Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice

Battaglia, G.; Busceti, Carla L.; Cuomo, Laura; Giorgi, Filippo Sean; Orzi, Francesco; Blasi, Antonio De; Nicoletti, Ferdinando; Ruggieri, Stefano; Fornai, Francesco

doi:10.1016/s0028-3908(01)00178-2

Cited by 26 publications

(15 citation statements)

References 20 publications

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“…27) or apomorphine (5 mg͞kg daily delivered s.c. with osmotic Alzet minipumps; n ϭ 5; ref. 28). In additional sets of mice, we measured MPTP and MPP ϩ concentrations as described (29), surgically removed pumps and striatum after 1-28 days of continuous MPTP infusions, and examined proteasome activities (16) (see Supporting Text for a detailed description).…”

Section: Methodsmentioning

confidence: 99%

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Fornai

Schlüter

Lenzi

et al. 2005

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

492

397

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In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and ␣-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking ␣-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an ␣-synucleindependent manner.neurodegeneration ͉ mitochondria ͉ neuronal inclusions ͉ Lewy bodies

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Section: Methodsmentioning

confidence: 99%

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Fornai

Schlüter

Lenzi

et al. 2005

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

492

397

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“…However, apomorphine may also play a role in preventing or slowing the rate of neurodegeneration associated with PD by scavenging iron and preventing dopamine-induced hydroxyl radical formation (41,42). Accordingly, we have observed antimutagenic and antioxidant activities of apomorphine against t-BOOH and H 2 O 2 on oxidative stress-sensitive strains such as the WP2-derivatives E. coli and TA102 S. typhimurium, and S. cerevisiae lacking antioxidant defenses (25).…”

Section: Brain Dna Damagementioning

confidence: 79%

“…Apomorphine was found to be a potent hydroxyl radical scavenger in an experimental model involving iron and dopamine perfusion in the rat striatum (42). Continuous subcutaneous infusion of apomorphine rescues nigrostriatal dopaminergic neurons from toxicity induced by MPTP in mice (41). The neuroprotective effect of apomorphine appears to be based on its antioxidant and free radical scavenging properties and does not seem to be related to its dopamine agonist activity.…”

Section: Neuroprotectionmentioning

confidence: 99%

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Picada

Roesler

Henriques

2005

Braz J Med Biol Res

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Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/ microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites. Correspondence

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“…76 Treatment with dopamine agonists in experimental models of PD showed prevention of dopaminergic neuronal death, 77 and it was believed that the causes could be due to its antioxidant properties, 78 to presynaptic autoreceptor stimulation that decrease dopamine release, or inhibition of excitotoxicity by decreasing glutamatergic hyperactivity of the subthalamic nucleus. 84 These studies were conducted in different animal models, such as: 6-OHDA, 85 methamphetamine 86 and MPTP models. 79,80 It is currently accepted that the neuroprotective effects are not only due to their action on dopamine receptors, but also to Apomorphine Is a potent agonist of the D1 and D2 dopamine receptors, which reduces or neutralizes both free radicals and their derivative production.…”

Section: Dopamine Agonistsmentioning

confidence: 99%

Neuroprotective Role of Dopamine Agonists

Herrero

Pagonabarraga²,

Linazasoro³

2011

The Neurologist

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Parkinson disease is a progressive neurodegenerative disease that affects, among other neurotransmitter systems, the nigrostriatal dopaminergic projection. Palliative treatment with levodopa and/or dopamine agonists improves motor symptoms even though patients continue to get clinically worse by the neurodegenerative process that continues to act as the major factor of physiological aging. Studies (in vitro and in vivo) with experimental models have shown that dopamine agonists have neuroprotective effects, directly or indirectly mediated by their ability to stabilize mitochondria, antioxidant effects, synthesis of growth factors, stabilization of the ubiquitin-proteasome system, activation of autophagy, antiapoptotic induction of Bcl2 family, or enhancement of neurogenesis (proliferation and migration) in the subventricular zone. Clinical studies have not completely confirmed these effects. Analysis in better characterized groups of patients with similar clinical symptoms, identical treatments, and the same evolution time are required. Technological advances which enable the learning of the etiology and the pathogenesis (genetic and environmental) of the disease, together with clinical assessment methods, bring hope to the development of new molecules in the symptomatic treatment of Parkinson disease. These molecules must display neuroprotective potential (prophylactic and/or therapeutic) which must be able to maintain the brain's physiological function and to modify or slow the natural course of the disease.

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Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice

Cited by 26 publications

References 20 publications

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Neuroprotective Role of Dopamine Agonists

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