Limits...
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

Western blot analysis of (A) TH and (B) DAT expression 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 TH and DAT were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM (N = 5 for chronic control and N = 8 for chronic MPD). Western blots revealed that there were significant reductions of TH and DAT content in the striatum of aged MPD 6 weeks after chronic treatment when compared with that of the control mice (*P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2874410&req=5

Figure 2: Western blot analysis of (A) TH and (B) DAT expression 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 TH and DAT were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM (N = 5 for chronic control and N = 8 for chronic MPD). Western blots revealed that there were significant reductions of TH and DAT content in the striatum of aged MPD 6 weeks after chronic treatment when compared with that of the control mice (*P < 0.001).

Mentions: It is possible that the functionality of mitochondria may gradually recover in young adult mice after the toxic species of MPTP are dissipated from the brain. Before ruling out the possible association between Parkinson-like neurodegeneration and mitochondrial disorder, we were curious to investigate whether mitochondrial dysfunction may exist and can be demonstrated in aged chronic MPD. Since aged mice are known to be more sensitive to MPTP neurotoxicity (Ricaurte et al., 1987) and also based on our own experience that aged mice will not survive the same chronic MPTP/probenecid regimen as in young adult mice, therefore we treated the aged chronic MPD with a lesser dose of MPTP (15 mg/kg) in the present study. Indeed, the 6- to 10-month-old mice when treated with 10 doses of MPTP (15 mg/kg, s.c.) and probenecid (250 mg/kg, i.p.) over 5 weeks had all survived and they displayed 64.6 and 53.3% loss of DA and DOPAC, respectively 6 weeks after the cessation of treatment (Table 3). Analyses of TH and DAT expression in the striatal tissue further revealed that there were significant losses of TH and DAT contents in the aged chronic MPD 6 weeks after treatment when compared with that of the control animals (Figures 2A,B). These results implicate that this modified chronic MPD treatment in aged mice generates a moderate and sustained loss of dopaminergic transmission and function in the striatum.


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

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

Western blot analysis of (A) TH and (B) DAT expression 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 TH and DAT were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM (N = 5 for chronic control and N = 8 for chronic MPD). Western blots revealed that there were significant reductions of TH and DAT content in the striatum of aged MPD 6 weeks after chronic treatment when compared with that of the control mice (*P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Western blot analysis of (A) TH and (B) DAT expression 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 TH and DAT were expressed as a ratio to that of GAPDH and each data point represents mean ± SEM (N = 5 for chronic control and N = 8 for chronic MPD). Western blots revealed that there were significant reductions of TH and DAT content in the striatum of aged MPD 6 weeks after chronic treatment when compared with that of the control mice (*P < 0.001).
Mentions: It is possible that the functionality of mitochondria may gradually recover in young adult mice after the toxic species of MPTP are dissipated from the brain. Before ruling out the possible association between Parkinson-like neurodegeneration and mitochondrial disorder, we were curious to investigate whether mitochondrial dysfunction may exist and can be demonstrated in aged chronic MPD. Since aged mice are known to be more sensitive to MPTP neurotoxicity (Ricaurte et al., 1987) and also based on our own experience that aged mice will not survive the same chronic MPTP/probenecid regimen as in young adult mice, therefore we treated the aged chronic MPD with a lesser dose of MPTP (15 mg/kg) in the present study. Indeed, the 6- to 10-month-old mice when treated with 10 doses of MPTP (15 mg/kg, s.c.) and probenecid (250 mg/kg, i.p.) over 5 weeks had all survived and they displayed 64.6 and 53.3% loss of DA and DOPAC, respectively 6 weeks after the cessation of treatment (Table 3). Analyses of TH and DAT expression in the striatal tissue further revealed that there were significant losses of TH and DAT contents in the aged chronic MPD 6 weeks after treatment when compared with that of the control animals (Figures 2A,B). These results implicate that this modified chronic MPD treatment in aged mice generates a moderate and sustained loss of dopaminergic transmission and function in the striatum.

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