The influence of the subthalamic nucleus upon the damage to the dopamine system following lesions of globus pallidus in rats

Wright, Angela; Arbuthnott, G.W.

doi:10.1111/j.1460-9568.2007.05706.x

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…The only conclusion that can be reached is that these delayed changes most likely reflect reactive neurochemical and/or anatomical adjustments that occur in the basal ganglia following the primary insult produced by Mn. This is consistent with the findings that selective injury to the globus pallidus, by as yet an undefined mechanism, can subsequently lead to significant reduction of the number of dopaminergic neurons in the substantia nigra (Wright et al 2004;Wright and Arbuthnott 2007).…”

Section: Symptoms Of Manganism and The Relationship To Parkinsonismsupporting

confidence: 90%

Are There Common Biochemical and Molecular Mechanisms Controlling Manganism and Parkisonism

Roth

2009

Neuromol Med

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Over the past several decades there has been considerable progress in our basic knowledge as to the mechanisms and factors regulating Mn toxicity. The disorder known as manganism is associated with the preferential accumulation of Mn in the globus pallidus of the basal ganglia which is generally considered to be the major and initial site of injury. Because the area of the CNS comprising the basal ganglia is very complex and dependent on the precise function and balance of several neurotransmitters, it is not surprising that symptoms of manganism often overlap with that of Parkinson's disease. The fact that neurological symptoms and onset of Mn toxicity are quite broad and can vary unpredictably probably reflects specific genetic variance of the physiological and biochemical makeup within the basal ganglia in any individual. Differences in response to Mn overexposure are, thus, likely due to underlying genetic variability which ultimately presents in deviations in both susceptibility as well as the characteristics of the neurological lesions and symptoms expressed. Although chronic exposure to Mn is not the initial causative agent provoking Parkinsonism, there is evidence suggesting that persistent exposure can predispose an individual to acquire dystonic movements associated with Parkinson's disease. As noted in this review, there appears to be common threads between the two disorders, as mutations in the genes, parkin and ATP13A2, associated with early onset of Parkinsonism, may also predispose an individual to develop Mn toxicity. Mutations in both genes appear to effect transport of Mn into the cell. These genetic difference coupled with additional environmental or nutritional factors must also be considered as contributing to the severity and onset of manganism.

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Section: Symptoms Of Manganism and The Relationship To Parkinsonismsupporting

confidence: 90%

Are There Common Biochemical and Molecular Mechanisms Controlling Manganism and Parkisonism

Roth

2009

Neuromol Med

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“…The threshold-like behavior of SNc cell loss and STN synchrony might be facilitated by the inhibitory drive from GPe to STN as result of the proliferation of GPe-STN synapses (Fan et al, 2012) which also acts as a presymptomatic compensatory mechanism. It was also reported that lesioning of GPe caused progressive SNc cell loss by increasing STN activity (Wright et al, 2002) and lesioning of STN proven to be neuroprotective (Wright and Arbuthnott, 2007).…”

Section: Excitotoxicity Modelmentioning

confidence: 98%

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2018

Preprint

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Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). A full understanding of the underlying pathogenesis of this cell loss is unavailable, though a number of mechanisms have been indicated in the literature. A couple of these mechanisms, however, show potential for the development of radical and promising PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells by virtue of their excessive energy demands; the other is the excitotoxicity caused by excessive glutamate release onto SNc by an overactive Subthalamic Nucleus (STN). To investigate the latter hypothesis computationally, we developed a spiking neuron network model of the SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in a '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 that leads to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned PD mechanisms: metabolic vulnerability and glutamate excitotoxicity. Our simulation results show that the excitotoxic cause of SNc cell loss in PD might be initiated by weak excitotoxicity mediated by energy deficit, followed by strong excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies are simulated in the model to test their efficacy in slowing down or arresting SNc cell loss. Among the current therapeutics,

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“…Nevertheless, further support for STN‐mediated glutamate excitotoxicity is given by the observation that lesioning the GPe in the rat also leads to some loss of dopaminergic cells in the SNc . This neurodegenerative effect could be prevented by prior lesioning of the STN, suggesting that it was likely mediated by increased STN activity because of loss of GABA‐ergic tone from the GPe . More recently, partial subthalamotomy was shown to improve cell survival following dopaminergic cell transplantation in 6‐OHDA‐lesioned rats, and the neuroprotective effect of subthalamotomy was confirmed in MPTP‐treated monkeys .…”

Section: The Subthalamic Nucleus As a Target To Halt Neurodegeneratiomentioning

confidence: 99%

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

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The influence of the subthalamic nucleus upon the damage to the dopamine system following lesions of globus pallidus in rats

Cited by 10 publications

References 36 publications

Are There Common Biochemical and Molecular Mechanisms Controlling Manganism and Parkisonism

Are There Common Biochemical and Molecular Mechanisms Controlling Manganism and Parkisonism

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

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