Locus ceruleus lesions and eosinophilic inclusions in MPTP‐treated monkeys

Forno, Lysia S.; Langston, J. William; DeLanney, Louis E.; Irwin, Ian; Ricaurte, George A.

doi:10.1002/ana.410200403

Cited by 321 publications

(123 citation statements)

References 25 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…However, a chronic model with implanted osmotic pumps delivering constant small amounts of the toxin would have been a more optimal model to mimic the disease (385). Despite prolonged administration, however, MPTP does not generate Lewy bodies (76), although it has been described in a few cases (386,387). In line with this, intracytoplasmic inclusions were not observed in our model.…”

Section: Mptp Model Of Pdsupporting

confidence: 87%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

Section: Mptp Model Of Pdsupporting

confidence: 87%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

“…One possibility is that basal ganglia function differs between species. However, although it was initially reported that MPTP did not cause LC cell death in nonhuman primates, it has now become clear that typical nonhuman primate MPTP regimens nearly always result in LC cell death and/or loss of NE from terminal fields (28)(29)(30)(31)(32)(33)(34). In contrast, typical MPTP dosing regimens cause profound DA depletion with little effect on LC neurons or NE content in mice (10,(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

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

175

116

View full text Add to dashboard Cite

Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

show abstract

“…This specific and reproducible neurotoxic effect to the nigrostriatal system is a strength of this model. Although intraneuronal inclusions reminiscent of Lewy bodies have been described in MPTP-injected monkeys (Forno et al 1986), in general, this pathological feature is absent in mice. However, it has been claimed that when mice are infused with a chronic low dose of MPTP over a period of 30 d using osmotic minipumps, inclusions immunoreactive for both ubiquitin and a-synuclein can be detected (Fornai et al 2005).…”

Section: K Tieumentioning

confidence: 99%

A Guide to Neurotoxic Animal Models of Parkinson's Disease

Tieu¹

2011

Cold Spring Harbor Perspectives in Medicine

408

299

View full text Add to dashboard Cite

Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway.

show abstract

Locus ceruleus lesions and eosinophilic inclusions in MPTP‐treated monkeys

Cited by 321 publications

References 25 publications

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

A Guide to Neurotoxic Animal Models of Parkinson's Disease

Contact Info

Product

Resources

About