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https://www.readbyqxmd.com/read/28922504/selective-remodeling-of-glutamatergic-transmission-to-striatal-cholinergic-interneurons-after-dopamine-depletion
#1
Jose de Jesus Aceves Buendia, Lior Tiroshi, Wei-Hua Chiu, Joshua A Goldberg
The widely-held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs)...
September 18, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28910611/revealing-a-role-for-nmda-receptors-in-regulating-stn-inputs-following-the-loss-of-dopamine
#2
Aphroditi A Mamaligas, Christopher P Ford
In this issue of Neuron, Chu et al. (2017) show that dopamine depletion using a 6-OHDA model causes a decrease in hyperdirect inputs from the motor cortex directly to the STN and that rescuing this loss alleviates Parkinsonian symptoms.
September 13, 2017: Neuron
https://www.readbyqxmd.com/read/28902994/discovery-structure-activity-relationship-and-anti-parkinsonian-effect-of-a-potent-and-brain-penetrant-chemical-series-of-positive-allosteric-modulators-of-metabotropic-glutamate-receptor-4
#3
Delphine Charvin, Vincent Pomel, Millan Ortiz, Mélanie Frauli, Sophie Scheffler, Edith Steinberg, Luc Baron, Laurène Deshons, Rachel Rudigier, Delphine Thiarc, Christophe Morice, Baptiste Manteau, Stanislas Mayer, Danielle Graham, Bruno Giethlen, Nadia Brugger, Gaël Hedou, François Conquet, Stephan Schann
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms, after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model...
September 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28890053/intrastriatal-chromospheres-transplant-reduces-nociception-in-hemiparkinsonian-rats
#4
Alejandra Gómez-Paz, René Drucker-Colín, Diana Milán-Aldaco, Marcela Palomero-Rivero, Mónica Ambriz-Tututi
The present study evaluates the possible antinociceptive effect of chromosphere transplants in rats injected with 6-hydroxydopamine (6-OHDA), a model of Parkinson's disease. Male adult Wistar rats received 40μg/0.5μl of 6-OHDA or 0.5μl of vehicle into the left substantia nigra (SNc). Rats were evaluated for mechanical allodynia, cold allodynia, thermal hyperalgesia and formalin. Rats with altered nociceptive threshold were transplanted with chromospheres. After transplant, rats were evaluated every week...
September 8, 2017: Neuroscience
https://www.readbyqxmd.com/read/28861768/capsaicin-protects-against-oxidative-insults-and-alleviates-behavioral-deficits-in-rats-with-6-ohda-induced-parkinson-s-disease-via-activation-of-trpv1
#5
ZhenXiang Zhao, JianFeng Wang, LingLing Wang, XiaoMei Yao, YiLin Liu, Ye Li, Si Chen, Tao Yue, XiaoTang Wang, WenFei Yu, YiMing Liu
Increasing evidence suggests that capsaicin may play a role in modulating neuronal function and controlling motor behavior. However, the underlying mechanism is still unclear and the activation of transient receptor potential vanilloid 1 (TRPV1) might be involved in. This study investigated the potential neuroprotective role of capsaicin in a rat model of 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD). Capsaicin was treated intraperitoneally for the 6-OHDA induced PD rats and the locomotor activity and abnormal involuntary movements were found alleviated...
August 31, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28861668/neuroprotective-activities-of-spirulina-platensis-in-the-6-ohda-model-of-parkinson-s-disease-are-related-to-its-anti-inflammatory-effects
#6
Francisco Arnaldo Viana Lima, Ivan Pinheiro Joventino, Francisca Pinheiro Joventino, Aline Cordeiro de Almeida, Kelly Rose Tavares Neves, Marta Regina do Carmo, Luzia Kalyne Almeida Moreira Leal, Geanne Matos de Andrade, Glauce Socorro de Barros Viana
Spirulina platensis (SPI) is a cyanobacterium, presenting anti-inflammatory and antioxidant actions. Considering the importance of inflammation and oxidative stress in Parkinson's disease (PD), SPI neuroprotective effects were evaluated in a model of PD. Male Wistar rats were divided into: sham-operated (SO), untreated 6-OHDA and 6-OHDA treated with SPI (25 and 50 mg/kg, p.o.). The 6-OHDA was injected into the right striata and SPI treatments started 24 h later for 2 weeks. The SO and untreated 6-OHDA-lesioned groups were administered with distilled water, for the same period...
August 31, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28854243/antiparkinsonian-effects-of-the-radiprodil-and-tozadenant-combination-in-mptp-treated-marmosets
#7
Anne Michel, Jean-Marie Nicolas, Sarah Rose, Michael Jackson, Peter Colman, Willy Briône, David Sciberras, Pierandrea Muglia, Dieter K Scheller, Martin Citron, Patrick Downey
OBJECTIVE: Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). BACKGROUND: In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. METHODS: Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD...
