Kynurenic Acid Restores Nrf2 Levels and Prevents Quinolinic Acid-Induced Toxicity in Rat Striatal Slices
Ferreira FS, Biasibetti-Brendler H, Pierozan P, Schmitz F, Bertó CG, Prezzi CA, Manfredini V and Wyse ATS
Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites produced in the degradation of tryptophan and have important neurological activities. KYNA/QUIN ratio changes are known to be associated with central nervous system disorders, such Alzheimer, Parkinson, and Huntington diseases. In the present study, we investigate the ability of KYNA in prevent the first events preceding QUIN-induced neurodegeneration in striatal slices of rat. We evaluated the protective effect of KYNA on oxidative status (reactive oxygen species production, antioxidant enzymes activities, lipid peroxidation, nitrite levels, protein and DNA damage, and iNOS immunocontent), mitochondrial function (mitochondrial mass, membrane potential, and respiratory chain enzymes), and Na,K-ATPase in striatal slices of rats treated with QUIN. Since QUIN alters the levels of Nrf2, we evaluated the influence of KYNA protection on this parameter. Striatal slices from 30-day-old Wistar rats were preincubated with KYNA (100 μM) for 15 min, followed by incubation with 100-μM QUIN for 30 min. Results showed that KYNA prevented the increase of ROS production caused by QUIN and restored antioxidant enzyme activities and the protein and lipid damage, as well as the Nrf2 levels. KYNA also prevented the effects of QUIN on mitochondrial mass and mitochondrial membrane potential, as well as the decrease in the activities of complex II, SDH, and Na,K-ATPase. We suggest that KYNA prevents changes in Nrf2 levels, oxidative imbalance, and mitochondrial dysfunction caused by QUIN in striatal slices. This study elucidates some of the protective effects of KYNA against the damage caused by QUIN toxicity.
The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson's Disease
Zhao YF, Qiong-Zhang , Zhang JF, Lou ZY, Zu HB, Wang ZG, Zeng WC, Kai-Yao and Xiao BG
Aging is an inevitable physiological challenge occurring in organisms over time, and is also the most important risk factor of neurodegenerative diseases. In this study, we observed cellular and molecular changes of different age mice and LPS-induced Parkinson disease (PD) model. The results showed that behavioral performance and dopaminergic (DA) neurons were declined, accompanied by increased expression of pro-inflammatory factors (TLR2, p-NF-kB-p65, IL-1β and TNF-α), as well as pro-oxidative stress factor gp91phox in aged mice compared with young mice. Aging exaggerated inflammatory M1 microglia, and destroyed the balance between oxidation and anti-oxidation. The intranasal LPS instillation induced PD model in both young and aged mice. The poor behavioral performance and the loss of DA neurons as well as TLR2, p-NF-kB-p65, IL-1β, TNF-α, iNOS and gp91phox were further aggravated in LPS-aged mice. Interestingly, the expression of Nrf2 and HO-1 was up-regulated by LPS only in young LPS-PD mice, but not in aged mice. The results indicate that the synergy of aging process and LPS exposure may prominently aggravate the DA neurons loss caused by more serious neuroinflammation and oxidative stress in the brain.
Prokineticin-2 promotes chemotaxis and alternative A2 reactivity of astrocytes
Neal M, Luo J, Harischandra DS, Gordon R, Sarkar S, Jin H, Anantharam V, Désaubry L, Kanthasamy A and Kanthasamy A
Astrocyte reactivity is disease- and stimulus-dependent, adopting either a proinflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. As astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in proinflammatory factors, and an increase in the antioxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1, and TM4SF1. A small-molecule PK2 agonist, IS20, not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases. PK2 signals through its receptors on astrocytes and promotes directed chemotaxis. PK2-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins while increasing glutamate uptake, along with decreased inflammatory factors. © 2018 Wiley Periodicals, Inc.
