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Neurodegenerative diseases such as Parkinson's disease (PD) are known to be related to oxidative stress and neuroinflammation, and thus, modulating neuroinflammation offers a possible means of treating PD-associated pathologies. Morin (2′,3,4′,5,7-pentahydroxy flavone) is a flavonol with anti-oxidative and anti-inflammatory effects found in wines, herbs, and fruits. The present study was undertaken to determine whether a morin-containing diet has protective effects in an MPTP-induced mouse model of PD. Mice were fed a control or morin diet for 34 days, and then MPTP (30 mg/kg, i.p.) was administered daily for 5 days to induce a PD-like pathology. We found that dietary morin prevented MPTP-induced motor dysfunction and ameliorated dopaminergic neuronal damage in striatum (STR) and substantia nigra (SN) in our mouse model. Furthermore, MPTP-induced neuroinflammation was significantly reduced in mice fed morin. In vitro studies showed that morin effectively suppressed glial activations in primary microglia and astrocytes, and biochemical analysis and a docking simulation indicated that the anti-inflammatory effects of morin were mediated by blocking the extracellular signal-regulated kinase (ERK)-p65 pathway. These findings suggest that morin effectively inhibits glial activations and has potential use as a functional food ingredient with therapeutic potential for the treatment of PD and other neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

A novel voltammetric sensor was developed to selectively determine dopamine (DA) concentration in the presence of ascorbic acid (AA) and 3,4-dihydroxyphenylacetic acid (DOPAC). This sensor utilizes a modified pencil graphite electrode (PGE) coated with a newly synthesized poly (3,4-ethylene dioxythiophene) (PEDOT):poly (styrene sulfonate- co -2-(3-(6-Methyl-4-oxo-1,4-dihydropyrimidin-2-yl) ureido) ethyl methacrylate) (P(SS- co -UPyMA)) composite. The PEDOT:P(SS-co-UPyMA) (PPU) composite was characterized using nuclear magnetic resonance, X-ray photoelectron, and Raman spectroscopies. The PPU-coated PGE was characterized using electrochemical techniques, including cyclic and differential pulse voltammetry. Compared to uncoated, PPU-coated PGE demonstrated improved sensitivity and selectivity for DA. The sensor exhibited a dynamic linear range of 0.1–300 μM for DA, with a detection limit of 44.4 nM (S/N = 3). Additionally, the PPU-coated PGE showed high reproducibility and storage stability for four weeks. To demonstrate its practical applicability, the PPU-coated PGE sensor was used for ex vivo brain slice samples from control and Parkinson's disease model mice. [Display omitted] • Disposable voltametric dopamine sensor based on modified pencil graphite electrode. • Newly synthesized PEDOT:PSS copolymer as electrode modifier. • The dopamine sensor showed a linear range: 0.1–300 μM & LOD: 44.4 nM. • The sensor was used on ex vivo brain samples from Parkinson's disease model mice. [ABSTRACT FROM AUTHOR]

A simple sensing methodology for rapid detection of multiple biomolecules in human health diagnostics remains a significant challenge. Herein, we developed a novel dispersant-free supra single-walled carbon nanotube (supra SWCNT)-coated glassy carbon electrode (GCE) for simultaneous sensing of biomolecules, such as ascorbic acid (AA), dopamine (DA), and uric acid (UA), in ex vivo mouse tissues. Supra SWCNTs with stable hydrogen bonds were synthesized via a simple chemical modification, after which they were characterized and confirmed using different physicochemical and electrochemical techniques. The supra SWCNT-coated GCE exhibited simultaneous sensing of AA, DA, and UA at linear dynamic ranges with lower detection limits of 12, 0.02, and 0.36 μM, respectively. Furthermore, they demonstrated high selectivity (with co-existing interference) and excellent reproducibility for effective sensing of the target biomolecules in different real samples. The rapid functioning, low cost, scalable preparation, and enhanced applicability for simultaneous sensing of target biomolecules in Parkinson's disease-induced mouse liver, kidney, and brain tissues suggest the suitability of the developed sensor for real-world applications. [Display omitted] • Dispersant-free supra SWCNT was prepared to facilitate step chemical modifications. • Supra SWCNTs freely dispersed in water without the addition of dispersing agents. • Supra SWCNTs/GCE were tested for highly sensitive simultaneous biomolecule sensing. • Real-time biomolecule sensing in PD mouse models achieved satisfying results. [ABSTRACT FROM AUTHOR]

