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astrocytes and MPTP

Sumit Sarkar, Edward Lu, James Raymick, Joseph Hanig, Qiang Gu
BACKGROUND: Parkinson disease (PD) is one of the most debilitating disorder of the elderly where dopaminergic neurons of the midbrain especially in the substantia nigra (SNc) are damaged. Dopaminergic neurons are synthesized in the midbrain project to the striatum (Caudate-putamen-CPU). Few evidence have suggested that the extracellular signal-regulated kinase ½ (ERK ½) in the brain is activated after 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia...
November 23, 2018: Current Neurovascular Research
Irene García-Domínguez, Karolina Veselá, Juan García-Revilla, Alejandro Carrillo-Jiménez, María Angustias Roca-Ceballos, Marti Santiago, Rocío M de Pablos, José L Venero
The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson's disease. Brain inflammation, microglia and astroglia activation, disruption of the blood-brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra...
2018: Frontiers in Cellular Neuroscience
Ying-Li Zhu, Meng-Fei Sun, Xue-Bing Jia, Kun Cheng, Yi-Da Xu, Zhi-Lan Zhou, Pei-Hao Zhang, Chen-Meng Qiao, Chun Cui, Xue Chen, Xu-Sheng Yang, Yan-Qin Shen
Astilbin (AST), a dihydro-flavonol glycoside, is a major bioactive ingredient in Astilbe thunbergii, Engelhardia roxburghiana, Smilax corbularia and Erythroxylum gonocladum, and has been shown to have anti-inflammatory, antioxidative and neuroprotective effects, suggesting potential therapeutic value in the treatment of Parkinson's disease (PD). We explored the neuroprotective effects of AST in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice. Mice were administered with MPTP (30 mg/kg, i...
November 9, 2018: International Immunopharmacology
Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Ramasamy Thangavel, Mohammad Ejaz Ahmed, Smita Zaheer, Keerthana Kuppamma Kumar, Anudeep Yelam, Harleen Kaur, Iuliia Dubova, Sudhanshu P Raikwar, Shankar S Iyer, Asgar Zaheer
Parkinson's disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators...
2018: Journal of Alzheimer's Disease: JAD
Matthew Neal, Jie Luo, Dilshan S Harischandra, Richard Gordon, Souvarish Sarkar, Huajun Jin, Vellareddy Anantharam, Laurent Désaubry, Anumantha Kanthasamy, Arthi Kanthasamy
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...
October 2018: Glia
Yujeong Lee, Jung-Hyun Cho, Seulah Lee, Wonjong Lee, Seung-Cheol Chang, Hae Young Chung, Hyung Ryong Moon, Jaewon Lee
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...
September 28, 2018: Brain Research
Saumitra S Singh, Sachchida N Rai, Hareram Birla, Walia Zahra, Gaurav Kumar, Mallikarjuna R Gedda, Neeraj Tiwari, Ranjana Patnaik, Rakesh K Singh, Surya P Singh
Oxidative stress and neuroinflammation play a key role in dopaminergic (DA) neuronal degeneration, which results in the hindrance of normal ongoing biological processes in the case of Parkinson's disease. As shown in several studies, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, different behavioral parameters have suggested motor impairment and damage of antioxidant defence. Thus, some specific biological molecules found in medicinal plants can be used to inhibit the DA neuronal degeneration through their antioxidant and anti-inflammatory activities...
2018: Frontiers in Pharmacology
Katriana A Popichak, Sean L Hammond, Julie A Moreno, Maryam F Afzali, Donald S Backos, Richard D Slayden, Stephen Safe, Ronald B Tjalkens
Inflammatory activation of glial cells promotes loss of dopaminergic neurons in Parkinson disease. The transcription factor nuclear factor κB (NF- κ B) regulates the expression of multiple neuroinflammatory cytokines and chemokines in activated glial cells that are damaging to neurons. Thus, inhibition of NF- κ B signaling in glial cells could be a promising therapeutic strategy for the prevention of neuroinflammatory injury. Nuclear orphan receptors in the NR4A family, including NR4A1 (Nur77) and NR4A2 (Nurr1), can inhibit the inflammatory effects of NF- κ B, but no approved drugs target these receptors...