Beneficial effects of n-3 polyunsaturated fatty acids administration in a partial lesion model of Parkinson's disease: The role of glia and NRf2 regulation
Hernando S, Requejo C, Herran E, Ruiz-Ortega JA, Morera-Herreras T, Lafuente JV, Ugedo L, Gainza E, Pedraz JL, Igartua M and Hernandez RM
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely associated to beneficial effect over different neurodegenerative diseases. In the present study, we tested the potential therapeutic effect of docohexanoic acid (DHA) and its hydroxylated derivate, DHAH, in a partial lesion model of Parkinson's disease (PD). One month before and four months after the striatal lesion with 6-OHDA was made, the animals were daily treated with DHA (50 mg/kg), DHAH (50 mg/kg), vehicle or saline, by intragastric administration. Animal groups under n-3 PUFA treatments exhibited a trend to improve in amphetamine-induced rotations and cylinder test. The beneficial effect seen in behavioral studies were confirmed with TH immunostaining. TH fibers and TH neurons increased in the experimental groups treated with both n-3 PUFAs, DHA and DHAH. Moreover, the n-3 PUFAs administration decreased the astrogliosis and microgliosis, in both the striatum and substantia nigra (SN), with a higher decrease of GFAP and Iba-1 cells for the DHAH treated group. This experimental group also revealed a positive effect on Nrf2 pathway regulation, decreasing the positive Nrf2 immmunostaining in the striatum and SN, which revealed a potential antioxidant effect of this compound. Taking together, these data suggest a positive effect of n-3 PUFAs administration, and more concretely of DHAH, for PD treatment as it exhibited positive results on dopaminergic system, neuroinflammation and oxidative stress.
Angiotensin II induces oxidative stress and upregulates neuroprotective signaling from the NRF2 and KLF9 pathway in dopaminergic cells
Parga JA, Rodriguez-Perez AI, Garcia-Garrote M, Rodriguez-Pallares J and Labandeira-Garcia JL
Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor that activates the antioxidant cellular defense in response to oxidative stress, leading to neuroprotective effects in Parkinson's disease (PD) models. We have previously shown that Angiotensin II (AngII) induces an increase in reactive oxygen species (ROS) via AngII receptor type 1 and NADPH oxidase (NOX), which may activate the NRF2 pathway. However, controversial data suggest that AngII induces a decrease in NRF2 signaling leading to an increase in oxidative stress. We analyzed the effect of AngII and the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in culture and in vivo, and examined the effects on the expression of NRF2-related genes. Treatment of neuronal cell lines Mes23.5, N27 and SH-SY5Y with AngII, 6-OHDA or a combination of both increased ROS production and reduced cell viability. Simultaneously, these treatments induced an increase in expression in the NRF2-regulated genes heme oxygenase 1 (Hmox1), NAD(P)H quinone dehydrogenase 1 (Nqo1) and Kruppel like factor 9 (Klf9). Moreover, overexpression of KLF9 transcription factor caused a reduction in the production of ROS induced by treatment with AngII or 6-OHDA and improved the survival of these neuronal cells. Rats treated with AngII, 6-OHDA or a combination of both also showed an increased expression of NRF2 related genes and KLF9. In conclusion, our data indicate that AngII induces a damaging effect in neuronal cells, but also acts as a signaling molecule to activate NRF2 and KLF9 neuroprotective pathways in cellular and animal models of PD.
Acteoside protects against 6-OHDA-induced dopaminergic neuron damage via Nrf2-ARE signaling pathway
Li M, Zhou F, Xu T, Song H and Lu B
Acteoside has been reported to have antioxidant and neuroprotective effect, which is a promising therapeutic way in prevention and treatment of Parkinson's disease. The present study was aimed to understand the neuroprotective effect of acteoside and to elucidate its underlying mechanism. 6-hydroxydopamine (6-OHDA)-induced neural damage in zebrafish model was used to study the protective effect of acteoside on Parkinson's disease (PD). Locomotion behavioral test showed that acteoside could prevent 6-OHDA-stimulated movement disorders. Anti-tyrosine hydroxylase (TH) whole-mount immunostaining analysis showed that acteoside could prevent 6-OHDA-induced dopaminergic neuron death. In addition, pretreatment with acteoside could upregulate antioxidative enzymes by activating the Nrf2/ARE signaling pathway in zebrafish. Meanwhile, acteoside was found to be distributed in the brain after intraperitoneal injection into the adult zebrafish, indicating that this compound could penetrate the blood-brain-barrier (BBB). This study demonstrated that acteoside could penetrate BBB and have potential therapeutic value for PD by activating the Nrf2/ARE signaling pathway and attenuating the oxidative stress.
