Ekstrand MI, et al. Guo YJ, et al. Pagano G, et al. Neuropathology of Parkinson disease. Besides the drug interventions, some surgical treatment methods also carry patients' new optimal approach. Chaudhuri KR, Schapira AH. Zondler L, et al. Challis C, et al. Apart from various GPCR signaling pathways, GPCR regulating/ interacting proteins are involved in the pathogenesis of Alzheimer's disease. Ferroptosis, a newly characterized form of cell death in Parkinsons disease that is regulated by PKC. The role of insulin/IGF-1/PI3K/Akt/GSK3 signaling in Parkinsons disease dementia. Fan C, et al. Pharmacological treatment of Parkinson disease: a review. Palle S, Neerati P. Improved neuroprotective effect of resveratrol nanoparticles as evinced by abrogation of rotenone-induced behavioral deficits and oxidative and mitochondrial dysfunctions in rat model of Parkinsons disease. Rui W, Li S, Xiao H, Xiao M, Shi J. Baicalein attenuates neuroinflammation by inhibiting NLRP3/caspase-1/GSDMD pathway in MPTP induced mice model of Parkinsons disease. Kim S, et al. Monoamine oxidase B inhibitors for the treatment of Parkinsons disease: a review of symptomatic and potential disease-modifying effects. Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Stoessl AJ, Lehericy S, Strafella AP. Key enzymes of the TSP, such as cystathionine -synthase and cystathionine -lyase, are essential regulators at multiple levels in this pathway. While scientists have understood this general process for many years, the exact details of how this happens are still murky. Chen X, et al. Sharma N, Nehru B. Curcumin affords neuroprotection and inhibits -synuclein aggregation in lipopolysaccharide-induced Parkinsons disease model. Triptolide up-regulates metabotropic glutamate receptor 5 to inhibit microglia activation in the lipopolysaccharide-induced model of Parkinsons disease. Effects of curcumin on microglial cells. Dryanovski DI, et al. However, they have been implicated in cardiac valvular fibrosis and pleuropulmonary fibrosis, raising important safety concerns. Finally, autonomic dysfunction is quite common in PD, especially during the late stage. Albani D, et al. Saha S, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Lin MW, Lin CC, Chen YH, Yang HB, Hung SY. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Exogenous -synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Typically, cell signaling is either mechanical or biochemical and can occur locally. Patients with PD have a variety of motor symptoms, including bradykinesia, muscle stiffness, rest tremor, and postural and gait difficulties.15,16 There are two main kinds of PD: tremor-dominant PD and non-tremor-dominant PD, based on clinical findings. Despite bulk studies focusing on intracellular mechanisms of PD inside DaNs, few studies have explored the pathogeneses outside DaNs, or between DaNs and other cells. Parkinson's disease (PD) is a major neurodegenerative disease, characterized clinically by a range of symptoms, in particular, impaired motor behaviour. Neuroprotective effects of curcumin on il-1-induced neuronal apoptosis and depression-like behaviors caused by chronic stress in rats. Gupta SC, Patchva S, Koh W, Aggarwal BB. Parkinson's disease (PD) is a neurodegenerative movement disorder characterized with dopaminergic neuron (DaN) loss within the substantia nigra (SN). Transmembrane endo-/lysosomal related proteins are encoded by PARK9, the ATPase 13A2 gene (ATP13A2). Iacono D, et al. The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinsons disease. Martins LM, et al. demonstrated the protective effects of curcumin on the injured hippocampus. The pathogenesis of PD may be related to environmental and genetic factors, and exposure to toxins and gene mutations may be the beginning of brain lesions. Lee DH, Gold R, Linker RA. Earls RH, et al. Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinsons disease-associated protein DJ-1. However, therapies remain uncertain and research for new treatment is mandatory. [. Environment, lifestyle, and Parkinsons disease: Implications for prevention in the next decade. Stone DK, Reynolds AD, Mosley RL, Gendelman HE. Arotcarena ML, et al. If ATP13A2 is functionally lost, this may lead to Zn2+ dysregulation and abnormal cell metabolism, including dysfunctional energy production and decreased lysosomal proteolysis.6668 In addition, it has been demonstrated that ATP13A2 reduces the neurotoxicity of -synuclein.69 The PARK15 protein, encoded by the F-box protein 7 gene (FBXO7), is a subunit of the F-box protein that functions as an adapter protein in the SKP1/cullin-1/F-box protein E3 ubiquitin ligase complex to recognize and mediate the non-degrading ubiquitination of glycogen synthase kinase (GSK)-3 and the translocase of outer mitochondrial membrane 20 to control mitophagy, mitochondria motility, mitochondria membrane potential, mitochondria bioenergetics, mitochondria biogenesis and mitochondria-associated apoptosis.7074 In addition, because FBXO7 is a stress-responsive protein, malfunction may lower complex-Is activity in the electron transport chain, lowering mitochondrial membrane potential and ATP levels while raising cytoplasmic ROS.75. Knockdown of SNAI2 decreased the expression of YAP and HIF1 while also reducing the viability of 6-OHDA-exposed MN9D cells and increasing cell apoptosis. Liu Q, et al. Pathological -synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model. Damier P, Hirsch EC, Agid Y, Graybiel AM. LRRK2 modulates vulnerability to mitochondrial dysfunction in. Short communication. A major problem with non-motor symptoms is that many are unresponsive to DA replacement therapy; some are even precipitated or aggravated by this treatment.230 Cholinesterase inhibitors have beneficial effects on cognitive disturbances in patients with PD and dementia. All authors have read, discussed and approved the article. Heiss CN, Olofsson LE. BDNF and GDNF secreted by activated astrocytes reduce iron accumulation in neurons by downregulating DMT1. Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K. The role of alpha-synuclein in Parkinsons disease: insights from animal models. The activation of GATA4 in embryonic cells is known to drive their differentiation to endoderm. Federal government websites often end in .gov or .mil. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinsons disease. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Bertolin G, et al. cAMP-dependent pathway. DA transporter-single-photon emission computed tomography (DAT-SPECT), structural magnetic resonance imaging (MRI), magnetic resonance diffusion-weighted imaging (MR-DWI), and genetic testing are frequently utilized to make a clinical diagnosis of PD. 8600 Rockville Pike Vives-Bauza C, et al. Chaturvedi RK, Beal MF. For instance, combining baicalein and low-dose L-DOPA significantly recovered gait function in patients to a level comparable with results from high-dose L-DOPA treatment, although some L-DOPA side effects were also present.287 Finally, baicalein antagonized rotenone-induced ROS overproduction, upregulated Bax and cleaved caspase-3, downregulated Bcl-2, and phosphorylated extracellular signal-regulated kinases (ERK) 1/2.288, Through acting on the Nrf2-NLRP3-caspase-1 pathway to inhibit the NLRP3 inflammasome, celastrol relieves motor deficits and nigrostriatal dopaminergic degeneration.289 In neurons, celastrol promotes autophagy, autophagosome biogenesis, and mitophagy, probably in association with MAPK pathways. Oxidative stress and regulated cell death in Parkinsons disease. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. The EIF4G1 gene and Parkinsons disease. Ascherio A, Schwarzschild MA. Oxidative stress induces activation of MAP kinase including extracellular receptor kinase (ERK) and p38, which is linked to abnormal mitochondrial and cell function (Jia et al., 2016).To explore the roles of MAP kinase in mitochondria and cell function, we first analyzed . The drug lovastatin enhances SHP2 activity and thus is a candidate for PD treatment. Gutbrain microbiota signaling encompasses the CNS, enteric nervous system, autonomic nervous system, and hypothalamicpituitaryadrenal axis. LeWitt PA, Fahn S. Levodopa therapy for Parkinson disease: a look backward and forward. A Drosophila model of Parkinsons disease. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinsons disease. A. et al. A number of pharmacological therapies are available that predominantly focus on the autonomic nervous system. In addition, mGlu5 appears to mediate the effect of triptolide on microglia-induced astrocyte activation in vitro and in vivo.293 Triptolide has also been described as a potent autophagy inducer in neuronal cells, helping to clear various forms of -synuclein via the autophagic pathway.294, The underlying neuroprotective mechanism of ginsenoside Rb1-improvements to synaptic plasticity involves promoting hippocampal CA3 -synuclein expression, restoring glutamate in the CA3schaffer collateral-CA1 pathway, and sequentially increasing postsynaptic density-95 expression.295 In LPS-treated rats, ginsenoside Rb1 treatment considerably lowered apomorphine-induced rotations, SN inflammation, and DA (plus metabolites) depletion in the striatum. Parkinsons disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction. Drosophila overexpressing wild-type (WT), A53T, and A30P -synuclein showed many PD characteristics, including age-dependent, selective loss of dopaminergic neurons and Lewy body-like filamentous inclusions.199 Nevertheless, they do not express -synuclein with the complexity of vertebrates, nor can these models exhibit key clinical features, such as resting tremors, bradykinesia, and rigidity. Frankel JP, Lees AJ, Kempster PA, Stern GM. Guiney SJ, Adlard PA, Bush AI, Finkelstein DI, Ayton S. Ferroptosis and cell death mechanisms in Parkinsons disease. Novel formulations and modes of delivery of levodopa. The genetics of Parkinson disease. A study published in . Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Parkinsons disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes -Synuclein externalization via exosomes. Puerarin promoted proliferation and differentiation of dopamine-producing cells in Parkinsons animal models. The Fyn/GSK-3 pathway facilitates Nrf2 accumulation in the nucleus, leading to de novo glutathione synthesis.271 Available evidence indicates that puerarin promotes dopaminergic neuron survival, proliferation, and differentiation via progesterone receptors.272,273 Puerarin also acts on the PI3K/Akt pathway to alleviate inflammatory responses274 and inhibit GSK-3 activity in neurons, thus limiting caspase-3 production and associated apoptosis.275,276 These interactions, along with inhibition of nuclear p53 accumulation, explain how puerarin protects against MPP+-induced neuroblastoma SH-SY5Y cell death.277 Baicalein administration reversed MPTP-induced motor dysfunction, dopaminergic neuronal loss, and proinflammatory cytokine elevation. Patterns of loss of dopamine-containing neurons in Parkinsons disease. Yue M, et al. Deng H, Wang P, Jankovic J. Inoculation of -synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Therefore, new drugs are still needed for treatment. Schober A. Voon V, Mehta AR, Hallett M. Impulse control disorders in Parkinsons disease: recent advances. Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. Preformed fibrils (PFFs), which resemble the structural components of Lewy bodies and Lewy neurites, were produced by researchers incubating recombinant -synuclein monomeric proteins under certain circumstances. Superoxide dismutase 2 or MnSOD may convert the superoxide radical to hydrogen peroxide, which the catalase enzyme can subsequently detoxify. Sequestration of iron by Lewy bodies in Parkinsons disease. Oxidative stress (OS) is a major process in aging that directly harms the CNS. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinsons disease. Transneuronal propagation of pathologic -synuclein from the gut to the brain models Parkinsons disease. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimers disease as well as in wild-type mice. Lu JH, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinsons and Alzheimers disease brains. Superoxide radical, the main ROS generated in mitochondria, was created when the one electron was transported from oxygen to oxygen. Allergy Drug Discov. 3.2. p38 MAPK is responsible for mitochondrial dysfunction related with cell apoptosis induced by -synuclein A53T. Kuwahara T, et al. 253 and rotenone.254,255 In experimentally induced PD, resveratrol protects against mitochondrial dysfunction, counteracting changes to mitochondrial morphology and mitochondrial membrane potential,250,254 while increasing mitochondrial biogenesis and complex-I activity.255,256 In several animal models, resveratrol stimulates autophagic degradation of -synuclein after sirtuin (SIRT) 1 activation and decreases -synuclein expression in the striatum.257,258 Another neuroprotective mechanism of resveratrol is similar to gastrodin action, activating HO-1 and mitogen-activated protein kinase (MAPK) pathways to increase autophagic flux.254,259 Regulation of astroglial activation also plays a role in neuroprotection. . Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinsons disease. Subcutaneous apomorphine in the treatment of Parkinsons disease. Nitric oxide synthase and neuronal vulnerability in Parkinsons disease. Developmental cysts are pathological epithelial-lined cavities arising in various organs as a result of systemic or hereditary diseases. Protective effects of berberine against MPTP-induced dopaminergic neuron injury through promoting autophagy in mice. Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide, and its treatment remains a big challenge. MicroRNAs (miRNAs), which are small and noncoding RNAs involved in many a biological process like apoptosis an In the review of Sun et al., numerous natural drugs such as tanshinone and andrographolide that are reported for the anti-inflammatory effects and may be potential drugs for the treatment of PD have been proposed for further investigations.265 Moreover, based on the complex mechanisms, multi-drug combinations may offer a new perspective on PD treatment such as the combination of biological and chemical drugs or natural small molecules. Kovac S, et al. In addition, IRN inhibition of the apoptosis signal-regulating kinase 1 (ASK1)/JNK pathway appears to suppress mitochondria-dependent apoptosis which suggests the protection of neurons.267270, The flavonoid puerarin has anti-parkinsonian effects that are dependent on Nrf2. Oxidative stress in neurodegeneration. The related drugs currently under development have not shown good effects, and may still require a long period of exploration. Hunot S, et al. Parkinsons disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-nave and drug-treated patients. Gaps in the understanding of the underlying molecular mechanisms hamper . Wang Y, et al. Pathogenic lysosomal depletion in Parkinsons disease. Langston JW, Ballard P, Tetrud JW, Irwin I. Neurons appear to be more susceptible to IL-17 or autologous Th17 cells and are eventually subjected to NF-B-dependent cell death.179 In addition, knockout or pharmacological inhibition of CD4 T cells downregulates major histocompatibility complex (MHC) II expression in CNS myeloid cells and protects against tyrosine hydroxylase (TH) neuron loss in the ipsilateral SN pars compacta (SNpc).179, The role of gut microbiota in neurological diseases has attracted considerable interest. Recent . Lavara-Culebras E, Paricio N. Drosophila DJ-1 mutants are sensitive to oxidative stress and show reduced lifespan and motor deficits.

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