Highlight • MHY908 attenuated MPTP-induced motor deficits and dopaminergic neuronal death. • MHY908 also ameliorated MPTP-induced glial activation in the STR and SN. • MHY908 pretreatment protected SH-SY5Y neuroblastoma cells against MPP+ toxicity. • Pretreatment of MHY908 inhibited MPP+-induced ROS generation. • MHY908 treatment attenuated MPP+-induced primary astrocyte activation and nuclear translocation of NF-κB. Abstract Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Neurons depend on mitochondria for homeostasis and survival, and thus, mitochondrial dysfunction has been implicated in neurodegenerative diseases, including Parkinson’s disease (PD). Increasing evidence indicates the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), protects neurons against neurodegeneration and enhances neural plasticity. Here, the authors evaluated the protective effects of intraperitoneally (i.p.) administered low dose DNP in an acute mouse model of PD. Mice were administered DNP (1 or 5 mg/kg) for 12 consecutive days, and then on day 13, MPTP (20 mg/kg, i.p.) was administered four times (with 2 h intervals between injections) to induce PD. It was found that MPTP-induced motor dysfunction was ameliorated in the DNP-treated mice versus vehicle-treated controls. Additionally, DNP effectively attenuated dopaminergic neuronal loss observed in MPTP treated mice. Moreover, in primary cultured neurons, DNP at 10 μM, but not at 100 μM, prevented MPP + -induced cell death and mitochondrial membrane potential (MMP) reduction. In addition, DNP was observed to cause the nuclear translocation of Nrf2 in primary neurons. Taken together, these findings of the present study suggest that DNP protects dopaminergic neurons against neurodegeneration and maintains MMP integrity in PD by activating adaptive stress responses. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second-most common neurodegenerative disease after Alzheimer’s disease, and is characterized by dopaminergic neuronal loss in midbrain. The MPTP-induced PD model has been well characterized by motor deficits and selective dopaminergic neuronal death accompanied by glial activation. Silibinin is a constituent of silymarin, an extract of milk thistle seeds, and has been proposed to have hepatoprotective, anti-cancer, anti-oxidative, and neuroprotective effects. In the present study, the authors studied the neuroprotective effects of silibinin in an acute MPTP model of PD. Silibinin was administered for 2 weeks, and then MPTP was administered to mice over 1 day (acute MPTP induced PD). Silibinin pretreatment effectively ameliorated motor dysfunction, dopaminergic neuronal loss, and glial activations caused by MPTP. In addition, an in vitro study demonstrated that silibinin suppressed astroglial activation and ERK and JNK phosphorylation in primary astrocytes in response to MPP + treatment. These findings show silibinin protected dopaminergic neurons in an acute MPTP-induced mouse model of PD, and suggest its neuroprotective effects might be mediated by the suppression of astrocyte activation via the inhibition of ERK and JNK phosphorylation. In conclusion, the study indicates silibinin should be viewed as a potential treatment for PD and other neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP+-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD. [ABSTRACT FROM AUTHOR]

Abstract: Senescence marker protein 30 (SMP30) was recently identified as gluconolactonase, which is involved in vitamin C (VC) biosynthesis. Therefore, the antioxidant property of SMP30 is thought to be mediated by its gluconolactonase function. However, pathologic effects of SMP30 deficiency independent of VC biosynthesis have not been studied in models of neurodegenerative diseases. In the present study, we evaluated the effect of SMP30 deficiency on Parkinson’s disease (PD) in SMP30 knockout (KO) mice. Wild type and SMP30 KO mice supplemented with VC were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results showed that MPTP-induced dopaminergic neuronal loss and motor function impairment were more significant in the SMP30 KO mice. Reactive oxygen species generation and microglia activation were higher in MPTP-treated SMP30 KO mice. However, SMP30 deficiency mitigated MPTP-induced astrocyte activation and glia-derived neurotrophic factor production. Cultures of astrocytes recovered from wild type and SMP30 KO mice revealed that SMP30 deficiency abolished 1-methyl-4-phenyl-pyridinium-induced astroglial activation by blocking the extracellular signal-regulated kinase pathway. Taken together, our findings demonstrate for the first time that SMP30 deficiency increases the severity of PD and suggest a beneficial role of SMP30 in protective astrocyte activation in response to neurodegeneration. The present study shows that modulation of astrocytic SMP30 can be a promising target for treating PD. [Copyright &y& Elsevier]

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer’s disease (AD), Parkinson’s and Huntington’s diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson’s disease (α-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease. [Copyright &y& Elsevier]

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson's disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD. [ABSTRACT FROM AUTHOR]

• Usnic acid alleviated motor dysfunction and prevented dopaminergic neuronal loss in MPTP-induced PD model. • Usnic acid attenuated MPTP-induced inflammatory response in substantia nigra. • Usnic acid repressed MPP+-induced astroglial activation in primary astrocyte. • Usnic acid inhibited MPP+-induced nuclear translocation of NF-κB in primary astrocyte. Neuroinflammation is often associated with astrocyte and microglial activations particularly in Parkinson's disease (PD) and other brain damage such as Alzheimer's disease. Therefore, the modulation of glial activation offers a possible target for treating PD-associated pathologies. Here, we evaluated the neuroprotective effects of usnic acid, a naturally occurring dibenzofuran derivative found in several lichen species in an acute mouse model of PD. Male mice were administered with vehicle or usnic acid (5 or 25 mg/kg) for 10 consecutive days, and then on day 11, MPTP (20 mg/kg, i.p.) was administered four times (with 2 hrs intervals between injections) to induce PD pathologies. It was found that MPTP-induced motor dysfunction and neuronal loss were ameliorated in the usnic acid-treated mice versus vehicle-treated controls. Further study revealed that usnic acid effectively inhibited MPP+-induced glial activation in primary astrocytes by blocking NF-κB activation. Taken together, these findings suggest that usnic acid could be considered potentially useful therapeutic candidates for PD and other neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]