Luteolin protects microglia against rotenone-induced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson's disease and inflammatory pathways
Elmazoglu Z, Yar Saglam AS, Sonmez C and Karasu C
Rotenone, an environmental toxin, triggers Parkinson's disease (PD)-like pathology through microglia-mediated neuronal death. The effects and molecular mechanisms of flavonoid luteolin against rotenone-induced toxicity was assessed in microglial BV2 cells. Cells were pretreated with luteolin (1-50 µM) for 12 h and then was co-treated with 20 µM of rotenone for an additional 12 h in the presence of luteolin. The viability (MTT), IL-1β and TNF-α levels and lactate dehydrogenase (LDH) release (ELISA), and Park2, Lrrk2, Pink1, Nrf2 and Trx1 mRNA levels (qRT-PCR) were measured. In rotenone exposed microglia, luteolin increased viability significantly at lower concentrations (1-5 µM) compared to higher concentrations (25-50 µM). Rotenone increased LDH release and IL-1β levels in a dose-dependent manner (1-20 µM). Luteolin inhibited rotenone-induced LDH release, however the activity decreased in concentration-dependent manner Neither rotenone nor luteolin altered TNF-α levels, but luteolin reduced IL-1β levels in a concentration dependent manner in rotenone exposed cells. The mRNA levels of Nrf2 and Trx1, which are the master regulators of redox state, were increased by rotenone, as well as by luteolin, which exhibited an inverse relationship between its concentration and effect (1-20 µM). Park2 mRNA levels increased by luteolin, but decreased by rotenone. Pink1 mRNA levels was not altered by rotenone or luteolin. Lrrk2 mRNA levels reduced by luteolin, while it was increased by rotenone. Results suggest that luteolin have favorable effects on regulation of oxidative stress response, genes associated with PD and inflammatory pathways, hence protects microglia against rotenone toxicity in a hormetic manner.
Pinostrobin Exerts Neuroprotective Actions in Neurotoxin-Induced Parkinson's Disease Models through Nrf2 Induction
Li C, Tang B, Feng Y, Tang F, Pui-Man Hoi M, Su Z and Ming-Yuen Lee S
The aim of the present study was to assess the neuroprotective effects of pinostrobin (PSB), a dietary bioflavonoid, and its underlying mechanisms in neurotoxin-induced Parkinson's disease (PD) models. First, PSB could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons and improve behavior deficiency in zebrafish, supporting its potential neuroprotective actions in vivo. Next, PSB could decreased apoptosis and death in the 1-methyl-4-phenylpyridinium (MPP)-intoxicated SH-SY5Y cells, evidenced by MTT, LDH, Annexin V-FITC/PI, and DNA fragmentation assay. PSB also blocked MPP-induced apoptotic cascades, including loss of mitochondrial membrane potential, activation of caspase 3, and reduced ratio of Bcl-2/Bax. In addition, PSB suppressed MPP-induced oxidative stress but increased antioxidant enzymes, evidenced by decrease of reactive oxygen species generation and lipid peroxidation and up-regulation of GSH-Px, SOD, CAT, GSH/GSSG, and NAD/NADH. Further investigations showed that PSB significantly enhanced Nrf2 expression and nuclear accumulation, improved ARE promoter activity and up-regulated expression of HO-1 and GCLC. Furthermore, Nrf2 knockdown via specific Nrf2 siRNA abolished PSB-induced antioxidative and antiapoptotic effects against MPP insults. Interestingly, we then found that PSB promoted phosphorylation of PI3K/AKT and ERK, and pharmacological inhibition of PI3K/AKT or ERK signaling diminished PSB-induced Nrf2/ARE activation and protective actions. In summary, PSB confers neuroprotection against MPTP/MPP-induced neurotoxicity in PD models. Promoting activation of Nrf2/ARE signaling contributes to PSB-mediated antioxidative and neuroprotective actions, which, in part, is mediated by PI3K/AKT and ERK.
Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?
Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA and Furfaro AL
Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer's and Parkinson's diseases. In this review, we summarize the current literature regarding the role of HO-1 in nervous system pointing out different molecular mechanisms possibly responsible for HO-1 up-regulation in nervous system homeostasis and neurodegeneration.
Paraquat and MPTP induce alteration in the expression profile of long noncoding RNAs in the substantia nigra of mice: Role of the transcription factor Nrf2
Wang L, Yang H, Wang Q, Zhang Q, Wang Z, Zhang Q, Wu S and Li H
Parkinson's disease (PD) is a common age-related degenerative disease of the central nervous system caused mainly by hereditary, pesticides, metals, and polychlorinated biphenyls. Paraquat (PQ), a widely used herbicide, causes PD. Long noncoding RNAs (lncRNAs) are nonprotein-coding transcripts, expressed in the brain and play irreplaceable roles in neurodegenerative diseases. NF-E2-related factor-2 (Nrf2) is an important genetic transcription regulator in oxidative stress. We aimed to discover novel PQ or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Nrf2-related lncRNAs and explore their association with PD. 17157 lncRNAs and 13707 mRNAs (fold change ≥2, P < 0.05) were identified by Microarray. And the expressions of six lncRNAs were confirmed by using qRT-PCR and two by FISH. Coding-noncoding analysis and qRT-PCR were applied to discover the functions of lncRNAs and predict the targeted genes. In mice, PQ and MPTP exposure caused alteration of the lncRNA expression profile, suggesting lncRNAs may be involved in PQ- and MPTP-induced neurotoxicity. The changes in their lncRNA expression were distinct but related. PQ caused lncRNA expression profiling alteration in the substantia nigra (SN) through an interaction with Nrf2, thus changing the NR_027648/Zc3h14/Cybb and NR_030777/Zfp326/Cpne5 mRNA pathways. Similarly, MPTP caused lncRNA expression profiling alteration in SN through an interaction with Nrf2. Nrf2 may be involved in the development of neurodegeneration induced by PQ and MPTP via interaction with lncRNAs as the molecular mechanism. Our findings indicate the potential roles of lncRNAs in the development of PD by PQ or MPTP and provide positive insights into future mechanism studies.
In vivo imaging of early signs of dopaminergic neuronal death in an animal model of Parkinson's disease
Rizzi N, Brunialti E, Cerri S, Cermisoni G, Levandis G, Cesari N, Maggi A, Blandini F and Ciana P
The Parkinson's disease (PD) evolves over an extended period of time with the onset occurring long before clinical signs begin to manifest. Characterization of the molecular events underlying the PD onset is instrumental for the development of diagnostic markers and preventive treatments, progress in this field is hindered by technical limitations. We applied an imaging approach to demonstrate the activation of Nrf2 transcription factor as a hallmark of neurodegeneration in neurotoxin-driven models of PD. In dopaminergic SK-N-BE neuroblastoma cells, Nrf2 activation was detected in cells committed to die as proven by time lapse microscopy; in the substantia nigra pars compacta area of the mouse brain, the Nrf2 activation preceded dopaminergic neurodegeneration as demonstrated by in vivo and ex vivo optical imaging, a finding confirmed by co-localization experiments carried out by immunohistochemistry. Collectively, our results identify the Nrf2 signaling as an early marker of neurodegeneration, anticipating dopaminergic neurodegeneration and motor deficits.
