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https://www.readbyqxmd.com/read/28092019/urb597-and-the-cannabinoid-win55-212-2-reduce-behavioral-and-neurochemical-deficits-induced-by-mptp-in-mice-possible-role-of-redox-modulation-and-nmda-receptors
#1
Angel Escamilla-Ramírez, Esperanza García, Guadalupe Palencia-Hernández, Ana Laura Colín-González, Sonia Galván-Arzate, Isaac Túnez, Julio Sotelo, Abel Santamaría
Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice...
January 14, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28053050/parkin-functionally-interacts-with-pgc-1%C3%AE-to-preserve-mitochondria-and-protect-dopaminergic-neurons
#2
Lu Zheng, Nathalie Bernard-Marissal, Norman Moullan, Davide D'Amico, Johan Auwerx, Darren J Moore, Graham Knott, Patrick Aebischer, Bernard L Schneider
To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated to autosomal recessive early-onset PD, and controls the transcription of PGC-1α, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co-expressing PGC-1α and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling...
January 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28035410/inhibiting-purinergic-p2x7-receptors-with-the-antagonist-brilliant-blue-g-is-neuroprotective-in-an-intranigral-lipopolysaccharide-animal-model-of-parkinson-s-disease
#3
Xin-Hong Wang, Xin Xie, Xiao-Guang Luo, Hong Shang, Zhi-Yi He
Parkinson's disease (PD) is a common neurodegenerative disorder, which is characterized by the selective and progressive death of dopaminergic (DA) neurons in the substantia nigra. Increasing evidence suggests that inflammation is important in the degeneration of DA neurons. The purinergic receptor subtype P2X7 receptor (P2X7R) is key in the activation and proliferation of microglia. The present study aimed to examine whether inhibiting purinergic P2X7 receptors is neuroprotective in a rat model of PD, specifically via inhibiting p38 mitogen‑activated protein kinase (MAPK)...
December 23, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28028868/neurometabolic-profiles-of-the-substantia-nigra-and-striatum-of-mptp-intoxicated-common-marmosets-an-in-vivo-proton-mrs-study-at-9-4%C3%A2-t
#4
Hwon Heo, Jae-Bum Ahn, Hyeong Hun Lee, Euna Kwon, Jun-Won Yun, Hyeonjin Kim, Byeong-Cheol Kang
Given the strong coupling between the substantia nigra (SN) and striatum (STR) in the early stage of Parkinson's disease (PD), yet only a few studies reported to date that have simultaneously investigated the neurochemistry of these two brain regions in vivo, we performed longitudinal metabolic profiling in the SN and STR of 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated common marmoset monkey models of PD (n = 10) by using proton MRS ((1) H-MRS) at 9.4 T. T2 relaxometry was also performed in the SN by using MRI...
December 28, 2016: NMR in Biomedicine
https://www.readbyqxmd.com/read/28024798/zonisamide-attenuates-lactacystin-induced-parkinsonism-in-mice-without-affecting-system-xc
#5
Eduard Bentea, Joeri Van Liefferinge, Lise Verbruggen, Katleen Martens, Sho Kobayashi, Lauren Deneyer, Thomas Demuyser, Giulia Albertini, Katrien Maes, Hideyo Sato, Ilse Smolders, Jan Lewerenz, Ann Massie
Zonisamide (ZNS), an anticonvulsant drug exhibiting symptomatic effects in Parkinson's disease (PD), was recently reported to exert neuroprotection in rodent models. One of the proposed neuroprotective mechanisms involves increased protein expression of xCT, the specific subunit of the cystine/glutamate antiporter system xc(-), inducing glutathione (GSH) synthesis. Here, we investigated the outcome of ZNS treatment in a mouse model of PD based on intranigral proteasome inhibition, and whether the observed effects would be mediated by system xc(-)...
December 24, 2016: Experimental Neurology
https://www.readbyqxmd.com/read/28012853/rat-brain-sagittal-organotypic-slice-cultures-as-an-ex-vivo-dopamine-cell-loss-system
#6
Amy McCaughey-Chapman, Bronwen Connor
BACKGROUND: Organotypic brain slice cultures are a useful tool to study neurological function as they provide a more complex, 3-dimensional system than standard 2-dimensional in vitro cell cultures. NEW METHOD: Building on a previously developed mouse brain slice culture protocol, we have developed a rat sagittal brain slice culture system as an ex vivo model of dopamine cell loss. RESULTS: We show that rat brain organotypic slice cultures remain viable for up to 6 weeks in culture...
