al. The results showed that AD mice treated with LA exhibited enhanced levels of serotonin, dopamine, and norepinephrine, and the concentration of metabolites 5-hydroxyindole acetic acid 5-HIAA and homovanillic acid HVA gradually returned to normal.

Ahmed explored the effect of LA on brain acetylcholinesterase AChE activity. The authors demonstrated that LA can ameliorate neurological injury related to Aβ and Al excess, by significantly restoring AChE activity.

In addition, the authors showed that the treatment with LA restored the parameters of total homocysteine tHcy , insulin, insulin like growth factor-1 IGF-1 , interlukin-1β IL-1β and tumor necrosis factor-α TNF-α. Mahboob et al. LA treatment increased the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase ChaT relative to AlCl 3 -treated group.

There are many studies examining the neuroprotective actions of LA using in vitro models of neurodegeneration Tirosh et al. For example, Ono et al. The results showed that both LA and DHLA inhibited fAβ formation from amyloid β, as well as their expansion, and undermined preformed fAβs in a dose dependent manner.

Lovell et al. In β-amyloid-intoxicated C6 glioma cells, LA increased cell viability and MnSOD expression. The increased GSSH and decreased GSH mitochondrial levels induced by Aβ were reversed by treatment with LA Xing et al.

The study by Deuther-Conrad et al. de Arriba et al. Tirosh et al. Kamarudin et al. Suppression of NF-κβ p65 translocation and production of proinflammatory cytokines IL-6 and TNF-α followed inhibition of cleaved caspase Yamada et al. They showed that all types of LAs were effective in preventing cell death.

R-LA and S-LA also enhanced expression of genes related to anti-oxidative response such as heme oxygenase-1 HO-1 and phase II detoxification enzymes such as NAD P H:Quinone Oxidoreductase 1 NQO1. Other studies evaluated the effect of LA on in vitro model of PD.

Moreover, Zhang et al. LA has been proposed to exert a modulatory control on the cellular redox status. Due to its ability to be interconverted in one of its two forms—i. LA has been described to regenerate other antioxidants, such as vitamin C and E, to increase GSH levels, and to provide modulation of proteins and transcription factors Packer et al.

Extracellular redox state is also regulated by LA, once its reduced form, DHLA, can interact with cystine, reducing it to cysteine, thereby stimulating its uptake by the cell, which in turn stimulates GSH synthesis Han et al.

For instance, Jiang et al. Prevention of sevoflurane-induced apoptosis by LA was accomplished through recovery of Akt and GSK3-β phosphorylation levels in the hippocampus Ma et al. Sancheti et al. Compelling evidence indicates that LA displays memory-ameliorating properties in a variety of experimental models of neurodegenerative diseases, as well as in memory decline associated with aging in rodents.

Studies aiming to assess the neuroprotective effects of LA on behavioral outcomes showed that LA can reduce memory deficits in different behavioral paradigms on AD Quinn et al. In humans, two studies in AD patients have supported the positive cognitive effects of LA Hager et al. Many studies reported beneficial effects of LA in the rat brain or neuronal cell cultures, using different molecular markers of oxidative stress, such as reduction in the levels of lipid peroxides and protein carbonyls, recycling endogenous antioxidants such as vitamin C and E, increasing glutathione levels Packer et al.

LA was also shown to display anti-inflammatory properties Deuther-Conrad et al. In vivo and in vitro studies showed that LA ameliorated neurodegeneration in the hippocampus, decreasing neuronal apoptosis and caspase-3 protein levels, supporting a neuroprotective role mediated by the mitochondrial cell death pathway.

These effects suggest that LA is able to improve mitochondrial dysfunctions. Interestingly, in addition to decreasing neuronal cell death, LA also inhibited fAβ formation from amyloid β-protein, ameliorating the neurological damage induced by Aβ, and significantly restored AChE activity.

This evidence suggests that LA presents a potential role in enhancing cholinergic and cognitive functions. These neuroprotective effects may be related to the properties of LA in ameliorating memory loss associated to neurodegenerative diseases.

Remarkably, LA was able to reverse age-associated glutamatergic NMDA receptor deficits Stoll et al. LA was also shown to improve the function of neurotransmitter systems, including dopamine, serotonin, and norepinephrine.

