Increased plasma levels of TNF-α but not of IL1-β in MPTP-treated monkeys one year after the MPTP administration

Barcia, Carlos; Pablos, Vicente de; Bautista-Hernández, Víctor; Sánchez-Bahillo, Ángel; Bernal, Inmaculada Mengual; Fernández-Villalba, Emiliano; Martin, Julia; Bañón, Rafael; Fernández-Barreiro, A; Herrero, M.T.

doi:10.1016/j.parkreldis.2005.05.006

Cited by 60 publications

(40 citation statements)

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“…After a harmful event, reactive microglia is involved in scavenging neuronal debris; however, an adverse role emerges when proinflammatory cytokines (i.e. INT-c; TNF-a) perpetuate inflammation, favoring neurodegeneration (Barcia et al 2005(Barcia et al , 2011Pott Godoy et al 2008). In this study, MPTPtreated mice develop a prominent but transient inflammation, which coincides with DA neuron and fiber degeneration; successive remission of this inflammation correlates with functional recovery of surviving neurons.…”

Section: Discussionmentioning

confidence: 64%

“…These features were also observed in the brain of young drug addicts, who made use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al 1983), and in animal models of Parkinsonism, such as MPTP-injected mice and monkeys (Barnum and Tansey 2010;Walsh et al 2011). Increased levels of pro-inflammatory cytokines in both SN (Hunot et al 1996;Hirsh et al 1998;Barcia et al 2005Barcia et al , 2011 and cerebrospinal fluid (Nagatsu et al 2000;Pott Godoy et al 2008) of PD patients and animal models have also been described. The complexity of the immune response, however, does not allow to unequivocally establish whether reactive ''neuroglia'' contributes to DA neuron death.…”

Section: Introductionmentioning

confidence: 82%

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Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

et al. 2014

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Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson's disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism. © 2014 Springer-Verlag Berlin Heidelberg

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 82%

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

et al. 2014

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“…CSF and postmortem brains of PD patients display elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF) as do animals treated with the dopaminergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) used to model nigral degeneration in nonhuman primates and rodents (Boka et al, 1994;Hunot et al, 1999;Mogi et al, 2000;Sriram et al, 2002;Barcia et al, 2005;Nagatsu and Sawada, 2005). TNF is synthesized as a type II transmembrane trimeric protein cleaved by the TACE (TNF-␣ converting enzyme) metalloprotease to a soluble form (Aggarwal et al, 2000;MacEwan, 2002); both forms are biologically active, but their relative roles in mediating DA neuron survival are unknown.…”

Section: Introductionmentioning

confidence: 99%

Blocking Soluble Tumor Necrosis Factor Signaling with Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons in Models of Parkinson's Disease

McCoy¹,

Martinez²,

Ruhn³

et al. 2006

J. Neurosci.

339

276

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The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominantnegative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDAinduced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.

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“…Thereupon, the present study revealed that PACAP38 and Ac-[Phe(pI) 6 , Nle 17 ]PACAP(1-27) abolished the induction of the inflammatory markers TNF-α and IL-6 mRNA expression induced by MPTP treatment, as well as the stimulation of the pro-apoptotic caspase 3 mRNA expression. The significant decrease of TNF-α mRNA by either peptide is important to point out because this pro-inflammatory cytokine is mainly responsible for promoting and maintaining chronic neuroinflammation in PD (Barcia et al, 2005). Thus, modulation of TNF-α should be an neuroprotective effects linked to a decrease of neuronal apoptosis and a reduction of inflammation.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

et al. 2016

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Increased plasma levels of TNF-α but not of IL1-β in MPTP-treated monkeys one year after the MPTP administration

Cited by 60 publications

References 38 publications

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Blocking Soluble Tumor Necrosis Factor Signaling with Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons in Models of Parkinson's Disease

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

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