2017: PloS One
https://www.readbyqxmd.com/read/28851733/brown-adipose-tissue-activation-in-a-rat-model-of-parkinson-s-disease
#8
Wenjuan Wang, Xiangzhi Meng, Chun Yang, Dongliang Fang, Xuemeng Wang, Jiaqiang An, Jingyi Zhang, Lulu Wang, Tao Lu, Hai-Bin Ruan, Yan Gao
Loss of body weight and fat mass is one of the non-motor symptoms of Parkinson's disease (PD). Weight loss is primarily due to reduced energy intake and increased energy expenditure. While inadequate energy intake in PD patients is mainly caused by appetite loss and impaired gastrointestinal absorption, the underlying mechanisms for increased energy expenditure remain largely unknown. Brown adipose tissue (BAT), a key thermogenic tissue in humans and other mammals, plays an important role in thermoregulation and energy metabolism; however, it has not been tested if BAT is involved in the negative energy balance in PD...
August 29, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28843848/depressive-like-neurochemical-and-behavioral-markers-of-parkinson-s-disease-after-6-ohda-administered-unilaterally-to-the-rat-medial-forebrain-bundle
#9
Kinga Kamińska, Tomasz Lenda, Jolanta Konieczny, Anna Czarnecka, Elżbieta Lorenc-Koci
BACKGROUND: Although Parkinson's disease (PD) is characterized by progressive neurodegeneration of multiple neurotransmitter systems, 6-hydroxydopamine (6-OHDA) as a model substance is mainly used to selectively damage the nigrostriatal dopaminergic neurons and induce parkinsonian-like motor disturbances in rats. We hypothesized that high doses of this neurotoxin affecting other monoaminergic systems may also evoke the depressive-like behavior. METHODS: The impact of 6-OHDA (8, 12, 16μg/4μl) administered unilaterally into the medial forebrain bundle on the sucrose solution intake (a measure of anhedonia) and on the tissue levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the striatum (STR), substantia nigra (SN), prefrontal cortex (PFC) and hippocampus (HIP) was examined in rats pretreated or non-pretreated with desipramine...
June 3, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28842681/cyclooxygenase-2-contributes-to-oxidopamine-mediated-neuronal-inflammation-and-injury-via-the-prostaglandin-e2-receptor-ep2-subtype
#10
Xu Kang, Jiange Qiu, Qianqian Li, Katherine A Bell, Yifeng Du, Da Woon Jung, Jae Yeol Lee, Jiukuan Hao, Jianxiong Jiang
Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE2) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE2-mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines - mouse Neuro-2a and human SH-SY5Y - after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE2 and upregulation of pro-inflammatory cytokine interleukin-1β...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28842186/an-altered-blood-brain-barrier-contributes-to-brain-iron-accumulation-and-neuroinflammation-in-the-6-ohda-rat-model-of-parkinson-s-disease
#11
Sonia Olmedo-Díaz, Héctor Estévez-Silva, Greger Orädd, Sara Af Bjerkén, Daniel Marcellino, Ana Virel
Brain iron accumulation is a common feature shared by several neurodegenerative disorders including Parkinson's disease. However, what produces this accumulation of iron is still unknown. In this study, the 6-hydroxydopamine (6-OHDA) hemi-parkinsonian rat model was used to investigate abnormal iron accumulation in substantia nigra. We investigated three possible causes of iron accumulation; a compromised blood-brain barrier (BBB), abnormal expression of ferritin, and neuroinflammation. We identified alterations in the BBB subsequent to the injection of 6-OHDA using gadolinium-enhanced magnetic resonance imaging (MRI)...
August 24, 2017: Neuroscience
https://www.readbyqxmd.com/read/28840516/deleterious-effects-of-vegfr2-and-ret-inhibition-in-a-preclinical-model-of-parkinson-s-disease
#12
C Requejo, J A Ruiz-Ortega, H Bengoetxea, S Bulnes, L Ugedo, J V Lafuente
Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot...
August 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28836128/purinergic-antagonism-prevents-mitochondrial-dysfunction-and-behavioral-deficits-associated-with-dopaminergic-toxicity-induced-by-6-ohda-in-rats
#13
Saket Kumar, Akanksha Mishra, Sairam Krishnamurthy
Purinoceptors are present in neurons, microglia and oligodendrocytes and regulate dopamine (DA) release, striatal-related function and striatal neuronal and DA cells damage. Therefore, purinoceptors may be involved in the pathology of Parkinson's disease (PD) and purinergic antagonism may show neuroprotective effect. The study investigated the role of the non-selective purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2('), 4(')-disulfonic acid (PPADS) and a selective purinergic receptor P2X7 receptor antagonist Brilliant Blue G (BBG) against 6-OHDA induced dopaminergic neurotoxicity in rats; while adenosine triphosphate (ATP) was used as a P2X receptor agonist...
August 24, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28835798/discovery-of-potent-and-selective-a2a-antagonists-with-efficacy-in-animal-models-of-parkinson-s-disease-and-depression
#14
Sujay Basu, Dinesh A Barawkar, Vidya Ramdas, Minakshi Naykodi, Yogesh D Shejul, Meena Patel, Sachin Thorat, Anil Panmand, K Kashinath, Rajesh Bonagiri, Vandna Prasad, Ganesh Bhat, Azfar Quraishi, Sumit Chaudhary, Amol Magdum, Ashwinkumar V Meru, Indraneel Ghosh, Ravi K Bhamidipati, Amol A Raje, Vamsi L M Madgula, Siddhartha De, Sreekanth R Rouduri, Venkata P Palle, Anita Chugh, Narayanan Hariharan, Kasim A Mookhtiar
Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33...