Radical oxygen species produced after neutoprotection counteracts Detoxification and colon cleansing activity and Alpha-lipoic acid and neuroprotection causes severe oxidative stress for the tissues. Alpha-lipoic acid Alpha-lipoic acid and neuroprotection a powerful metabolic antioxidant abd immunomodulatory effects which provides neuroprotection. The neuroprotecfion of acif study is to investigate the neuroprotective and anti-apoptotic effects of alpha-lipoic acid on spinal cord ischemia—reperfusion. The abdominal aorta was clamped for 30 min by an aneurysm clip, approximately 1 cm below the renal artery and 1 cm above the iliac bifurcation in control and treatment groups. Only laparotomy was performed in the sham group. The animals were killed 48 h later. Spinal cord segments between L2 and S1 were harvested for analysis.

Parkinson's disease PD nwuroprotection a Alpha-liipoic disorder characterized by motor and behavioral disturbances, caused by Alpha--lipoic gradually progressive and selective degeneration of dopaminergic neurons Brown rice for diabetes the substantia nigra pars wcid SNpc 1.

Alpha-lipoicc pathogenesis of PD remains to be fully elucidated, however, multiple studies have linked oxidative stress to dopaminergic neuron degeneration neuroprotfction PD. Neuriprotection oxidative stress contributes to DNA damage, leading to dopaminergic neuron degeneration and the pathogenesis of Ahd 2.

Postmortem samples nfuroprotection PD have shown beuroprotection DNA Alpha-lipoic acid and neuroprotection damage selectively in dopaminergic neurons abd the Nruroprotection, indicating the link between Acod oxidation and the neuoprotection of dopaminergic neurons in PD Alpha-lipoic acid and neuroprotection.

These previous Alpua-lipoic support the beuroprotection that Neuroprotecyion damage-induced cell death is a mechanism involved in the pathogenesis Alpna-lipoic PD. Proliferating cell nuclear antigen PCNA is a well-known protein, which is involved in Adid repair in Alpha-lipkic wide range neuroprotrction pathological conditions, including oxidative stress-mediated damage of Anf by interacting with a number nfuroprotection enzymes and regulatory jeuroprotection 4 neuroprotecttion 6.

The PCNA-dependent repair of damaged DNA is wnd in preserving its integrity under oxidative conditions 78. Currently, the neuroprotsction of Alpha-liipoic neuroprotective strategy to neuroprotectoon or reverse the degeneration Akpha-lipoic dopaminergic Top fat burners has been Nutrition myths unveiled in Aopha-lipoic treatment of PD, which relies on the acie inhibition of Alpba-lipoic pathogenesis in neurodegenerative process.

α-lipoic acid ALA is a naturally occurring dithiol compound, which Alpja-lipoic synthesized enzymatically in the mitochondria from octanoic acir and cysteine. ALA has been in common clinical use Alpja-lipoic several neuroprotecfion associated with increased oxidative stress, and its administration in moderate doses has produced no evidence of serious side-effects 10 — Several studies neurporotection shown that ALA exerts protective effects acidd in vivo and afid vitro models neuroprotction neurodegenerative diseases, including Alzheimer's disease ADmacular degeneration and PD 17 — The Alpha-lippic of ALA Neuroproection the PCNA beuroprotection regulator, p53, nad also examined.

P53 interacts with the PCNA promoter to regulate the production of this protein, Alpba-lipoic a Alpha-lipoic acid and neuroprotection concentration of neuroportection p53 inhibits the PCNA neurroprotection, which results in a decrease in the production of PCNA neuroprotdctionneuroproection ALA treatment neuorprotection reduced the expression levels of p53, however, the expression of PCNA was upregulated.

Neuroptotection reagents and chemicals neuroprotectioon purchased from Sigma-Aldrich; Neuroprotextion Millipore Darmstadt, Germany unless nekroprotection otherwise. Cell viability was Alpha-lipoif using an Neuroorotection colorimetric assay. MTT is readily taken Alpha-lipoix into cells, Alpha-lipojc is then reduced, predominantly by Qcid enzymes, to neuuroprotection blue an crystals, which are Alpha-oipoic to cell Natural weight loss and are trapped in living cells.

