Limits...
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.

Show MeSH

Related in: MedlinePlus

Behavioral tests of rotenone-exposed rats.Rotenone exposure was carried out as described in Figure 2. Each rat was placed in a round bucket after apomorphine administration and the movement was video-taped for 30 min. Data were analyzed for the four groups; Ctl (n = 3), Ctl+Rot (n = 14), NDI1 (n = 5) and NDI1+Rot (n = 20). n = number of animals. A: Speed of movement of rats was calculated as the number of full turns per minute. B: The number of rats exhibiting fully lateralized turning in either direction was counted. Histograms represent percentage of animals turning only in one direction. (*: p<0.05; **: p<0.01). All values are presented with standard deviation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2175531&req=5

pone-0001433-g005: Behavioral tests of rotenone-exposed rats.Rotenone exposure was carried out as described in Figure 2. Each rat was placed in a round bucket after apomorphine administration and the movement was video-taped for 30 min. Data were analyzed for the four groups; Ctl (n = 3), Ctl+Rot (n = 14), NDI1 (n = 5) and NDI1+Rot (n = 20). n = number of animals. A: Speed of movement of rats was calculated as the number of full turns per minute. B: The number of rats exhibiting fully lateralized turning in either direction was counted. Histograms represent percentage of animals turning only in one direction. (*: p<0.05; **: p<0.01). All values are presented with standard deviation.

Mentions: In our rotenone model, the rats were seemingly active in movement throughout the period of the experiments. We measured the speed of movement of each animal by counting the number of full turns per minute after an apomorphine injection. The rotenone treatment slowed down the animals only slightly but with a statistically significant difference (Figure 5A). A similar slowdown was observed in the animals expressing the Ndi1 protein. It should be noted that we have deliberately chosen a unilateral delivery of the NDI1 gene to achieve unequivocal assessment of the consequences of the target gene expression by comparing the two sides in the same animal. The impact on the overall movement may be rather insignificant. However, this unilateral treatment made it possible to carry out behavioral tests involving turning preferences. A difference in the integrity between the right and the left side of the dopaminergic pathways should lead to an asymmetric behavior. Individual animals placed in a container were monitored for their lateralization after an apomorphine injection (Movie S2). Because the direction of rotation induced by apomorphine seems to be dependent on multiple factors, we decided to count the number of animals exhibiting 100% lateralized rotation irrespective of the direction (for review see [33]). As illustrated in Figure 5B, in the groups of rats that were not exposed to rotenone, a small difference was noticed between the NDI1 group and the non-NDI1 control group. However, this difference was not statistically significant (p = 0.242, student T-test). In the animals bearing the Ndi1 protein in the SN, rotenone boosted the lateralized turning significantly. The preferential turning of the NDI1 group of rats completely agrees with the histochemical and biochemical analyses described above.


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)

Behavioral tests of rotenone-exposed rats.Rotenone exposure was carried out as described in Figure 2. Each rat was placed in a round bucket after apomorphine administration and the movement was video-taped for 30 min. Data were analyzed for the four groups; Ctl (n = 3), Ctl+Rot (n = 14), NDI1 (n = 5) and NDI1+Rot (n = 20). n = number of animals. A: Speed of movement of rats was calculated as the number of full turns per minute. B: The number of rats exhibiting fully lateralized turning in either direction was counted. Histograms represent percentage of animals turning only in one direction. (*: p<0.05; **: p<0.01). All values are presented with standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001433-g005: Behavioral tests of rotenone-exposed rats.Rotenone exposure was carried out as described in Figure 2. Each rat was placed in a round bucket after apomorphine administration and the movement was video-taped for 30 min. Data were analyzed for the four groups; Ctl (n = 3), Ctl+Rot (n = 14), NDI1 (n = 5) and NDI1+Rot (n = 20). n = number of animals. A: Speed of movement of rats was calculated as the number of full turns per minute. B: The number of rats exhibiting fully lateralized turning in either direction was counted. Histograms represent percentage of animals turning only in one direction. (*: p<0.05; **: p<0.01). All values are presented with standard deviation.
Mentions: In our rotenone model, the rats were seemingly active in movement throughout the period of the experiments. We measured the speed of movement of each animal by counting the number of full turns per minute after an apomorphine injection. The rotenone treatment slowed down the animals only slightly but with a statistically significant difference (Figure 5A). A similar slowdown was observed in the animals expressing the Ndi1 protein. It should be noted that we have deliberately chosen a unilateral delivery of the NDI1 gene to achieve unequivocal assessment of the consequences of the target gene expression by comparing the two sides in the same animal. The impact on the overall movement may be rather insignificant. However, this unilateral treatment made it possible to carry out behavioral tests involving turning preferences. A difference in the integrity between the right and the left side of the dopaminergic pathways should lead to an asymmetric behavior. Individual animals placed in a container were monitored for their lateralization after an apomorphine injection (Movie S2). Because the direction of rotation induced by apomorphine seems to be dependent on multiple factors, we decided to count the number of animals exhibiting 100% lateralized rotation irrespective of the direction (for review see [33]). As illustrated in Figure 5B, in the groups of rats that were not exposed to rotenone, a small difference was noticed between the NDI1 group and the non-NDI1 control group. However, this difference was not statistically significant (p = 0.242, student T-test). In the animals bearing the Ndi1 protein in the SN, rotenone boosted the lateralized turning significantly. The preferential turning of the NDI1 group of rats completely agrees with the histochemical and biochemical analyses described above.

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