October 2018: Molecular Pharmacology
Atsushi Fujita, Hiroo Yamaguchi, Ryo Yamasaki, Yiwen Cui, Yuta Matsuoka, Ken-Ichi Yamada, Jun-Ichi Kira
BACKGROUND: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. METHODS: On days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis...
August 13, 2018: Journal of Neuroinflammation
Sathiya Sekar, Sugumar Mani, Barathidasan Rajamani, Thamilarasan Manivasagam, Arokiasamy Justin Thenmozhi, Abid Bhat, Bipul Ray, Musthafa Mohamed Essa, Gilles J Guillemin, Saravana Babu Chidambaram
Many studies reported the neuroprotective effects of angiotensin II type 1 receptor (AT1R) antagonists in Parkinson's disease (PD). However, the role of AT1R blockade on astroglial, in turn, dopaminergic functions in chronic PD is still to be studied. In the present study, telmisartan (TEL; 3 and 10 mg/kg/day; p.o), was used to study the effects AT1R blockade on astrocytic and dopaminergic functions in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsonism (250 mg/kg, i...
July 13, 2018: Neurotoxicity Research
Layal Maatouk, Chenju Yi, Maria-Angeles Carrillo-de Sauvage, Anne-Claire Compagnion, Stéphane Hunot, Pascal Ezan, Etienne C Hirsch, Annette Koulakoff, Frank W Pfrieger, François Tronche, Luc Leybaert, Christian Giaume, Sheela Vyas
The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls...
July 13, 2018: Cell Death and Differentiation
Ying-Li Zhu, Meng-Fei Sun, Xue-Bing Jia, Pei-Hao Zhang, Yi-Da Xu, Zhi-Lan Zhou, Zhou-Heng Xu, Chun Cui, Xue Chen, Xu-Sheng Yang, Yan-Qin Shen
Aucubin (AUC) is a major bioactive ingredient in Eucommia ulmoides, Plantain asiatica, and Aucuba japonica, and has been shown to exert anti-inflammatory, antioxidative, and neuroprotective effects. We explore the neuroprotective effects of AUC in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Mice were administered MPTP (30 mg/kg) daily for 5 days, followed by treatment with AUC for 7 days. Measurement of dopamine levels was performed by high-performance liquid chromatography and tyrosine hydroxylase expression was assessed by western blot...
September 5, 2018: Neuroreport
Jingsi Zhang, Zhennian Zhang, Wen Zhang, Xiangting Li, Ting Wu, Tingting Li, Min Cai, Zhonghai Yu, Jun Xiang, Dingfang Cai
As a classical prescription of Traditional Chinese medicine, the Jia-Jian-Di-Huang-Yin-Zi (JJDHYZ) decoction has long been used to treat movement disorders. The present study evaluated the effects of JJDHYZ on dopaminergic (DA) neurons and their survival-enhancing microenvironment as well as the possible mechanisms involved using a mouse model of Parkinson's disease. In MPTP-lesioned mice, a high dosage of JJDHYZ (34 g/kg/day) attenuated the loss of DA neurons, reversed the dopamine depletion, and improved the expression of glial-derived neurotrophic factor (GDNF) compared to the untreated model group...
June 29, 2018: Scientific Reports
Duraisamy Kempuraj, Ramasamy Thangavel, Gvindhasamy Pushpavathi Selvakumar, Mohammad Ejaz Ahmed, Smita Zaheer, Sudhanshu P Raikwar, Haris Zahoor, Daniyal Saeed, Iuliia Dubova, Gema Giler, Shelby Herr, Shankar S Iyer, Asgar Zaheer
Inflammatory mediators released from activated microglia, astrocytes, neurons, and mast cells mediate neuroinflammation. Parkinson's disease (PD) is characterized by inflammation-dependent dopaminergic neurodegeneration in substantia nigra. 1-Methyl-4-phenylpyridinium (MPP+ ), a metabolite of parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), induces inflammatory mediators' release from brain cells and mast cells. Brain cells' interaction with mast cells is implicated in neuroinflammation...
