Biochemical and Immunocytochemical Changes Induced by Intrastriatal 6-Hydroxydopamine Injection in the Rat Nigrostriatal Dopamine Neuron System: Evidence for Cell Death in the Substantia Nigra

Ichitani, Yukio; Okamura, Hitoshi; Nakahara, Daiichiro; Nagatsu, Ikuko; Ibata, Yasuhiko

doi:10.1006/exnr.1994.1205

Cited by 56 publications

(41 citation statements)

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“…Loss of immunoreactivity for TH, the rate-limiting enzyme for dopamine synthesis, was used to identify injury to SNc neurons and their striatal termini. TH immunoreactivity correlates tightly with other measures of dopaminergic neuron injury (18,20). Intrastriatal injection of 6-OHDA into the right mouse striatum produced a dose-dependent decrease in TH staining, indicating damage to dopaminergic termini (Fig.…”

Section: Characterization Of Transgene Expression In Mouse Brains-mentioning

confidence: 68%

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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Section: Characterization Of Transgene Expression In Mouse Brains-mentioning

confidence: 68%

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

Callio

Oury

Chu

2005

Journal of Biological Chemistry

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“…In adult animals, injection of 6-OHDA into striatum results in the death of dopaminergic neurons (Sauer and Oertel, 1994). In adult animals, however, direct injection of 6-OHDA into SN (Jeon et al, 1995) or injection into striatum (Ichitani et al, 1991(Ichitani et al, , 1994 does not appear to induce apoptotic cell death. Nevertheless, it remains possible that immature dopaminergic neurons respond differently to the toxin than mature neurons do, and they die with an apoptotic morphology.…”

Section: Discussionmentioning

confidence: 99%

“…In the former instance, it is possible, for example, that the apoptotic cell death is attributable to the loss of target-derived support, whereas the nonapoptotic death is attributable to the direct effect of retrogradely transported toxin (Ichitani et al, 1991(Ichitani et al, , 1994Sauer and Oertel, 1994). In the latter instance, it is possible that as the animal matures the morphology changes from an apoptotic to a nonapoptotic form, while the death mechanism remains that of programmed cell death.…”

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confidence: 99%

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

et al. 1997

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Many developing neural systems with peripheral projections depend on their target for trophic support during a critical period of natural cell death. Much less is known about central systems. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development is suggested by the presence of a natural apoptotic cell death event in these neurons that can be augmented by an early developmental axon-sparing striatal injury. To further assess the target dependence of these neurons, we have used the selective neurotoxin 6-hydroxydopamine to lesion their terminals within the striatum during development, while sparing intrinsic striatal target neurons. This lesion results in an induction of apoptotic cell death in phenotypically defined dopaminergic neurons that appears on the third postlesion day and persists until the tenth. This inducibility of cell death is dependent on developmental age: it is most marked before postnatal day (PND) 14. As late as PND42, inducibility is still detectable but much less so. In addition, at day 42 the morphology of cell death changes and becomes nonapoptotic in some cells. We conclude that terminal injury during a critical period of postnatal development, like axon-sparing target injury, induces augmented apoptotic death in mesencephalic dopaminergic neurons. These results suggest that these neurons have a period of target dependence. Regulation of this dependence is likely to influence the mature adult number of dopaminergic neurons.

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“…Statistics and abbreviations as in Table 1 have been well described. 4,14,15 The most salient feature is the decrease in dopaminergic function, including the profound reduction in TH enzyme activity and depletion of DA levels. These observations are consistent with the present results of attenuated striatal dopaminergic function and also comparable to our previous report of the destruction of TH-immunoreactive nerve terminals in 6-OHDAlesioned striatum, 20 suggesting that biochemical changes caused by 6-OHDA neurotoxicity are parallel to those revealed by TH immunocytochemistry.…”

Section: Figmentioning

confidence: 99%

Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned rats

et al. 1998

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Biochemical and Immunocytochemical Changes Induced by Intrastriatal 6-Hydroxydopamine Injection in the Rat Nigrostriatal Dopamine Neuron System: Evidence for Cell Death in the Substantia Nigra

Cited by 56 publications

References 0 publications

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

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

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned rats

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