Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Collins, Louise; Toulouse, André; Connor, Thomas J.; Nolan, Yvonne M.

doi:10.1016/j.neuropharm.2012.01.028

Cited by 248 publications

(155 citation statements)

References 251 publications

(244 reference statements)

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“…In vivo brain imaging of Parkinson's disease patients reveals an association between widespread microglial activation and the pathological process [4][5][6] (see also [7]). In addition, both cellular and molecular studies of post-mortem human brain tissue show neuroinflammatory processes in the affected brain regions of these patients (for review, see [8 -10]).…”

Section: Introductionmentioning

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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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: Introductionmentioning

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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“…Neuroinflammation can be triggered by immunological challenges (viral or bacterial infections), neuronal injury (brain trauma or stroke) and other epigenetic factors including chronic inflammatory syndromes (arthritis, atherosclerosis, Crohn's disease and multiple sclerosis) and environmental toxins such as MPTP, paraquat, rotenone, particulate material, heavy metals and organophophorate compounds 23 . In addition, there are several epidemiological reports which correlate the incidence of secondary parkinsonism with systemic inflammatory events such as viral infections caused by influenza A-H1N1, influenza A-H5N1, coxsackie, St. Louis, west Nile and human immunodeficiency viruses (HIV) and Japanese-encephalitis B 24 . These peripheral insults may cause the increase in blood brain barrier permeability which could allow the infiltration of lymphocytes and macrophages in brain parenquima 10 .…”

Section: Evidence Of Neuroinflammation In Parkinson's Diseasementioning

confidence: 99%

“…LPS exacerbated the neurodegeneration, accelerated and increased motor signs, and changed microglia to a proinflammatory phenotype with increased secretion of IL-1b Exacerbation of neurodegeneration and motor signs were inhibited by dexamethasone and IL-1 inhibitors 27 . Despite the neuroprotective effects of dexamethasone in several preclinical studies, some authors point that the severe side effects associated with the prolonged use of glucocorticoids make them unfeasible as neuroprotective therapy in patients with PD 5,24 . The involvement of the inflammatory process in the pathophysiology of PD is also supported by reports from animal models, because the neurotoxin-induced degeneration of nigral dopaminergic neurons can be prevented by some non-steroidal anti-inflammatory drugs (NSAIDs).…”

Section: Therapeutic Evidence Of Anti-inflammatory Drugs In Parkinsonmentioning

confidence: 99%

“…When this receptor is activated by its natural ligands eicosanoids and prostaglandin J2, it reduces the expression of proinflammatory factors such as NF-kB, iNOS, COX-2 and a broad spectrum of cytokines. Other drugs such as pioglitazone and rosiglitazone, both synthetic agonists of the PPARg receptor approved for the treatment of type 2 diabetes, exhibit neuroprotective effect in models of neurodegenerative diseases, including PD, by preventing inflammation, oxidative damage and apoptosis 24,33 . As mentioned above, NSAIDs seem to exert their neuroprotective actions not only by inhibiting COX activity, and consequently, prostaglandins production; but also by the activation of PPARg receptor, inactivation of NF-kB, suppression of iNOS mRNA transcription, direct scavenging of ROS and RNS, and probably by other unknown mechanisms.…”

Section: Therapeutic Evidence Of Anti-inflammatory Drugs In Parkinsonmentioning

confidence: 99%

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Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

Bassani

Vital

Rauh

2015

Arq. Neuro-Psiquiatr.

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Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1.6% of people over 60 years old 1,2 . PD is also the most common cause of parkinsonism, corresponding to 74.7% of all cases in a Brazilian study 3 . The disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), loss of their ascending projections to the striatum (caudate and putamen), and consequent decrease of striatal dopamine (DA) content, which leads to severe locomotion difficulties and cardinal motor symptoms such as tremor at rest, rigidity, postural instability and slowness of body movements (bradykinesia) 4,5 . By the time a patient is diagnosed, approximately 60% of SNpc neurons are degenerated and 80% of striatal DA content is depleted 4,5 . In addition to neuronal damage, PD is characterized by the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites, mainly in the SNpc 6 . Currently, the pharmacological and non-pharmacological treatments approved for PD offer only symptomatic relief for patients. As these treatments are not able to stop or reverse the neurodegenerative process, PD remains incurable. The motor symptoms can be reduced by many drugs that increase the DA level in the central nervous system (CNS) or mimic its effects. The gold standard for the treatment of PD nowadays is Levodopa, a DA precursor. Other drugs commonly prescribed are DA receptor agonists, monoaminoxidase (MAO) AbStrACtParkinson's disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.Keywords: Parkinson's disease, neuroinflammation, anti-inflammatory. ResumoA doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. ...

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“…Increased levels of the systemic cytokines TNF-α, IL-2, IL-6, and RANTES (Collins et al, 2012) have been detected in serum from PD patients. In one study, high plasma IL-6 levels correlated with increased risk to develop PD (Chen et al, 2008).…”

Section: Parkinson Diseasementioning

confidence: 99%

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

Rodríguez‐Ramírez¹,

Adalid‐Peralta²,

Fragoso³

et al. 2015

JCI

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A complex, highly specialized immunomodulatory microenvironment exists in the central nervous system, as a number of protective mechanisms against insults of different kinds have evolved over time to help in maintaining homoeostasis in this compartment.Inflammation in the central nervous system (neuroinflammation) is an elaborate process, triggered in response to challenges of diverse nature. Characterized by increased glial activation (phagocytic phenotype) and the production of pro-inflammatory cytokines, it often leads to blood-brain barrier disruption and leukocyte invasion. While the initial response to an injury involving oxidative and nitrosative stress usually causes acute neuroinflammation, it seldom affects long-term neuronal survival. Chronic neuroinflammation, on the other side, may affect cell survival and brain functions, as observed in several neurodegenerative disorders. Various peripheral and central injuries can alter the homeostasis in the central nervous system, triggering a persistent adaptive inflammatory response that could lead to a vicious circle of neuronal damage.The purpose of this review is to describe the most relevant players in this phenomenon, and to highlight their detrimental role in different neurologic diseases.

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Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Cited by 248 publications

References 251 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?

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

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