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Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson’s disease: comparison of mice strains and dose regimens

Abstract

Heterogenous diseases such as Parkinson’s disease (PD) needs an efficient animal model to enhance understanding of the underlying mechanisms and to develop therapeutics. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin, has been widely used to replicate the pathophysiology of PD in rodents, however, the knowledge about its effects on energy metabolism is limited. Moreover, susceptibility to different dose regimens of MPTP also varies among mice strains. Thus, the present study compares the effect of acute and sub-acute MPTP administration on mitochondrial functions in C57BL/6 and BALB/c mice. In addition, activity of enzymes involved in energy metabolism was also studied along with behavioural alterations. The findings show that acute dose of MPTP in C57BL/6 mice had more profound effect on the activity of electron transport chain complexes. Further, the activity of MAO-B was increased following acute and sub-acute MPTP administration in C57BL/6 mice. However, no significant change was observed in BALB/c mice. Acute MPTP treatment resulted in decreased mitochondrial membrane potential along with increased swelling of mitochondria in C57BL/6 mice. In addition, perturbations were observed in hexokinase, the rate limiting enzyme of glycolysis and pyruvate dehydrogenase, the enzymes that connects glycolysis and TCA cycle. The activity of TCA cycle enzymes; citrate synthase, aconitase, isocitrate dehydrogenase and fumarase were also altered following MPTP intoxication. Furthermore, acute MPTP administration led to drastic reduction in dopamine levels in striatum of C57BL/6 as compared to BALB/c mice. Behavioral tests such as open field, narrow beam walk and footprint analysis revealed severe impairment in locomotor activity in C57BL/6 mice. These results clearly demonstrate that C57BL/6 strain is more vulnerable to MPTP-induced mitochondrial dysfunctions, perturbations in energy metabolism and motor defects as compared to BALB/c strain. Thus, the findings suggest that the dose and strain of mice need to be considered for pre-clinical studies using MPTP-induced model of Parkinson’s disease.

Graphical abstract

Highlights

  • MPTP-induced mitochondrial perturbations were studied in C57BL/6 and BALB/c mice.

  • C57BL/6 mice had higher susceptibility to MPTP in terms of mitochondrial dysfunctions and motor defects.

  • Motor impairments were accompanied by decrease in dopamine levels in C57BL/6 mice following acute MPTP administration.

  • Acute and sub-acute MPTP administration impaired glycolytic and TCA cycle enzymes.

  • The findings suggest acute MPTP administration in C57BL/6 mice is a suitable toxin-induced PD model for pre-clinical studies.

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Data availability

The data that support the findings of this study are available on reasonable request from the corresponding author.

Abbreviations

BSA:

Bovine serum albumin

CS:

Citrate synthase

DA:

Dopamine

DMEM:

Dulbecco’s Modified Eagle’s Medium

ETC:

Electron transport chain

EDTA:

Ethylene diamine tetra-acetic acid

HEPES:

4-(2-Hydroxyethyl)- 1-piperazineethanesulfonic acid

MAO:

Monoamine oxidase

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD:

Parkinson’s Disease

PDHc:

Pyruvate dehydrogenase complex

TCA:

Tri-carboxylic acid

SN:

Substantia nigra

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Acknowledgements

The financial assistance provided by the University Grants Commission (UGC), New Delhi under the Basic Science Research (UGC Ref. No. F.25-1/2014-15(BSR)/7-209/2009[BSR]) is acknowledged. The authors also acknowledge Department of Biotechnology (DBT), Government of India for the financial support (BT/PR17127/NER/95/453/2015).

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AP and RS conceptualized and designed the study. AP and PG conducted experiments and analyzed the data. All authors contributed in drafting and editing the manuscript.

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Correspondence to Rajat Sandhir.

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Pathania, A., Garg, P. & Sandhir, R. Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson’s disease: comparison of mice strains and dose regimens. Metab Brain Dis 36, 2343–2357 (2021). https://doi.org/10.1007/s11011-021-00840-2

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Keywords

  • BALB/c
  • Behaviour
  • C57BL/6
  • Cytochrome c oxidase
  • Dopamine
  • F1–F0 ATPase Synthase
  • Mitochondria
  • MPTP
  • NADH Dehydrogenase
  • Neurotransmitter
  • Parkinson’s disease
  • Succinate Dehydrogenase