December 21, 2016: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28004859/parkinson-s-disease-related-increase-of-t2-weighted-hypointensity-in-substantia-nigra-pars-compacta
#7
Jason Langley, Daniel E Huddleston, Jan Sedlacik, Kai Boelmans, Xiaoping P Hu
BACKGROUND: In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T2 / T2*-weighted contrasts to define the regions of interest in the SN. Given that T2 / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately...
December 22, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27982501/motor-associations-of-iron-accumulation-in-deep-grey-matter-nuclei-in-parkinson-s-disease-a-cross-sectional-study-of-iron-related-magnetic-resonance-imaging-susceptibility
#8
A Martin-Bastida, N P Lao-Kaim, C Loane, M Politis, A A Roussakis, N Valle-Guzman, Z Kefalopoulou, G Paul-Visse, H Widner, Y Xing, S T Schwarz, D P Auer, T Foltynie, R A Barker, P Piccini
BACKGROUND AND PURPOSE: To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD). METHODS: Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups...
December 16, 2016: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/27956238/enhanced-dopaminergic-neurotoxicity-mediated-by-mptp-in-il-32%C3%AE-transgenic-mice
#9
Yu Yeon Jung, Nikita Katila, Sabita Neupane, Sina Shadfar, Uttam Ojha, Sunil Bhurtel, Sunil Strivastav, Dong Ju Son, Pil-Hoon Park, Do Young Yoon, Jin Tae Hong, Dong-Young Choi
Parkinson's disease (PD) is a neurodegenerative disorder characterized by prominent loss of the nigral dopaminergic neurons and motor symptoms, such as resting tremor and bradykinesia. Evidence suggests that neuroinflammation may play a critical role in PD pathogenesis. Interleukin (IL)-32 is a newly-identified proinflammatory cytokine, which regulates innate and adaptive immune responses by activating p38 MAPK and NF-κB signaling pathways. The cytokine has been implicated in cancers and autoimmune, inflammatory, and infectious diseases...
December 9, 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27943027/fty720-attenuates-6-ohda-associated-dopaminergic-degeneration-in-cellular-and-mouse-parkinsonian-models
#10
Manru Ren, Minxing Han, Xinbing Wei, Ying Guo, Huanying Shi, Xiumei Zhang, Ruth G Perez, Haiyan Lou
FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice...
December 9, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27933309/impact-of-age-and-vector-construct-on-striatal-and-nigral-transgene-expression
#11
Nicole K Polinski, Fredric P Manfredsson, Matthew J Benskey, D Luke Fischer, Christopher J Kemp, Kathy Steece-Collier, Ivette M Sandoval, Katrina L Paumier, Caryl E Sortwell
Therapeutic protein delivery using viral vectors has shown promise in preclinical models of Parkinson's disease (PD) but clinical trial success remains elusive. This may partially be due to a failure to include advanced age as a covariate despite aging being the primary risk factor for PD. We investigated transgene expression following intracerebral injections of recombinant adeno-associated virus pseudotypes 2/2 (rAAV2/2), 2/5 (rAAV2/5), 2/9 (rAAV2/9), and lentivirus (LV) expressing green fluorescent protein (GFP) in aged versus young adult rats...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27928028/mitochondrial-pyruvate-carrier-regulates-autophagy-inflammation-and-neurodegeneration-in-experimental-models-of-parkinson-s-disease
#12
Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N Hildebrandt, Jennifer A Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, William G McDonald, Martha L Escobar Galvis, Jeffrey H Kordower, Jeremy M Van Raamsdonk, Jerry R Colca, Patrik Brundin
Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP(+)) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model...