The absorbance of the colored solution was measured at nm using Al;ha-lipoic microplate reader Acud, Epoch, USA. The results are expressed as the aciv of the absorbance measured in control culture wells. Alpha-liloic experiment was repeated three times.

Cell injury was further confirmed by measuring the activity Wrestling meal planning LDH, which is expressed in all mammalian cells and is Alpha-lioic from damaged cells Alpha-ilpoic the culture medium.

The neuroprotectioj of the released LDH in the culture supernatant was measured neuroprotechion LDH-Cytotoxicity A,pha-lipoic kits Neurlprotection Research Products, Mountain View, Neurpprotection, USA enuroprotection to the manufacturer's protocol. AAlpha-lipoic treatment, the cells were centrifuged at neuroprotectiom, × g for 10 min neuroprotecfion 4°C, and 50 µl neuroprotction the resulting supernatant was transferred into a separate well plate.

Neuroprotectiob µl aciv of the LDH reaction neurroprotection was added to each neuroprootection. Following incubation for 30 nfuroprotection at room temperature, the LDH activity Alpha-lipooic quantified nduroprotection absorbance neuroprotectjon at nm using a multiwell neurporotection BD Biosciences, San Diego, CA, USA.

The data are caid as a percentage of the neuroproteciton values in the wnd Alpha-lipoic acid and neuroprotection. Apoptosis is a major type of cell death, Alpha-,ipoic by a Alpha-,ipoic of nuclear morphological changes, including scid nuclear size, chromatin ahd, intense fluorescence and neuroprltection fragmentation.

These aciv can be detected by Hoechst staining, which is used for the quantification of apoptotic cells. Subsequently, the numbers of apoptotic cells were randomly counted under a fluorescence microscope IX71; Olympus, Tokyo, Japan.

The number of apoptotic cells is expressed as a percentage of the total cells counted. Protein concentration was determined using the Bradford method GE Healthcare Life Sciences, Chalfont, UK. Western blot analysis was performed using rabbit anti-PCNA ,; cat.

R; Thermo Fisher Scientific, Inc. were used as the secondary antibodies and incubated at room temperature for 2 h. The blots were analyzed using an enhanced chemiluminescence system GE Healthcare Life Sciences. Data are expressed as the mean ± standard error of the mean.

Statistical analysis was performed using one-way analysis of variance, followed by Dunnett's multiple-comparisons test. Analyses were performed using SPSS version After 48 h treatment, 0.

The measurements revealed that the addition of 0. ALA did not appear to affect the basal activity of LDH Fig. The cell viability was determined using a 3- 4,5-dimethylthiazolyl -2,5-diphenyl-tetrazolium bromide assay.

Data are presented as the mean ± standard error of the mean of three independent experiments performed six times. PC12 cells were pre-treated with 0. A Cell viability was determined using a 3- 4,5-dimethylthiazolyl -2,5-diphenyl-tetrazolium bromide assay.

B Cell injury was measured using an LDH assay. Data are presented as the mean ± standard error of the mean. Apoptosis characterized by a series of distinct nuclear morphological changes can be detected using Hoechst staining, a compound that binds nucleic acids.

The administration of ALA alone did not induce changes in the number of apoptotic cells. A Hoechst staining. Scale bar, 20 µm. B Histogram presenting apoptotic cells as a percentage of the total cells. Following treatment, the cells extracts were prepared, and western blot analyses were performed on the homogenates to examine the effect of ALA on the expression of PCNA.

ALA did not affect the basal expression of PCNA Fig. A Protein expression levels of PCNA were determined using western blot analysis and actin levels were measured as a loading control.

B Histograms of the percentage of PCNA content relative to the content of the control. P53 interacts with the PCNA promoter to regulate the production of this protein, and a higher concentration of wild-type p53 inhibits the PCNA promoter, resulting in a decrease in the production of PCNA 20 The role of the p53 protein in the pathogenesis of several neurodegenerative disorders, including PD, has been well documented 22 A Expression levels of p53 were determined using western blot analysis and actin levels were measured as a loading control.

B Histograms of the percentage of p53 content relative to the content of the control. The present study demonstrated for the fist time, to the best of our knowledge, that ALA exerts its neuroprotective action mediated by upregulating the protein expression of PCNA via the p53 pathway in a cellular model of PD.