June 18, 2018: Molecular Neurobiology
Qing Wang, Qian He, Yifei Chen, Wei Shao, Chao Yuan, Yizheng Wang
BACKGROUND: Amplified inflammation is important for the progression of Parkinson's disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of microglial DICER would be responsible for the amplified inflammation in the mouse model of PD. METHODS: The microglia or C57BL/6 mice were treated or injected with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+ ), respectively, for the model establishment...
June 15, 2018: Journal of Neuroinflammation
Yigang Liu, Jingxing Zhang, Ming Jiang, Qiong Cai, Jianmin Fang, Lingjing Jin
OBJECTIVE: This study aimed to investigate the therapeutic effect of mesencephalic astrocyte-derived neurotrophic factor (MANF) on the MPTP/MPP+ -induced model of Parkinson's disease (PD) and the potential mechanism. METHODS: Male C57BL/6 mice PD model with MPTP-induced were randomly injected bilaterally with MANF or PBS into the striatum. Two weeks later, Rotarod test, immunohistochemistry, and detection of dopamine (DA) and its metabolites, superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were performed...
2018: American Journal of Translational Research
Linfang Chen, Liujun Xue, Jinlong Zheng, Xiangyang Tian, Yingdong Zhang, Qiang Tong
Recent studies have indicated that peroxisome proliferator-activated receptor β/δ (PPARß/δ) agonists exert neuroprotective effects in the model of Parkinson's disease (PD). Furthermore, PPARß/δ agonists have been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. Emerging evidence indicates that the nucleotide-binding domain and leucine-rich-repeat-protein 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathogenesis of PD. In the present study we investigate whether PPARß/δ agonists alleviate NLRP3-mediated neuroinflammation in the 1- methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD...
January 1, 2019: Behavioural Brain Research
Goodwell Nzou, R T Wicks, E E Wicks, S A Seale, C H Sane, A Chen, S V Murphy, J D Jackson, A J Atala
The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex...
May 9, 2018: Scientific Reports
Marika Cordaro, Rosalba Siracusa, Rosalia Crupi, Daniela Impellizzeri, Alessio Filippo Peritore, Ramona D'Amico, Enrico Gugliandolo, Rosanna Di Paola, Salvatore Cuzzocrea
Current pharmacological management of Parkinson disease (PD) does not provide for disease modification, but addresses only symptomatic features. Here, we explore a new approach to neuroprotection based on the use of 2-pentadecyl-2-oxazoline (PEA-OXA), the oxazoline derivative of the fatty acid amide signaling molecule palmitoylethanolamide (PEA), in an experimental model of PD. Daily oral treatment with PEA-OXA (10 mg/kg) significantly reduced behavioral impairments and neuronal cell degeneration of the dopaminergic tract induced by four intraperitoneal injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on 8-week-old male C57 mice...
December 2018: Molecular Neurobiology
Sean L Hammond, Katriana A Popichak, Xi Li, Lindsay G Hunt, Evan H Richman, Pranav U Damale, Edwin K P Chong, Donald S Backos, Stephen Safe, Ronald B Tjalkens
The orphan nuclear receptor Nurr1 (also called nuclear receptor-4A2) regulates inflammatory gene expression in glial cells, as well as genes associated with homeostatic and trophic function in dopaminergic neurons. Despite these known functions of Nurr1, an endogenous ligand has not been discovered. We postulated that the activation of Nurr1 would suppress the activation of glia and thereby protect against loss of dopamine (DA) neurons after subacute lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
June 2018: Journal of Pharmacology and Experimental Therapeutics
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