Influence of intranasal exposure of MPTP in multiple doses on liver functions and transition from non-motor to motor symptoms in a rat PD model

Abstract

Besides the effects on the striatum, the impairment of visceral organs including liver functions has been reported in Parkinson’s disease (PD) patients. However, it is yet unclear if liver functions are affected in the early stage of the disease before the motor phase has appeared. The aim of our present study was thus to assess the effect of intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in different doses on striatum and liver functions. Deterioration of non-motor activities appeared on single exposure to MPTP along with rise in striatum oxidative stress and decline in antioxidant levels. Decreases in dopamine, noradrenaline, and GABA and increase in serotonin were detected in striatum. Motor coordination was impaired with a single dose of MPTP, and with repeated MPTP exposure, there was further significant impairment. Locomotor activity was affected from second exposure of MPTP, and the impairment increased with third MPTP exposure. Impairment of liver function through increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels was observed after first MPTP insult, and it worsened with second and third administrations. First administration of MPTP triggered systemic inflammation showing significant increase in inflammatory markers in the liver. Our data shows for the first time that an intranasal route of entry of MPTP affects liver from the non-motor phase of PD itself, occurring concomitantly with the reduction of striatal dopamine. It also suggests that a single dose is not enough to bring about progression of the disease from non-motor to locomotor deficiency, and a repeated dose is needed to establish the motor severity phase in the rat intranasal MPTP model.

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Acknowledgements

We thank National Institute of Mental Health and Neurosciences and Al-Ameen College of Pharmacy for providing the basic infrastructure for conducting the study. We are grateful to Prof. Ramesh Bhonde for his valuable comments and Mr. A. Datta for his assistance in statistical analysis.

Authors’ contribution statement

Conceived and designed study—ID; execution and analysis of experiments—MSR, ID, AK, KG and RR; paper writing—ID; critical analysis and review of paper—ID and RR. All authors read and approved the manuscript.

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Correspondence to Indrani Datta.

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The ethical clearance for conducting the experiment was obtained from the Institutional animal ethical committee of Al-Ameen College of Pharmacy, Bengaluru under approval no.: AACP/IAEC/Dec2016/01. The laboratory animals were used in accordance with the ‘Guide for the Care and Use of Experimental Animals’ approved by the CPCSEA.

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Supplementary figure 1
figure7

– (A) Dopamine estimation of MPTP group 1 rats versus control group at 7 days and 42 days post MPTP administration. (B&C) Olfactory function and motor co-ordination of MPTP group 1 rats and control rats till 42 days post MPTP administration of MPTP. Values are represented as mean ± SEM. **(P< 0.001) vs control. (PNG 536 kb)

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Datta, I., Mekha, S.R., Kaushal, A. et al. Influence of intranasal exposure of MPTP in multiple doses on liver functions and transition from non-motor to motor symptoms in a rat PD model. Naunyn-Schmiedeberg's Arch Pharmacol 393, 147–165 (2020). https://doi.org/10.1007/s00210-019-01715-1

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Keywords

  • Alanine aminotransferase
  • MPTP model
  • Parkinson’s disease
  • Olfactory discrimination
  • Non-motor symptoms
  • Intranasal multiple doses of MPTP
  • Liver function
  • Aspartate-aminotransferase
  • Alanine aminotransferase
  • Oxidants and antioxidants in striatum
  • Neurotransmitter levels in striatum
  • Inflammatory marker expression in liver
  • Chronic PD rat model