Cellular pathology of Parkinson?s disease: astrocytes, microglia and inflammation

Teismann, Peter; Schulz, Jörg B.

doi:10.1007/s00441-004-0944-0

Cited by 332 publications

(212 citation statements)

References 151 publications

(150 reference statements)

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“…Microglial activation has been found to be an important mechanism by which thrombin could damage dopaminergic neurons [8,10,25]. While the direct contribution of microglia to the pathogenesis of PD has remained a controversial topic, a great deal of research suggests that they do indeed play a role [38]. It is possible here that low dose thrombin at the time of 6-OHDA increases the injury through some level of microglial activation.…”

Section: Discussionmentioning

confidence: 99%

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

Cannon

Hua

Richardson

et al. 2007

Behavioural Brain Research

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Recent results in animal models suggest that thrombin may modulate brain injury in Parkinson's disease (PD). High doses of thrombin (∼20 U) can damage dopaminergic neurons, while we have found that low dose thrombin (1 U), given several days before a brain insult (thrombin preconditioning), is protective in models of PD and stroke. However, the effects of such low levels of thrombin at the time of, or after, exposure to the dopamine neurotoxin 6-hydroxydopamine (6-OHDA) have not been examined and are the focus of this study. In the first set of experiments, rats received co-administration of thrombin (1 U) or saline and 6-OHDA (5 μg) into the medial forebrain bundle. 6-OHDA + thrombin resulted in striking increases in behavioral deficits, compared to 6-OHDA + saline. Similarly, co-administration of an agonist to protease-activated receptor (PAR)-1, a thrombin receptor, also resulted in significantly greater behavioral deficits. In a second set of experiments, thrombin (1 U) or saline was administered 1 or 7 days after 6-OHDA to determine the effects of thrombin after 6-OHDA. Surprisingly, the rats that received saline had strikingly increased behavioral and neurochemical deficits resulting from the 6-OHDA lesion, while delayed thrombin administration prevented this effect. The results indicate that thrombin has differential effects in the

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Section: Discussionmentioning

confidence: 99%

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

Cannon

Hua

Richardson

et al. 2007

Behavioural Brain Research

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“…Activation of both, microglia and astroglia is seen in animal models of PD and they are considered active participants in the nigrostriatal degeneration (Halliday and Stevens, 2011;Mena and Garcia de, 2008;Teismann and Schulz, 2004;Wu et al, 2002). Yet, in the brain parenchyma astrocytes are responsible for creating and maintaining an environment that optimizes neuronal function (Barres, 2008;Episcopo et al, 2013;Hertz and Zielke, 2004;Hirrlinger and Dringen, 2010;Kimelberg, 2010;Volterra and Meldolesi, 2005).…”

Section: Midbrain Astroglia Responsesmentioning

confidence: 99%

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Sikorska

Lanthier

Miller

et al. 2014

Neurobiology of Aging

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Although the support for the use of antioxidants, such as coenzyme Q 10 (CoQ 10 ), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ 10 is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ 10 (Ubisol-Q 10 ) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q 10 was delivered in drinking water. Prophylactic application of Ubisol-Q 10 , started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q 10 group by day 28). Therapeutic application of Ubisol-Q 10 , given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q 10 concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ 10 /kg body weight/day, showing clearly that high doses of CoQ 10 were not required to deliver these effects. Furthermore, the Ubisol-Q 10 treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q 10 was capable of halting the neurodegeneration already in progress;

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“…Our current understanding of the pathogenic mechanisms in PD involves three pathways, protein aggregation (143, 144); impaired protein degradation, i.e., dysfunction of the proteasome and lysosome systems (38,68,69,88); and mitochondrial dysfunction͞ oxidative stress (10,112,143). Other processes, such as inflammation, may also contribute to the death of cells (145,146). These three processes likely overlap and interact (38,143,147).…”

Section: Conclusion Questions and Hypothesesmentioning

confidence: 99%

Lewy bodies

Shults

2006

Proc. Natl. Acad. Sci. U.S.A.

408

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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Cellular pathology of Parkinson?s disease: astrocytes, microglia and inflammation

Cited by 332 publications

References 151 publications

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Lewy bodies

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