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

Abstract

BackgroundParkinsons 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 MethodWe 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. ResultsIt 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 MethodsOur 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. ConclusionsWe show that our proposed model was able to capture LDOPA-induced toxicity in SNc, caused by energy deficiency.