TGFβ1 and TGFβ2 Concentrations Are Elevated in Parkinson's Disease in Ventricular Cerebrospinal Fluid

Vawter, Marquis P.; Dillon‐Carter, Ora; Tourtellotte, Wallace W.; Carvey, Paul M.; Freed, William J.

doi:10.1006/exnr.1996.0200

Cited by 142 publications

(88 citation statements)

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“…33 We are not aware of any studies comparing TGF-␤1 concentration in the brain and in the serum; however, studies comparing cerebrospinal fluid (CSF) expression and serum suggest an association between increased CSF TGF-␤1 and reduction in the serum. 34,35 This could be a result of passage of this cytokine from the peripheral circulation to the intrathecal compartment across the blood-brain barrier. 36 We could not see any …”

Section: Discussionmentioning

confidence: 99%

Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke

Slevin

Krupiński

Słowik

et al. 2000

Stroke

216

149

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Background and Purpose —Both vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) are expressed in higher than normal concentrations in the penumbra of patients after ischemic stroke. Because both cytokines are central to the processes of angiogenesis, tissue inflammation, and fibrosis, we performed serial measurements of these cytokines in patients with cerebral infarction and determined their relationship to stroke etiology and volume. Methods —We serially (at days 0, 1, 3, 7, and 14) measured the serum levels of VEGF and active TGF-β1 in 29 patients with acute ischemic stroke. Age-matched healthy subjects (n=26) were used as controls. Results —Expression of VEGF was significantly increased in the majority of patients after acute stroke at each of the time points compared with normal controls. Highest expression occurred at day 7 (588±121 pg/mL; P =0.005), and it remained significantly elevated at 14 days after stroke. Expression of VEGF correlated with infarct volume, clinical disability (Scandinavian Stroke Scale), and peripheral leukocytosis and was significantly higher in patients with atherothrombotic large-vessel disease and ischemic heart disease ( P <0.05 in all cases). In contrast, expression of active TGF-β1 was not significantly different from control patients at any of the measured time points. When the mean concentration of TGF-β1 from each patient (pooled time points) was compared with the control mean, a significant increase was found in only 2 patients, whereas levels decreased in 12 patients ( P <0.05). There was no correlation between circulating active TGF-β1 and VEGF expression, leukocytosis, stroke subtype, or patient disability as assessed by Scandinavian Stroke Scale score. Conclusions —VEGF but not TGF-β1 showed a dramatic increase in serum of stroke patients. Correlation between stroke severity and VEGF concentration suggests it could be involved in the subsequent repair processes resulting in partial recovery after stroke. Correlation between VEGF expression and peripheral leukocytosis suggests that these changes may also reflect the immunologic status of the patient. VEGF may play an important role in the pathophysiology of acute ischemic stroke and could be of value in future treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke

Slevin

Krupiński

Słowik

et al. 2000

Stroke

216

149

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“…Its clinical manifestations result from selective loss of dopaminergic (DA) neurons in the ventral mesencephalon substantia nigra pars compacta (SNpc), with a resulting decrease in striatal dopamine. The critical molecular mediators and mechanisms that elicit death of nigral DA neurons have yet to be identified; but a wealth of studies implicate microglia and inflammatory processes in the pathophysiology of PD (McGeer et al, 1988;Vawter et al, 1996;Hald and Lotharius, 2005;Hirsch et al, 2005), and chronic use of nonsteroidal anti-inflammatory drugs can lower risks for development of PD in humans by 46% (Chen et al, 2003).…”

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.

335

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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“…A major issue in understanding the brain immune surveillance and its pathology in neurodegenerative diseases concerns the delicate balance between pro-and contrainflammatory cytokines secreted by the glial environment. Ex vivo assessment of the cerebrospinal fluid has unveiled a preponderance of pro-inflammatory cytokines like IL-1␤, IL-6, and TNF-␣ in entities such as ParkinsonЈs disease, stroke, or multiple sclerosis (Mogi et al, 1996;Navikas and Link, 1996;Olsson, 1994;Tarkowski et al, 1999;Vawter et al, 1996). These observations led to the assumption that dysregulation of microglia-derived cytokine expression and secretion could be involved in the etiopathogenesis of the aforementioned diseases.…”

Section: Pro-inflammatory Cytokines Andmentioning

confidence: 95%

From theory to therapy: Implications from an in vitro model of ramified microglia

Rosenstiel

Lucius

Deuschl

et al. 2001

Microscopy Res & Technique

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Microglia are the principal immune cells in the central nervous system (CNS), characterized by a highly specific morphology and unusual antigenic phenotype. An increasing number of studies have focused on the role of microglia in the pathogenesis of neurodegenerative diseases. To elucidate the function of microglial cells under several neuropathological conditions, we have studied and established a cell culture model that allows us to cultivate microglial cells in their inactive, resting (ramified) phenotype. In the first part of this work, we describe the interaction of microglia cells with their epithelial (astrocytic) microenvironment. The second part reviews experiments with microglia cell cultures to elucidate underlying signalling pathways and summarizes recent advances of our knowledge in microglial molecular pathways that may ultimately lead to neurodegeneration.

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TGFβ1 and TGFβ2 Concentrations Are Elevated in Parkinson's Disease in Ventricular Cerebrospinal Fluid

Cited by 142 publications

References 0 publications

Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke

Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke

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

From theory to therapy: Implications from an in vitro model of ramified microglia

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