Molecular Markers of Dopamine Transport in Nigrostriatal Dopaminergic Neurons as an Index of Neurodegeneration and Neuroplasticity

Mingazov, E. R.; Ugryumov, M. V.

doi:10.1134/s181971241901015x

Cited by 2 publications

(2 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The impaired DA metabolism causes oxidative stress (ROS), leading to PD pathogenesis (Masato et al, 2019 ). It was reported that abnormal activity of vesicular monoamine transporter 2 (VMAT2) leads to reduced vesicular DA storage and increased cytoplasmic DA, which results in oxidative stress-induced degeneration of cell bodies (soma) and terminals (Kariya et al, 2005 ; Caudle et al, 2007 ; Pifl et al, 2014 ; Mingazov and Ugryumov, 2019 ). It was reported that glutathione (GSH) administration improves PD symptoms, but the underlying mechanism is unclear (Zeevalk et al, 2008 ; Hauser et al, 2009 ; Mischley et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

Muddapu

Vijayakumar²,

Ramakrishnan³

et al. 2022

Front. Neurosci.

View full text Add to dashboard Cite

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 has traced the cause of PD neurodegeneration to metabolic deficiency. Levodopa (L-DOPA), a precursor of dopamine, used as a symptom-relieving treatment for PD, leads to positive and negative outcomes. Several researchers inferred that L-DOPA might be harmful to SNc cells due to oxidative stress. The role of L-DOPA in the course of the PD pathogenesis is still debatable. We hypothesize that energy deficiency can lead to L-DOPA-induced toxicity in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a systems-level computational model of SNc-striatum, which will help us understand the mechanism behind neurodegeneration postulated above and provide insights into developing disease-modifying therapeutics. It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During L-DOPA therapy, it was observed that higher L-DOPA dosage results in increased loss of terminals in SNc. It was also observed that co-administration of L-DOPA and glutathione (antioxidant) evades L-DOPA-induced toxicity in SNc neurons. Our proposed model of the SNc-striatum system is the first of its kind, where SNc neurons were modeled at a biophysical level, and striatal neurons were modeled at a spiking level. We show that our proposed model was able to capture L-DOPA-induced toxicity in SNc, caused by energy deficiency.

show abstract

Section: Methodsmentioning

confidence: 99%

A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

Muddapu

Vijayakumar²,

Ramakrishnan³

et al. 2022

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The impaired DA metabolism causes oxidative stress (ROS), which in turn leads to PD pathogenesis (Masato et al, 2019). It was reported that abnormal activity of vesicular monoamine transporter 2 (VMAT2) leads to reduced vesicular DA storage and increased cytoplasmic DA which results in oxidative stress-induced degeneration of cell bodies (soma) and terminals (Caudle et al, 2007;Kariya et al, 2005;Mingazov and Ugryumov, 2019;Pifl et al, 2014). It was reported that the glutathione (GSH) administration results in the improvement of PD symptoms, but the underlying mechanism is not clear (Hauser et al, 2009;Mischley et al, 2017;Zeevalk et al, 2008).…”

Section: Glutathione Therapymentioning

confidence: 99%

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

Vijayakumar²,

Ramakrishnan

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Molecular Markers of Dopamine Transport in Nigrostriatal Dopaminergic Neurons as an Index of Neurodegeneration and Neuroplasticity

Cited by 2 publications

References 29 publications

A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

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

Contact Info

Product

Resources

About