December 7, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27927762/urinary-incontinence-incident-parkinsonism-and-parkinson-s-disease-pathology-in-older-adults
#13
Noa M Buchman, Sue E Leurgans, Raj J Shah, Veronique VanderHorst, Robert S Wilson, Yaacov G Bachner, David Tanne, Julie A Schneider, David A Bennett, Aron S Buchman
OBJECTIVE: To test the hypothesis that urinary incontinence (UI) is associated with incident parkinsonism in older adults. METHODS: We used data from 2,617 older persons without dementia. Assessment included baseline self-report UI and annual structured exam which assessed parkinsonian signs, motor performances, cognitive function, and self-report disabilities. We used a series of Cox proportional hazards models to examine the association of UI with parkinsonism and adverse health outcomes and a mixed-effect model to examine the association of UI with the annual rate of cognitive decline...
December 7, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/27927222/tollip-an-early-regulator-of-the-acute-inflammatory-response-in-the-substantia-nigra
#14
Marie Humbert-Claude, D Duc, D Dwir, L Thieren, J Sandström von Tobel, C Begka, F Legueux, D Velin, M H Maillard, K Q Do, F Monnet-Tschudi, L Tenenbaum
BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease...
December 7, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27904494/anti-apoptotic-effect-of-shudipingchan-granule-in-the-substantia-nigra-of-rat-models-of-parkinson-s-disease
#15
Qing Ye, Xiao-Lei Yuan, Jing He, Jie Zhou, Can-Xing Yuan, Xu-Ming Yang
Levodopa is the gold-standard treatment for Parkinson's disease. However, although it alleviates the clinical symptoms, it cannot delay the progressive apoptosis of dopaminergic neurons or prevent motor complications in the long term. In the present study, we investigated the effect of Shudipingchan granule on neuronal apoptosis in a rat model of Parkinson's disease, established by injecting 6-hydroxydopamine into the substantia nigra pars compacta and ventral tegmental area. We then administered levodopa (20 mg/kg intraperitoneally, twice daily) with or without Shudipingchan granule (7...
October 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27903866/nigral-dopaminergic-pak4-prevents-neurodegeneration-in-rat-models-of-parkinson-s-disease
#16
So-Yoon Won, Mee-Hee Park, Soon-Tae You, Seung-Won Choi, Hyong-Kyu Kim, Catriona McLean, Suk-Chul Bae, Sang Ryong Kim, Byung Kwan Jin, Kun Ho Lee, Eun-Young Shin, Eung-Gook Kim
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD...
November 30, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27902767/towards-a-non-human-primate-model-of-alpha-synucleinopathy-for-development-of-therapeutics-for-parkinson-s-disease-optimization-of-aav1-2-delivery-parameters-to-drive-sustained-expression-of-alpha-synuclein-and-dopaminergic-degeneration-in-macaque
#17
James B Koprich, Tom H Johnston, Gabriela Reyes, Vanessa Omana, Jonathan M Brotchie
Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27900791/robust-graft-survival-and-normalized-dopaminergic-innervation-do-not-obligate-recovery-in-a-parkinson-disease-patient
#18
Jeffrey H Kordower, Christopher G Goetz, Yaping Chu, Glenda M Halliday, Daniel A Nicholson, Timothy F Musial, David J Marmion, A Jon Stoessl, Vesna Sossi, Thomas B Freeman, C Warren Olanow
OBJECTIVE: The main goal of dopamine cell replacement therapy in Parkinson disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying 16 years following fetal nigral grafting. METHODS: A 55-year-old levodopa-responsive woman with PD received bilateral putaminal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial...
November 30, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27862327/an-order-in-lewy-body-disorders-retrograde-degeneration-in-hyperbranching-axons-as-a-fundamental-structural-template-accounting-for-focal-multifocal-lewy-body-disease
#19
REVIEW
Toshiki Uchihara 内原 俊記
Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs)...
November 14, 2016: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/27813160/subcortical-18-f-av-1451-binding-patterns-in-progressive-supranuclear-palsy
#20
Hanna Cho, Jae Yong Choi, Mi Song Hwang, Seung Ha Lee, Young Hoon Ryu, Myung Sik Lee, Chul Hyoung Lyoo
BACKGROUND: Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). (18) F-AV-1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP. OBJECTIVES: The objectives of this study were to investigate cortical and subcortical (18) F-AV-1451 binding patterns in patients with PSP. METHODS: We recruited 14 PSP patients and compared their cortical and subcortical binding patterns in (18) F-AV-1451 positron emission tomography (PET) studies with those of 15 Parkinson's disease (PD) patients and 15 healthy controls...
November 3, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
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