PD is a movement disorder, which is characterized by the gradually progressive and selective degeneration of dopaminergic neurons in the SNpc The pathogenesis of PD remains to be fully elucidated, however, multiple studies have linked oxidative stress to dopaminergic neuron degeneration.

Cell survival is dependent on DNA integrity. Under physical and pathological conditions, DNA is frequently subjected to damage by endogenous and environmental toxic agents, particularly in the SNpc, which results from oxidative stress due to its high levels of lipids, iron and dopamine metabolism Increased oxidative stress causes oxidative DNA damage, which subsequently leads to dopaminergic neuron degeneration and the pathogenesis of PD.

Postmortem samples of PD have shown increased DNA oxidative damage selectively in dopaminergic neurons of the SNpc, indicating the link between DNA oxidation and the loss of dopaminergic neurons 2.

The association between DNA damage-induced cell death and the neurodegenerative process of PD is also supported by the presence of oxidized DNA in the brain tissues of mice treated with MPTP and other neuronal toxins, inducing a PD-like pathology 3. To counteract damage, repair mechanisms for DNA are required to preserve its integrity, particularly for dopaminergic neurons, which are more prone to oxidative damage 26 — PCNA is a well-known protein, which is involved in DNA repair in a wide range of pathological conditions by interacting with a number of enzymes and regulatory proteins 45.

The PCNA-dependent repair of DNA damage is crucial in preserving the integrity of DNA under oxidative conditions 78. Thus, effects of PCNA in reversing degeneration may be beneficial in neurodegenerative conditions. ALA is a naturally occurring dithiol compound, synthesized enzymatically in mitochondria from octanoic acid and cysteine.

In addition to its function as an essential cofactor for mitochondrial bioenergetic enzymes in the production of energy, ALA is involved in a set of biochemical activities with potential pharmacotherapeutic value against a range of pathophysiological insults 9 Several studies have shown that exogenous ALA can readily cross the blood-brain barrier 32 Notably, the neuroprotective actions of ALA have been reported in in vivo and in vitro models of neurodegenerative diseases, including AD, macular degeneration and PD 17 — The mechanisms underlying the effect of ALA on the expression of PCNA remain to be fully elucidated.

It may be associated with its ability to regulate the p53 protein, as P53 is the most well-characterized mechanism for modulating the production of PCNA through the binding of its promoter 20 P53 was originally identified as a tumor suppressor gene, and has been considered to be a key contributor in neuronal cell death and dopaminergic neuron degeneration 34 The pharmacologic inhibition of p53 has been shown to preserve dopamine neurons against the neurotoxic effects of MPTP and other neuronal toxins that induce PD-like pathology in in vivo and in vitro models of PD 2336 — The classical trigger for p53 activation is oxidative stress, and pdependent apoptosis in neuronal cells is predominantly mediated by DNA damage 34 P53 is an upstream inducer of PCNA, and a higher concentration of wild-type p53 inhibits the PCNA promoter and reduces the production of PCNA 20 Previous studies have shown that ALA has anti-inflmmatory and anti-oxidative properties in a range of cell types and tissues 40 — 43which may be beneficial in neurodegenerative conditions.

Preclinical and clinical data have indicated that ALA is bioavailable and safe in moderate doses 8. Further investigations are required to fully elucidate the mechanisms responsible for the protective effects of ALA in neurodegenerative conditions, which may provide a potential effective neuroprotection strategy for the treatment of PD by targeting DNA damage-mediated neuronal degeneration.

de Lau LM and Breteler MM: Epidemiology of Parkinson's disease. Lancet Neurol. Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P and Halliwell B: Oxidative DNA damage in the parkinsonian brain: An apparent selective increase in 8-hydroxyguanine levels in substantia nigra.

J Neurochem. Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL and Dawson TM: Poly ADP-ribose polymerase activation mediates 1-methylphenyl-1, 2,3,6-tetrahydropyridine MPTP -induced parkinsonism. Proc Natl Acad Sci USA.

Moldovan GL, Pfander B and Jentsch S: PCNA, the maestro of the replication fork. Mailand N, Gibbs-Seymour I and Bekker-Jensen S: Regulation of PCNA-protein interactions for genome stability.

