Abstract
Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in substantia nigra pars compacta (SNc). Although the exact cause of cell death is not clear, the hypothesis that metabolic deficiency is a key factor has been gaining attention in recent years. In the present study, we investigated this hypothesis using a multi-scale computational model of the subsystem of the basal ganglia comprising the subthalamic nucleus (STN), globus pallidus externa (GPe), and SNc. The proposed model is a multiscale model in that interaction among the three nuclei are simulated using more abstract Izhikevich neuron models, while the molecular pathways involved in cell death of SNc neurons are simulated in terms of detailed chemical kinetics. Simulation results obtained from the proposed model showed that energy deficiencies occurring at cellular and network levels could precipitate the excitotoxic loss of SNc neurons in PD. At the subcellular level, the models show how calcium elevation leads to apoptosis of SNc neurons. The therapeutic effects of several neuroprotective interventions are also simulated in the model. From neuroprotective studies, it was clear that glutamate inhibition and apoptotic signal blocker therapies were able to halt the progression of SNc cell loss when compared to other therapeutic interventions, which only slowed down the progression of SNc cell loss.
Highlights
Parkinson’s disease (PD) is predominantly considered as a motor disorder, which affects more than 6 million people around the world (Chaudhuri et al, 2006)
Dopamine released by the substantia nigra pars compacta (SNc) neuron during phasic bursting peaked as high as ∼ 150 × 10−6 mM (Figure 2I), which is in the range of (150 − 400) × 10−6 mM observed experimentally (Schultz, 1998)
We believe that the proposed model provided significant insight into understanding the mechanism behind excitotoxicity in SNc neurons under energy deficiency conditions
Summary
Parkinson’s disease (PD) is predominantly considered as a motor disorder, which affects more than 6 million people around the world (Chaudhuri et al, 2006) It is caused by the loss of dopaminergic neurons in substantia nigra pars compacta (SNc) situated in the midbrain region (Fu et al, 2018). The cardinal symptoms of PD, such as tremor, rigidity, bradykinesia, and postural instability (Goldman and Postuma, 2014) are thought to be considered as the first sign of PD pathogenesis Other symptoms such as anosmia (loss of smell) (Omori and Okutani, 2020), constipation (Lubomski et al, 2020), sleep disorders ( rapid eye movement behavior sleep disorder) (Postuma et al, 2019), and depression (Bayram et al, 2020) emerge well before motor impairments. With the help of a computational model, Muddapu et al (2019) have recently suggested that the excitotoxic loss of SNc cells might be due to energy deficiencies occurring at different levels in the neural hierarchy
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