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Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease.

Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T - PLoS ONE (2008)

Bottom Line: It is widely recognized that mitochondrial dysfunction, most notably defects in the NADH-quinone oxidoreductase (complex I), is closely related to the etiology of sporadic Parkinson's disease (PD).A single, unilateral injection of recombinant adeno-associated virus carrying the NDI1 gene into the vicinity of the substantia nigra resulted in expression of the Ndi1 protein in the entire substantia nigra of that side.The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
It is widely recognized that mitochondrial dysfunction, most notably defects in the NADH-quinone oxidoreductase (complex I), is closely related to the etiology of sporadic Parkinson's disease (PD). In fact, rotenone, a complex I inhibitor, has been used for establishing PD models both in vitro and in vivo. A rat model with chronic rotenone exposure seems to reproduce pathophysiological conditions of PD more closely than acute mouse models as manifested by neuronal cell death in the substantia nigra and Lewy body-like cytosolic aggregations. Using the rotenone rat model, we investigated the protective effects of alternative NADH dehydrogenase (Ndi1) which we previously demonstrated to act as a replacement for complex I both in vitro and in vivo. A single, unilateral injection of recombinant adeno-associated virus carrying the NDI1 gene into the vicinity of the substantia nigra resulted in expression of the Ndi1 protein in the entire substantia nigra of that side. It was clear that the introduction of the Ndi1 protein in the substantia nigra rendered resistance to the deleterious effects caused by rotenone exposure as assessed by the levels of tyrosine hydroxylase and dopamine. The presence of the Ndi1 protein also prevented cell death and oxidative damage to DNA in dopaminergic neurons observed in rotenone-treated rats. Unilateral protection also led to uni-directional rotation of the rotenone-exposed rats in the behavioral test. The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD.

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Related in: MedlinePlus

Reduction of striatal dopamine by rotenone exposure and its retention by expression of the Ndi1 protein.Procedures for the NDI1 gene injection and rotenone exposure were the same as those described in Figure 2. The striatal portions of unfixed brains were dissected and homogenized. Samples were analyzed for dopamine contents on an HPLC system coupled with an electrochemical detector. The dopamine contents were determined for the left and right hemisphere from the four groups, Ctl (n = 3), Ctl+Rot (n = 8), NDI1 (n = 3) and NDI1+Rot (n = 11). n = number of animals. All values are presented with standard deviation.
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pone-0001433-g004: Reduction of striatal dopamine by rotenone exposure and its retention by expression of the Ndi1 protein.Procedures for the NDI1 gene injection and rotenone exposure were the same as those described in Figure 2. The striatal portions of unfixed brains were dissected and homogenized. Samples were analyzed for dopamine contents on an HPLC system coupled with an electrochemical detector. The dopamine contents were determined for the left and right hemisphere from the four groups, Ctl (n = 3), Ctl+Rot (n = 8), NDI1 (n = 3) and NDI1+Rot (n = 11). n = number of animals. All values are presented with standard deviation.

Mentions: A decrease in dopamine content is associated with PD symptoms and measurement of dopamine is commonly used for assessment of neurodegeneration. In our rat model, the dopamine level in the striatum of animals exposed to rotenone was decreased by 45% of the control group (Figure 4). In the group that received the NDI1 gene in the SN unilaterally, the striatum contralateral to the SN of the injection side lost dopamine to about the same extent as the rotenone group without the NDI1 gene. The ipsilateral striatum, however, retained the same concentration of dopamine as the non-rotenone group. These results demonstrate that the Ndi1 protein expression in the SN protected the nigrostriatal pathway in the rotenone-administered rats.


Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease.

Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T - PLoS ONE (2008)

Reduction of striatal dopamine by rotenone exposure and its retention by expression of the Ndi1 protein.Procedures for the NDI1 gene injection and rotenone exposure were the same as those described in Figure 2. The striatal portions of unfixed brains were dissected and homogenized. Samples were analyzed for dopamine contents on an HPLC system coupled with an electrochemical detector. The dopamine contents were determined for the left and right hemisphere from the four groups, Ctl (n = 3), Ctl+Rot (n = 8), NDI1 (n = 3) and NDI1+Rot (n = 11). n = number of animals. All values are presented with standard deviation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2175531&req=5

pone-0001433-g004: Reduction of striatal dopamine by rotenone exposure and its retention by expression of the Ndi1 protein.Procedures for the NDI1 gene injection and rotenone exposure were the same as those described in Figure 2. The striatal portions of unfixed brains were dissected and homogenized. Samples were analyzed for dopamine contents on an HPLC system coupled with an electrochemical detector. The dopamine contents were determined for the left and right hemisphere from the four groups, Ctl (n = 3), Ctl+Rot (n = 8), NDI1 (n = 3) and NDI1+Rot (n = 11). n = number of animals. All values are presented with standard deviation.
Mentions: A decrease in dopamine content is associated with PD symptoms and measurement of dopamine is commonly used for assessment of neurodegeneration. In our rat model, the dopamine level in the striatum of animals exposed to rotenone was decreased by 45% of the control group (Figure 4). In the group that received the NDI1 gene in the SN unilaterally, the striatum contralateral to the SN of the injection side lost dopamine to about the same extent as the rotenone group without the NDI1 gene. The ipsilateral striatum, however, retained the same concentration of dopamine as the non-rotenone group. These results demonstrate that the Ndi1 protein expression in the SN protected the nigrostriatal pathway in the rotenone-administered rats.

Bottom Line: It is widely recognized that mitochondrial dysfunction, most notably defects in the NADH-quinone oxidoreductase (complex I), is closely related to the etiology of sporadic Parkinson's disease (PD).A single, unilateral injection of recombinant adeno-associated virus carrying the NDI1 gene into the vicinity of the substantia nigra resulted in expression of the Ndi1 protein in the entire substantia nigra of that side.The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
It is widely recognized that mitochondrial dysfunction, most notably defects in the NADH-quinone oxidoreductase (complex I), is closely related to the etiology of sporadic Parkinson's disease (PD). In fact, rotenone, a complex I inhibitor, has been used for establishing PD models both in vitro and in vivo. A rat model with chronic rotenone exposure seems to reproduce pathophysiological conditions of PD more closely than acute mouse models as manifested by neuronal cell death in the substantia nigra and Lewy body-like cytosolic aggregations. Using the rotenone rat model, we investigated the protective effects of alternative NADH dehydrogenase (Ndi1) which we previously demonstrated to act as a replacement for complex I both in vitro and in vivo. A single, unilateral injection of recombinant adeno-associated virus carrying the NDI1 gene into the vicinity of the substantia nigra resulted in expression of the Ndi1 protein in the entire substantia nigra of that side. It was clear that the introduction of the Ndi1 protein in the substantia nigra rendered resistance to the deleterious effects caused by rotenone exposure as assessed by the levels of tyrosine hydroxylase and dopamine. The presence of the Ndi1 protein also prevented cell death and oxidative damage to DNA in dopaminergic neurons observed in rotenone-treated rats. Unilateral protection also led to uni-directional rotation of the rotenone-exposed rats in the behavioral test. The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD.

Show MeSH
Related in: MedlinePlus