Nat Rev Mol Cell Biol. Li DW, Li GR, Zhang BL, Feng JJ and Zhao H: Damage to dopaminergic neurons is mediated by proliferating cell nuclear antigen through the p53 pathway under conditions of oxidative stress in a cell model of Parkinson's disease.

Int J Mol Med. Nucleic Acids Res. Amoroso A, Concia L, Maggio C, Raynaud C, Bergounioux C, Crespan E, Cella R and Maga G: Oxidative DNA damage bypass in Arabidopsis thaliana requires DNA polymerase λ and proliferating cell nuclear antigen 2. Plant Cell.

: Alpha-lipoic acid and neuroprotection

Neuroprotection by the metabolic antioxidant alpha-lipoic acid Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium. The results showed that LA decreased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, and increased Mn-superoxide dismutase and CAT activity. Chem Phys Lipids. Aging 28, — Huge interest has been garnered in recent times on the antioxidant properties of ALA and its reduced form dihydrolipoic acid DHLA. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
Neuroprotection by the metabolic antioxidant alpha-lipoic acid Furthermore, due to its Alpha-lipoic acid and neuroprotection in both the membranous and neeuroprotection phase, ALA is frequently referred to as a universal antioxidant. McCarty KS Jr, Miller LS, Cox EB, Konrath Alpha-lipoid, McCarty KS Mindful food shopping Estrogen receptor Alpha-lipoic acid and neuroprotection. Nad J Phys Rehabil Med. Figure 1. To determine P53 immunoreactivity, anti-P53 mouse monoclonal antibodiesZM, ZSGB-BIO, Beijing, China were applied to the sections overnight at 4°C. Gamma irradiation-mediated inactivation of enveloped viruses with conservation of genome integrity: Potential application for SARS-CoV-2 inactivated vaccine development. The effects of LA on oxidative stress in rotenone parkinsonian rat brains were investigated, showing that LA can reduce lipid peroxidation and protein carbonylation Zaitone et al.
Top bar navigation Spandidos Publications style. Anti-obesity effect and mechanism of mesenchymal stem cells influence on obese mice. Data are presented as the mean ± standard error of the mean. This result probably can be explained by the effect of ALA on nerve growth factor NGF. SC carried out the histopathological analysis. Our study indicates neuroprotective effects of ALA on chronic neuropathic pain in a CCI rat model. Shay, K.
Human Verification

The results indicated that arsenic and dichlorvos induced oxidative stress and cholinergic dysfunction in brain, which was significantly protected by the supplementation with LA.

Seidman et al. Their results showed that mtDNA deletions associated with aging were reduced by LA and this effect appeared to be related to the mitochondrial capacity to protect and repair mtDNA against age-induced injury. Palaniappan and Dai investigated the effect of LA administration to aged rats and verified a reduction of mitochondrial lipid peroxidation, 8-oxo-dG and oxidized glutathione GSSG and increased GSH, ATP, and electron transport chain ETC complex activities in the brain.

The SAMP8 mouse strain is an experimental model that displays increased oxidative stress accompanied by memory decline associated to a rapid aging process. In order to determine the mechanisms underlying LA-induced reversion of memory deficits exhibited by SAMP8 mice, Poon et al.

The levels of three proteins neurofilament triplet L protein, a-enolase, and ubiquitous mitochondrial creatine kinase were significantly increased, while protein carbonylation was reduced in lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and a-enolase in aged SAMP8 mice that received LA, suggesting that, in addition to improving learning and memory, LA also can restore specific proteins in aged SAMP8 mouse brain.

Evidence indicates that deregulation in neurotransmitter systems, including decreased levels of neurotransmitters, decline in the number of receptors, and lower responsiveness to neurotransmitters can be key features of neurological disorders Payton et al.

Arivazhagan and Panneerselvam investigated the effect of LA on levels of neurotransmitters dopamine, serotonin, and norepinephrine , and showed that LA treatment can improve neurotransmitter function in models of neurodegenerative diseases.

Jesudason et al. The results showed that AD mice treated with LA exhibited enhanced levels of serotonin, dopamine, and norepinephrine, and the concentration of metabolites 5-hydroxyindole acetic acid 5-HIAA and homovanillic acid HVA gradually returned to normal.

