"... A
couple of the proposed mechanisms, however, show
potential for the
development of a novel line of PD (Parkinson's disease) therapeutics. One of these
mechanisms is the peculiar metabolic vulnerability of SNc (Substantia Nigra pars compacta) cells
compared to other dopaminergic clusters; the other is the SubThalamic
Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter
hypothesis computationally, we developed a spiking neuron
network-model of SNc-STN-GPe system. In the model, prolonged
stimulation of SNc cells by an overactive STN leads to an increase in
‘stress’ variable; when the stress in a SNc neuron exceeds a stress
threshold, the neuron dies. The model shows that the interaction
between SNc and STN involves a positive-feedback due to which, an
initial loss of SNc cells that crosses a threshold causes a
runaway-effect, leading to an inexorable loss of SNc cells, strongly
resembling the process of neurodegeneration. The model further
suggests a link between the two aforementioned mechanisms of SNc cell
loss. Our simulation results show that the excitotoxic cause of SNc
cell loss might initiate by weak-excitotoxicity mediated by energy
deficit, followed by strong-excitotoxicity, mediated by a disinhibited
STN. A variety of conventional therapies were simulated to test their
efficacy in slowing down SNc cell loss. Among them, glutamate
inhibition, dopamine restoration, subthalamotomy and deep brain
stimulation showed superior neuroprotective-effects in the proposed
model."
Reference:
1 .
Muddapu VR, Mandali A, Chakravarthy VS, Ramaswamy S (2019) A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity. Front Neural Circuits 13:11 [PubMed]
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