Astroglial DJ-1 over-expression up-regulates proteins involved in redox regulation and is neuroprotective in vivo
Frøyset AK, Edson AJ, Gharbi N, Khan EA, Dondorp D, Bai Q, Tiraboschi E, Suster ML, Connolly JB, Burton EA and Fladmark KE
DJ-1, a Parkinson's disease-associated protein, is strongly up-regulated in reactive astrocytes in Parkinson's disease. This is proposed to represent a neuronal protective response, although the mechanism has not yet been identified. We have generated a transgenic zebrafish line with increased astroglial DJ-1 expression driven by regulatory elements from the zebrafish GFAP gene. Larvae from this transgenic line are protected from oxidative stress-induced injuries as caused by MPP, a mitochondrial complex I inhibitor shown to induce dopaminergic cells death. In a global label-free proteomics analysis of wild type and transgenic larvae exposed to MPP, 3418 proteins were identified, in which 366 proteins were differentially regulated. In particular, we identified enzymes belonging to primary metabolism to be among proteins affected by MPP in wild type animals, but not affected in the transgenic line. Moreover, by performing protein profiling on isolated astrocytes we showed that an increase in astrocytic DJ-1 expression up-regulated a large group of proteins associated with redox regulation, inflammation and mitochondrial respiration. The majority of these proteins have also been shown to be regulated by Nrf2. These findings provide a mechanistic insight into the protective role of astroglial up-regulation of DJ-1 and show that our transgenic zebrafish line with astrocytic DJ-1 over-expression can serve as a useful animal model to understand astrocyte-regulated neuroprotection associated with oxidative stress-related neurodegenerative disease.
Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models
Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, Gao G, Wu X, Wang X and Yang H
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy.
Neuroprotective Role of Astroglia in Parkinson Disease by Reducing Oxidative Stress Through Dopamine-Induced Activation of Pentose-Phosphate Pathway
Mashima K, Takahashi S, Minami K, Izawa Y, Abe T, Tsukada N, Hishiki T, Suematsu M, Kajimura M and Suzuki N
Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice. The rates of glucose phosphorylation in astroglia were evaluated using the [C]deoxyglucose method. PPP activity was measured using [1-C]glucose and [6-C]glucose after acute (60 min) or chronic (15 hr) exposure to dopamine. ROS production was measured using 2',7'-dichlorodihydrofluorescein diacetate. The involvement of the Kelch-like ECH-associated protein 1 (Keap1) or nuclear factor-erythroid-2-related factor 2 (Nrf2) system was evaluated using Nrf2 gene knockout mice, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction analysis for heme oxygenase-1. Acute exposure to dopamine elicited increases in astroglial glucose consumption with lactate release. PPP activity in astroglia was robustly enhanced independently of Na-dependent monoamine transporters. In contrast, chronic exposure to dopamine induced moderate increases in PPP activity via the Keap1/Nrf2 system. ROS production from dopamine increased gradually over 12 hr. Dopamine induced neuronal cell damage that was prevented by coculturing with astroglia but not with Nrf2-deficient astroglia. Dopamine-enhanced astroglial PPP activity in both acute and chronic manners may possibly reduce neuronal oxidative stress.
The Protective Role of Brain CYP2J in Parkinson's Disease Models
Li Y, Wu J, Yu X, Na S, Li K, Yang Z, Xie X, Yang J and Yue J
CYP2J proteins are present in the neural cells of human and rodent brain regions. The aim of this study was to investigate the role of brain CYP2J in Parkinson's disease. Rats received right unilateral injection with lipopolysaccharide (LPS) or 6-hydroxydopamine (6-OHDA) in the substantia nigra following transfection with or without the CYP2J3 expression vector. Compared with LPS-treated rats, CYP2J3 transfection significantly decreased apomorphine-induced rotation by 57.3% at day 12 and 47.0% at day 21 after LPS treatment; moreover, CYP2J3 transfection attenuated the accumulation of -synuclein. Compared with the 6-OHDA group, the number of rotations by rats transfected with CYP2J3 decreased by 59.6% at day 12 and 43.5% at day 21 after 6-OHDA treatment. The loss of dopaminergic neurons and the inhibition of the antioxidative system induced by LPS or 6-OHDA were attenuated following CYP2J3 transfection. The TLR4-MyD88 signaling pathway was involved in the downregulation of brain CYP2J induced by LPS, and CYP2J transfection upregulated the expression of Nrf2 via the inhibition of miR-340 in U251 cells. The data suggest that increased levels of CYP2J in the brain can delay the pathological progression of PD initiated by inflammation or neurotoxins. The alteration of the metabolism of the endogenous substrates (e.g., AA) could affect the risk of neurodegenerative disease.

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