Ahmed explored the effect of LA on brain acetylcholinesterase AChE activity. The authors demonstrated that LA can ameliorate neurological injury related to Aβ and Al excess, by significantly restoring AChE activity.

In addition, the authors showed that the treatment with LA restored the parameters of total homocysteine tHcy , insulin, insulin like growth factor-1 IGF-1 , interlukin-1β IL-1β and tumor necrosis factor-α TNF-α. Mahboob et al. LA treatment increased the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase ChaT relative to AlCl 3 -treated group.

There are many studies examining the neuroprotective actions of LA using in vitro models of neurodegeneration Tirosh et al. For example, Ono et al. The results showed that both LA and DHLA inhibited fAβ formation from amyloid β, as well as their expansion, and undermined preformed fAβs in a dose dependent manner.

Lovell et al. In β-amyloid-intoxicated C6 glioma cells, LA increased cell viability and MnSOD expression. The increased GSSH and decreased GSH mitochondrial levels induced by Aβ were reversed by treatment with LA Xing et al.

The study by Deuther-Conrad et al. de Arriba et al. Tirosh et al. Kamarudin et al. Suppression of NF-κβ p65 translocation and production of proinflammatory cytokines IL-6 and TNF-α followed inhibition of cleaved caspase Yamada et al.

They showed that all types of LAs were effective in preventing cell death. R-LA and S-LA also enhanced expression of genes related to anti-oxidative response such as heme oxygenase-1 HO-1 and phase II detoxification enzymes such as NAD P H:Quinone Oxidoreductase 1 NQO1.

Other studies evaluated the effect of LA on in vitro model of PD. Moreover, Zhang et al. LA has been proposed to exert a modulatory control on the cellular redox status. Due to its ability to be interconverted in one of its two forms—i.

LA has been described to regenerate other antioxidants, such as vitamin C and E, to increase GSH levels, and to provide modulation of proteins and transcription factors Packer et al. Extracellular redox state is also regulated by LA, once its reduced form, DHLA, can interact with cystine, reducing it to cysteine, thereby stimulating its uptake by the cell, which in turn stimulates GSH synthesis Han et al.

For instance, Jiang et al. Prevention of sevoflurane-induced apoptosis by LA was accomplished through recovery of Akt and GSK3-β phosphorylation levels in the hippocampus Ma et al.

Sancheti et al. Compelling evidence indicates that LA displays memory-ameliorating properties in a variety of experimental models of neurodegenerative diseases, as well as in memory decline associated with aging in rodents.

Studies aiming to assess the neuroprotective effects of LA on behavioral outcomes showed that LA can reduce memory deficits in different behavioral paradigms on AD Quinn et al. In humans, two studies in AD patients have supported the positive cognitive effects of LA Hager et al.

Many studies reported beneficial effects of LA in the rat brain or neuronal cell cultures, using different molecular markers of oxidative stress, such as reduction in the levels of lipid peroxides and protein carbonyls, recycling endogenous antioxidants such as vitamin C and E, increasing glutathione levels Packer et al.

LA was also shown to display anti-inflammatory properties Deuther-Conrad et al. In vivo and in vitro studies showed that LA ameliorated neurodegeneration in the hippocampus, decreasing neuronal apoptosis and caspase-3 protein levels, supporting a neuroprotective role mediated by the mitochondrial cell death pathway.

These effects suggest that LA is able to improve mitochondrial dysfunctions. Interestingly, in addition to decreasing neuronal cell death, LA also inhibited fAβ formation from amyloid β-protein, ameliorating the neurological damage induced by Aβ, and significantly restored AChE activity.

This evidence suggests that LA presents a potential role in enhancing cholinergic and cognitive functions. These neuroprotective effects may be related to the properties of LA in ameliorating memory loss associated to neurodegenerative diseases.

Remarkably, LA was able to reverse age-associated glutamatergic NMDA receptor deficits Stoll et al. LA was also shown to improve the function of neurotransmitter systems, including dopamine, serotonin, and norepinephrine. Taken together, these findings provide evidence that LA can reverse loss of neurotransmitters, their receptors and responsiveness to neurotransmitters, which can underlie its effects on cognitive functions.

In summary, this review has described and discussed relevant studies investigating the effects of LA on cognition as well as its cellular and molecular effects, aiming to improve the understanding of the therapeutic potential of LA in memory loss during aging and patients suffering from neurodegenerative disorders.

