Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat

Martı́, Marı́a José; Saura, Josep; Burke, Robert E.; Jackson‐Lewis, Vernice; Jiménez, Anna; Bonastre, Mercè; Tolosa, Eduard

doi:10.1016/s0006-8993(02)03694-6

Cited by 62 publications

(46 citation statements)

References 31 publications

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“…18,24) Exposure to 6-OHDA induced DNA damage, mitochondria dysfunction, and apoptotic cell death. 25,26) In agreement with previous studies, our results indicate dose-dependent viability loss (Fig. 1) and essential morphologic forms of apoptosis with caspase 3 activation (Fig.…”

Section: Discussionsupporting

confidence: 93%

Isoliquiritigenin Isolated from LicoriceGlycyrrhiza uralensisPrevents 6-Hydroxydopamine-Induced Apoptosis in Dopaminergic Neurons

Hwang

Chun

2012

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionsupporting

confidence: 93%

Isoliquiritigenin Isolated from LicoriceGlycyrrhiza uralensisPrevents 6-Hydroxydopamine-Induced Apoptosis in Dopaminergic Neurons

Hwang

Chun

2012

Bioscience, Biotechnology, and Biochemistry

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“…This is concordant with published reports in mice and rats, which show that SNc injury is not detectable until 7-10 days after lesion (22), with the bulk of SNc cell loss occurring in the 2nd week (19,21,22). In rats, SNc lesions remain stable for months after injury (18,20).…”

Section: Characterization Of Transgene Expression In Mouse Brains-supporting

confidence: 91%

Manganese Superoxide Dismutase Protects against 6-Hydroxydopamine Injury in Mouse Brains

Callio

Oury

Chu

2005

Journal of Biological Chemistry

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Dopaminergic neurons of the substantia nigra are susceptible to toxin-based insults. Intrastriatal injection of 6-hydroxydopamine results in selective toxicity to these neurons. A mechanistic role for reactive oxygen species is supported by observations that antioxidants confer protection from 6-hydroxydopamine. Although cell culture studies have suggested extracellular or nonmitochondrial mechanisms in 6-hydroxydopamine toxicity, the compartmentalization of oxidative injury mechanisms is incompletely defined in vivo. Transgenic mice overexpressing mitochondrial manganese superoxide dismutase or extracellular superoxide dismutase received unilateral intrastriatal injections of 6-hydroxydopamine. Mice that overexpress manganese superoxide dismutase showed significantly smaller striatal lesions than littermate controls. There were no differences in nonspecific striatal injury associated with contralateral vehicle injection. Manganese superoxide dismutase overexpression also protected against loss of neuronal cell bodies in the substantia nigra. In contrast, mice overexpressing extracellular superoxide dismutase showed no protection from 6-hydroxydopamine toxicity in either brain region. Protection of the nigrostriatal system by overexpression of manganese superoxide dismutase supports a role for mitochondrially derived superoxide in 6-hydroxydopamine toxicity. Mitochondrial oxidative stress appears to be a common mechanism among diverse models of Parkinson disease, whether involving toxins, mutated genes, or cybrid cells containing patient mitochondria. Antioxidant therapies that target this subcellular compartment may prove promising. Reactive oxygen species (ROS)1 have been hypothesized to play a mechanistic role in central nervous system diseases including stroke, seizures, and neurodegeneration. However, administration of a given antioxidant may show beneficial, indifferent, or harmful effects in different model systems. For example, superoxide dismutase (SOD) isoforms can exacerbate brain injuries mediated by nitric oxide or hydrogen peroxide (1, 2) while protecting against other brain injuries (3-5). Extracellular inhibition of oxidative reactions may promote toxicity inside cultured cells by allowing higher levels of unaltered toxin to enter the cell (6). Likewise, individual metal chelators may stimulate, inhibit, or show no effect on catecholamine autoxidation, whereas the combination of SOD and chelators is generally inhibitory (7). Given the growing recognition of ROS as mediators of cellular communication (8, 9), understanding the compartments or sites of ROS generation that contribute to injury will facilitate appropriate targeting of antioxidant therapies.Parkinson disease is a common neurodegenerative disease characterized by disabling movement abnormalities. Although it is known that injury to substantia nigra pars compacta (SNc) neurons of the nigrostriatal projection leads to parkinsonian symptoms, the mechanisms contributing to dysfunction and death of these dopaminergic neurons are incompletely...

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“…25), 6OHDA may model this process. Second, among models of PD associated with SN DA neuron death, intrastriatal 6OHDA has been demonstrated unequivocally to induce apoptosis (26). Third, among PD models, the 6OHDA model is the most destructive, typically resulting in over 80% loss of SN DA neurons.…”

Section: Discussionmentioning

confidence: 98%

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Ries

Henchcliffe²,

Kareva³

et al. 2006

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

156

160

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Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.apoptosis ͉ dopamine ͉ neurotrophic ͉ programmed cell death ͉ substantia nigra

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Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat

Cited by 62 publications

References 31 publications

Isoliquiritigenin Isolated from LicoriceGlycyrrhiza uralensisPrevents 6-Hydroxydopamine-Induced Apoptosis in Dopaminergic Neurons

Isoliquiritigenin Isolated from LicoriceGlycyrrhiza uralensisPrevents 6-Hydroxydopamine-Induced Apoptosis in Dopaminergic Neurons

Manganese Superoxide Dismutase Protects against 6-Hydroxydopamine Injury in Mouse Brains

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

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