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Mitochondrial dysfunction in the striatum of aged chronic mouse model of Parkinson's disease.

Patki G, Che Y, Lau YS - Front Aging Neurosci (2009)

Bottom Line: The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam.Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD.Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston Houston, TX, USA.

ABSTRACT
Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (MPD). Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine (DA) deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4) and adenosine 5'-diphosphate-stimulated (state 3) respiration and a fall in adenosine triphosphate level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs.

No MeSH data available.


Related in: MedlinePlus

Protein expression of (A) Mn SOD, (B) Cu–Zn SOD, and (C) cytochrome c in the striatum of aged chronic probenecid control and aged chronic MPD mice. A representative image of western blot protein bands was correspondingly shown above each set of bar graph. The protein contents of Mn SOD, Cu–Zn SOD, and cytochrome c were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM, N = 6 per group of animals. Statistical analyses revealed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c in the striatum of aged chronic MPD 6 weeks after chronic treatment were significantly lower than that of chronic control animals (*P < 0.05).
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Figure 3: Protein expression of (A) Mn SOD, (B) Cu–Zn SOD, and (C) cytochrome c in the striatum of aged chronic probenecid control and aged chronic MPD mice. A representative image of western blot protein bands was correspondingly shown above each set of bar graph. The protein contents of Mn SOD, Cu–Zn SOD, and cytochrome c were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM, N = 6 per group of animals. Statistical analyses revealed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c in the striatum of aged chronic MPD 6 weeks after chronic treatment were significantly lower than that of chronic control animals (*P < 0.05).

Mentions: Interestingly, both the basal (state 4) and ADP-stimulated (state 3) mitochondrial respiration in the striatum of aged chronic MPD mice were significantly impaired when compared to the chronic control animals (Table 4). There was a 50.8 and 41.0% reduction of state 3 and state 4 respiration, respectively 6 weeks after the chronic MPD treatment (Table 4). The mitochondrial ATP level was also decreased by 46.9% (Table 4). These data demonstrate that 6 weeks after chronic MPTP/probenecid treatment in the aged mice, there is a sustained attenuation of mitochondrial respiration and ATP production in the striatum. Western blot analyses of anti-oxidant proteins additionally showed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c were significantly reduced in the striatal mitochondria of the aged chronic MPD 6 weeks after treatment (Figures 3A–C).


Mitochondrial dysfunction in the striatum of aged chronic mouse model of Parkinson's disease.

Patki G, Che Y, Lau YS - Front Aging Neurosci (2009)

Protein expression of (A) Mn SOD, (B) Cu–Zn SOD, and (C) cytochrome c in the striatum of aged chronic probenecid control and aged chronic MPD mice. A representative image of western blot protein bands was correspondingly shown above each set of bar graph. The protein contents of Mn SOD, Cu–Zn SOD, and cytochrome c were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM, N = 6 per group of animals. Statistical analyses revealed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c in the striatum of aged chronic MPD 6 weeks after chronic treatment were significantly lower than that of chronic control animals (*P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874410&req=5

Figure 3: Protein expression of (A) Mn SOD, (B) Cu–Zn SOD, and (C) cytochrome c in the striatum of aged chronic probenecid control and aged chronic MPD mice. A representative image of western blot protein bands was correspondingly shown above each set of bar graph. The protein contents of Mn SOD, Cu–Zn SOD, and cytochrome c were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM, N = 6 per group of animals. Statistical analyses revealed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c in the striatum of aged chronic MPD 6 weeks after chronic treatment were significantly lower than that of chronic control animals (*P < 0.05).
Mentions: Interestingly, both the basal (state 4) and ADP-stimulated (state 3) mitochondrial respiration in the striatum of aged chronic MPD mice were significantly impaired when compared to the chronic control animals (Table 4). There was a 50.8 and 41.0% reduction of state 3 and state 4 respiration, respectively 6 weeks after the chronic MPD treatment (Table 4). The mitochondrial ATP level was also decreased by 46.9% (Table 4). These data demonstrate that 6 weeks after chronic MPTP/probenecid treatment in the aged mice, there is a sustained attenuation of mitochondrial respiration and ATP production in the striatum. Western blot analyses of anti-oxidant proteins additionally showed that the levels of Mn SOD, Cu–Zn SOD, and cytochrome c were significantly reduced in the striatal mitochondria of the aged chronic MPD 6 weeks after treatment (Figures 3A–C).

Bottom Line: The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam.Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD.Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston Houston, TX, USA.

ABSTRACT
Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (MPD). Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine (DA) deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4) and adenosine 5'-diphosphate-stimulated (state 3) respiration and a fall in adenosine triphosphate level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs.

No MeSH data available.


Related in: MedlinePlus