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28827552/baicalein-prevents-6-ohda-ascorbic-acid-induced-calcium-dependent-dopaminergic-neuronal-cell-death
#15
Sheng-Fang Wang, Liang-Feng Liu, Ming-Yue Wu, Cui-Zan Cai, Huanxing Su, Jieqiong Tan, Jia-Hong Lu, Min Li
6-OHDA plus ascorbic acid (AA) has long been used to induce Parkinson's disease in rodents, while only 6-OHDA is commonly used to induce cell damage in cellular PD models. AA was believed to act as an anti-oxidant to prevent the degradation of 6-OHDA; however, some studies suggested that AA dramatically enhanced the selectivity and toxicity of 6-OHDA. To understand the mechanisms by which 6-OHDA/AA induces cell death, we established a 6-OHDA/AA cell toxicity model in human dopaminergic neuroblastoma SH-SY5Y cells...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821831/targeted-inhibition-of-rage-in-substantia-nigra-of-rats-blocks-6-ohda-induced-dopaminergic-denervation
#16
Juciano Gasparotto, Camila Tiefensee Ribeiro, Rafael Calixto Bortolin, Nauana Somensi, Thallita Kelly Rabelo, Alice Kunzler, Natália Cabral Souza, Matheus Augusto de Bittencourt Pasquali, José Claudio Fonseca Moreira, Daniel Pens Gelain
The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with inflammation in most cell types. RAGE up-regulates the expression of proinflammatory mediators and its own expression via activation of NF-kB. Recent works have proposed a role for RAGE in Parkinson's disease (PD). In this study, we used the multimodal blocker of RAGE FPS-ZM1, which has become available recently, to selectively inhibit RAGE in the substantia nigra (SN) of rats intracranially injected with 6-hydroxydopamine (6-OHDA)...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28819676/granger-causality-supports-abnormal-functional-connectivity-of-beta-oscillations-in-the-dorsolateral-striatum-and-substantia-nigra-pars-reticulata-in-hemiparkinsonian-rats
#17
Qiang Wang, Min Li, Zhengyuan Xie, Junbin Cai, Nanxiang Li, Hu Xiao, Ning Wang, Jinyan Wang, Fei Luo, Wangming Zhang
Synchronized oscillatory neuronal activity in the beta frequency range has been reported in the basal ganglia (BG) of patients with Parkinson disease (PD) and PD animal models. The coherent abnormal oscillatory activities in the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr) that accompany parkinsonian states have not been resolved. In this study, we recorded local field potentials (LFPs) in the dStr and SNr of 6-hydroxydopamine (6-OHDA)-induced dopamine (DA)-lesioned rats in an awake, resting state...
August 17, 2017: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/28807729/cpg-demethylation-in-the-neurotoxicity-of-1-methyl-4-phenylpyridinium-might-mediate-transcriptional-up-regulation-of-%C3%AE-synuclein-in-sh-sy5y-cells
#18
Jian Yang, Zhaofei Yang, Xuan Wang, Min Sun, Yong Wang, Xiaomin Wang
The accumulation of α-synuclein is the primary pathological hallmark of Parkinson's disease (PD). In PD patients, CpG demethylation of intron-1 has been reported to be associated with α-synuclein up-regulation. Environmental factor, for example neurotoxin, is a major etiological risk factor in PD pathogenesis. However, the role of CpG methylation in neurotoxin-induced PD has not been addressed completely yet. To explore CpG methylation associating with α-synuclein transcription and its underlying mechanisms in the neurotoxin-induced PD pathology, human neuroblastoma SH-SY5Y cells were treated with neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP(+))...
August 12, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28802652/an-autophagic-mechanism-is-involved-in-the-6-hydroxydopamine-induced-neurotoxicity-in-vivo
#19
Xin He, Wei Yuan, Zijian Li, Juan Feng
6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied...
August 9, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28801819/treadmill-exercise-prevents-increase-of-neuroinflammation-markers-involved-in-the-dopaminergic-damage-of-the-6-ohda-parkinson-s-disease-model
#20
Caroline Cristiano Real, Priscila Crespo Garcia, Luiz R G Britto
Parkinson's disease (PD) involves loss of dopaminergic neurons in the substantia nigra (SN), which can be correlated to neuroinflammatory changes with the aging of the nervous system. On the other hand, exercise can reduce the deleterious effects promoted by age, but the mechanism involved is still unclear. This study investigated the preventive exercise-induced changes on neuroinflammatory processes in a rat model of PD induced by unilateral striatal injections of 6-hydroxydopamine (6-OHDA). Adult male Wistar rats were divided into two groups: (1) sedentary (SED) or (2) exercised (EX), animals that did treadmill exercise three times per week, every other day, for 4 weeks prior to 6-OHDA or saline injection...
August 11, 2017: Journal of Molecular Neuroscience: MN
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