Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Teismann, Peter; Tieu, Kim; Choi, Dong‐Kug; Wu, Du-Chu; Naini, Ali; Hunot, Stéphane; Vila, Miquel; Jackson‐Lewis, Vernice; Przedborski, Serge

doi:10.1073/pnas.0837397100

Cited by 614 publications

(540 citation statements)

References 24 publications

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“…Cholinergic interneurons and DARP-32 projection neurons play a key and selective role in L-DOPA-induced dyskinesia. In Parkinson's disease, COX2 expression occurs mostly in glial cells in the substantia nigra compacta, being potentially involved with neurodegeneration [76][77][78][79][80]. In agreement with this, COX2 knockout mice are more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated intoxication [77,80,81].…”

Section: Discussionmentioning

confidence: 68%

“…On the other hand, evidence has been accumulated indicating that COX2 expression in Parkinson's disease does seem to derive from a mechanism distinct from the inflammatory properties of prostanoids [77]. In accordance, the inflammatory response associated with dopaminergic neurodegeneration in COX2 knockout mice did not differ from that observed in their wild-type counterparts [77]. Finally, non-steroidal anti-inflammatory drug treatment targeting COX2 has been studied in Parkinson's disease patients but with variable results [82].…”

Section: Discussionmentioning

confidence: 99%

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Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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Inflammatory mechanisms are proposed to play a role in l -DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates l -DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with l -DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with l -DOPA (21 days) combined with 7-nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l -DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented l -DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after l -DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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“…Immunofluorscent staining was performed as described in (Teismann et al, 2003). Primary antibodies were rat anti‐MHC II (1:200; eBioscience, Hatfield, UK), mouse anti‐TH (1:500; Chemicon, Temecula, CA), mouse anti‐human GFAP (1:100; DAKO, Cambridgeshire, UK) and rabbit anti‐Iba‐1 (1:1000; Wako Chemicals, Neuss, Germany).…”

Section: Methodsmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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“…Male C57Bl/6 mice (6-8 months old) were administered MPTP in saline vehicle at a total dose of 60 mg/kg of MPTP given in four intraperitoneal injections 2 hours apart on a single day (Teismann, et al, 2003). Controls received saline using the same protocol.…”

Section: Animals and Mptp Treatmentmentioning

confidence: 99%

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

207

196

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Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

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Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Cited by 614 publications

References 24 publications

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

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