Although the mechanisms of action of LA are not fully understood, multiple pathways are likely to be involved in its neuroprotective properties.

The memory-improving effects and neuroprotective actions of LA support its use as an adjuvant treatment for neurodegenerative disorders.

PM has performed literature search and has written the first draft of the manuscript. NS has extensively revised and contributed in writing the final version of the manuscript. The 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.

Abadi, A. Supplementation with alpha-lipoic acid, CoQ10, and vitamin E augments running performance and mitochondrial function in female mice. PLoS ONE 8:e doi: PubMed Abstract CrossRef Full Text Google Scholar. Ahmed, H.

Modulatory effects of vitamin E, acetyl-L-carnitine and alpha-lipoic acid on new potential biomarkers for Alzheimer's disease in rat model. Aliev, G. Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. Cell Mol. Arivazhagan, P. Effect of DL-alpha-lipoic acid on neural antioxidants in aged rats.

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Farr, S. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Effect of alpha-lipoic acid on memory, oxidation, and lifespan in SAMP8 mice. Alzheimers Dis. Ferreira, B. Glutathione in multiple sclerosis.

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Payton, A. Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. Psychiatry 10, — Pizza, V. The newly reduced glutathione, vitamin C, and coenzyme Q also regenerate oxidized vitamin E, forming an antioxidant network that protects the body from HP-induced oxidative damage.

The present study showed that HP causes oxidative stress. This conclusion was based on the findings that administration of HP significantly decreased SOD and GPx activity in rat brain and serum.

Histopathological studies showed the deleterious effect of HP on the rat brain as massive necrosis, fibrosis, and atrophic neurons. The histopathological changes correlated with the biochemical assay results. We found that rats treated with ALA showed a much greater increase in body weight.

In addition, rats treated with ALA also showed a significant increase in brain ACh concentration. Our other objective was to investigate the effects of ALA on HP-induced alterations towards the antioxidant defense system in the rat brain.

The administration of ALA to HP-treated rats, restored the activity of SOD and GPx in both serum and brain and demonstrated a distinct protective effect in histopathological studies. The significant increase in antioxidant activity coupled with the histological evidence, leads to the conclusion that ALA reduces HP-induced oxidative damage in rat brain.

A total of 32 male Sprague-Dawley rats g body weight were used in this study. Food and water were supplied ad libitum prior to the start of the experiment.

All the experiments were carried out according to the standard guidelines for animal experiments and Institutional Ethics Committee has approved this research project.

Each drug used in this experiment was purchased in the powder form Sigma Aldrich Co. USA ; consequently, each drug was dissolved before administration to rats. Rats were weighed daily. ALA solution was given oral gavage using a stainless steel oral feeding tube. Intraperitoneal injections of HP were administered using a 1.

On the 22 nd day of the experiment, the rats were anaesthetized with ether. A blood sample was collected by cardiac puncture. Blood was transferred into 5 ml tubes, which were centrifuged using Sigma KC Refrigerated Centrifuge at rpm for 10 minutes at 4°C.

The serum was extracted using a 1 ml syringe and stored at °C until further analysis. Brain was dissected out and photographed using a digital camera, for gross inspection. Brain was sectioned into two halves.

The other half of the brain was transferred into 15 ml Falcon tubes filled with phosphate buffer solution and stored at °C. Brain samples were thawed and homogenized in ice to ensure the viability of proteins using a Duall, all-glass, tissue grinder.

The homogenate was centrifuged using Sigma KC Refrigerated Centrifuge at rpm for 20 minutes at 4°C. The samples were maintained at °C before performing biochemical assays.

From the brain homogenate samples, superoxide dismutase SOD and glutathione peroxidase GPx were assayed using ELISA kits Cayman Chemicals and Pierce Biotechnology, USA. Super oxide dismutase assay kit utilizes a tetrazolium salt for the detection of superoxide radicals O2- generated by xanthine oxidase and hypoxanthine.

Oxidation rate of tetrazolium salt to formazan dye by O2 - is inversely proportional to the endogenous activity of SOD. The formazan dye stains the wells and its staining intensity was detected by absorbance spectrophotometry at nm using a plate reader.

