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A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease

View ORCID ProfileVignayanandam Ravindernath Muddapu, Karthik Vijayakumar, Keerthiga Ramakrishnan, View ORCID ProfileV Srinivasa Chakravarthy
doi: https://doi.org/10.1101/2020.04.05.026807
Vignayanandam Ravindernath Muddapu
1Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
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Karthik Vijayakumar
2Department of Biotechnology, Rajalakshmi Engineering College, Chennai 602105, Tamil Nadu, India
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Keerthiga Ramakrishnan
3Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham NG8 1BB, United Kingdom
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V Srinivasa Chakravarthy
1Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
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ABSTRACT

Background Parkinson’s disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking traces the cause of PD neurodegeneration to metabolic deficiency. Due to exceptionally high energy demand, SNc neurons exhibit a higher basal metabolic rate and higher oxygen consumption rate, which results in oxidative stress. Recently, we have suggested that the excitotoxic loss of SNc cells might be due to energy deficiency occurring at different levels of neural hierarchy. Levodopa (LDOPA), a precursor of dopamine, which is used as a symptom-relieving treatment for PD, leads to outcomes that are both positive and negative. Several researchers suggested that LDOPA might be harmful to SNc cells due to oxidative stress. The role of LDOPA in the course of PD pathogenesis is still debatable.

New Method We hypothesize that energy deficiency can lead to LDOPA-induced toxicity (LIT) in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a multiscale computational model of SNc-striatum system, which will help us in understanding the mechanism behind neurodegeneration postulated above and provides insights for developing disease-modifying therapeutics.

Results It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During LDOPA therapy, it was observed that higher LDOPA dosage results in increased loss of somas and terminals in SNc. It was also observed that co-administration of LDOPA and glutathione (antioxidant) evades LDOPA-induced toxicity in SNc neurons.

Comparison with Existing Methods Our proposed multiscale model of SNc-striatum system is first of its kind, where SNc neuron was modelled at biophysical level, and striatal neurons were modelled at spiking level.

Conclusions We show that our proposed model was able to capture LDOPA-induced toxicity in SNc, caused by energy deficiency.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 06, 2020.
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A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease
Vignayanandam Ravindernath Muddapu, Karthik Vijayakumar, Keerthiga Ramakrishnan, V Srinivasa Chakravarthy
bioRxiv 2020.04.05.026807; doi: https://doi.org/10.1101/2020.04.05.026807
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A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease
Vignayanandam Ravindernath Muddapu, Karthik Vijayakumar, Keerthiga Ramakrishnan, V Srinivasa Chakravarthy
bioRxiv 2020.04.05.026807; doi: https://doi.org/10.1101/2020.04.05.026807

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