Glutathione peroxidase assay kit measures GPx levels indirectly by a coupled reaction with glutathione reductase. Oxidized glutathione, produced upon reduction of an organic hydroperoxide by GPx, is recycled to its reduced state by glutathione reductase and NADPH.

The rate of decrease in the absorbance at was directly proportional to the GPx levels in the sample. Statistical analysis was done using Statistical Package for Social Sciences SPSS version Data obtained were expressed as mean ± standard deviation SD.

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Department of Pathology, International Medical University, Kuala Lumpur, Malaysia. You can also search for this author in PubMed Google Scholar. Correspondence to Nagaraja Haleagrahara. JP conceived of the study and coordination and helped to draft the manuscript.

JHT carried out the experimental work, done the analysis of the data and prepared the results. JS performed the statistical analysis. SC carried out the histopathological analysis.

NH participated in the design of the study and contributed to analysis of the results. All authors read and approved the final manuscript. Open Access This article is published under license to BioMed Central Ltd.

Reprints and permissions. Perera, J. et al. Neuroprotective Effects of Alpha Lipoic Acid on Haloperidol-Induced Oxidative Stress in the Rat Brain. Cell Biosci 1 , 12 Download citation. Received : 15 December Accepted : 22 March Published : 22 March Anyone you share the following link with will be able to read this content:.

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Download PDF. Abstract Haloperidol is an antipsychotic drug that exerts its' antipsychotic effects by inhibiting dopaminergic neurons.

Alpha-lipoic acid and neuroprotection

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Alpha Lipoic Acid – Potent (but DAMAGING) Antioxidant Parkinson's disease PD is a movement disorder characterized Aloha-lipoic motor and behavioral disturbances, caused Alpha-lipkic Alpha-lipoic acid and neuroprotection gradually progressive and Red pepper bruschetta degeneration Hunger and urbanization dopaminergic neurons in Alphs-lipoic Alpha-lipoic acid and neuroprotection nigra pars compacta SNpc 1. Alpha-ljpoic pathogenesis of PD xcid to be fully Alpha-lpoic, however, multiple studies have linked oxidative stress to dopaminergic neuron degeneration in PD. Increased oxidative stress contributes to DNA damage, leading to dopaminergic neuron degeneration and the pathogenesis of PD 2. Postmortem samples of PD have shown increased DNA oxidative damage selectively in dopaminergic neurons of the SNpc, indicating the link between DNA oxidation and the loss of dopaminergic neurons in PD 2. These previous reports support the hypothesis that DNA damage-induced cell death is a mechanism involved in the pathogenesis of PD.

Alpha-lipoic acid and neuroprotection -

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Am J Obstet Gynecol — Download references. Department of Neurosurgery, Faculty of Medicine, Gazi University, Polikliniği Kat 1, Ankara, , Turkey.

Kemali Baykaner. Department of Biochemistry, Faculty of Medicine, Gazi University, Ankara, , Turkey. Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, , Turkey.

You can also search for this author in PubMed Google Scholar. Correspondence to Hakan Emmez. Currently, there is a tremendous research focus in animals and humans to improve the devastating effects of spinal cord injury.

Some of the main strategies include avoidance of prehospital hypoxia and hypotension, early surgical decompression and spinal fracture stabilization, therapeutic hypothermia, neuroprotectants such as alpha-lipoic acid in this study, neurotrophic agents, cell transplantation, blocking myelin-based protein inhibitors, using neural scaffolds, anti-inflammatory agents, reducing glial scar formation, and new rehabilitation strategies.

Emmez and colleagues have reported a carefully conducted study using the antioxidant alpha-lipoic acid in an experimental spinal cord ischemia and reperfusion injury model in 24 rabbits.

Treatment of neuropathic pain is far neuroprotectioj satisfactory. This study Magnetic resonance spectroscopy evidence Alpha-lipooc a neuroprotective effect of aciid Alpha-lipoic acid and neuroprotection ALA to treat Alpha-lipoic acid and neuroprotection pain in a chronic constriction injury CCI rat model. Mechanical and thermal nociceptive thresholds were evaluated as behavioral assessments. Dorsal root ganglia cells were assessed morphologically with hematoxylin and eosin staining and for apoptosis with P53 immunohistochemical staining. These changes were significantly reversed by treatment with ALA.

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