The Noradrenergic System in Parkinson’s Disease

Paredes-Rodriguez, Elena; Vegas-Suárez, Sergio; Morera-Herreras, Teresa; Deurwaerdère, Philippe De; Miguélez, Cristina

doi:10.3389/fphar.2020.00435

Cited by 91 publications

(69 citation statements)

References 207 publications

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“…As mentioned previously, noradrenergic mechanisms are involved in the non-motor symptoms observed in PD patients. Idazoxan, a presynaptic alpha2-adrenergic antagonist, enhances NA release, increasing the noradrenergic activity that modulates L-DOPA effects (for a review, see [ 93 ]). Recently, atomoxetine, a NA transporter blocker, has been shown to increase the standing blood pressure and to reduce OH symptoms when compared with placebo in patients with neurogenic OH [ 94 ].…”

Section: Interaction Between Small Heat Shock Protein 27 and α-Synmentioning

confidence: 99%

Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

Navarro‐Zaragoza

Cuenca‐Bermejo

Almela

et al. 2021

IJMS

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Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaperoning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson’s disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dysfunction is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement. However, certain non-motor symptoms with a great impact on quality of life do not respond to dopaminergic drugs; therefore, the development and testing of new treatments for non-motor symptoms of PD remain a priority. Since small HSP27 was shown to prevent α-synuclein aggregation and cytotoxicity, this protein might constitute a suitable target to prevent or delay the motor and non-motor symptoms of PD. In the first part of our review, we focus on the cardiovascular dysregulation observed in PD patients. In the second part, we present data on the possible role of HSP27 in preventing the accumulation of amyloid fibrils and aggregated forms of α-synuclein. We also include our own studies, highlighting the possible protective cardiac effects induced by L-DOPA treatment through the enhancement of HSP27 levels and activity.

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Section: Interaction Between Small Heat Shock Protein 27 and α-Synmentioning

confidence: 99%

Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

Navarro‐Zaragoza

Cuenca‐Bermejo

Almela

et al. 2021

IJMS

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“…Lack of DA causes movement control alteration, leading to typical motor symptoms, such as resting tremor or stiffness. Beside for the SNc and the dopaminergic system, other neurotransmission systems can be affected by α-synuclein (α-syn) deposition, including glutamatergic, noradrenergic, serotoninergic, cholinergic, and histaminergic neurons [4]. In fact, the first brain area affected by α-syn deposition appears in the anterior olfactory structures and the dorsal motor nucleus of the vagus nerve, which comprises stage 1 according to Braak theory; afterwards the raphe system and the locus coeruleus can suffer of α-syn deposition (stage 2) [5].…”

Section: Parkinson's Disease Outlinementioning

confidence: 99%

“…The progression described by Braak shows that noradrenergic and serotoninergic systems are also disturbed in PD. Additionally, specific clinical signs can be explained by noradrenergic dysfunction, which can be significant and anticipate onset of motor symptoms [4]. It is mandatory to keep in mind that the loss of DA in the nigrostriatal pathway is secondary to the axonal degeneration caused by homeostatic disturbances in the SNc [6].…”

Section: Parkinson's Disease Outlinementioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

et al. 2020

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Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.

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“…Both pupillary response and activation of noradrenergic neurons in the locus coeruleus have been shown to increase in a correlated manner with increased cognitive workload ( Varazzani et al, 2015 ). Although locus coeruleus is one of the first areas undergoing degeneration due to the PD pathophysiology ( Micieli et al, 1991 ; Paredes-Rodriguez et al, 2020 ), dopamine replacement therapy has been shown to restore pupillary response in individuals with PD ( Manohar and Husain, 2015 ). Also, a previous study showed that pupillary response during “ON” medication reflects cognitive workload in individuals with PD ( Kahya et al, 2018a ).…”

Section: Introductionmentioning

confidence: 99%

Pupillary Response to Postural Demand in Parkinson’s Disease

Kahya¹,

Lyons²,

Pahwa³

et al. 2021

Front. Bioeng. Biotechnol.

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Background: Individuals with Parkinson’s disease (PD) may need to spend more mental and physical effort (i.e., cognitive workload) to maintain postural control. Pupillary response reflects cognitive workload during postural control tasks in healthy controls but has not been investigated as a measure of postural demand in PD.Objectives: To compare pupillary response during increased postural demand using vision occlusion and dual tasking between individuals with PD and healthy controls.Methods: Thirty-three individuals with PD and thirty-five healthy controls were recruited. The four conditions lasted 60 s and involved single balance task with eyes open; single balance task with eyes occluded; dual task with eyes open; dual task with eyes occluded. The dual task comprised the Auditory Stroop test. Pupillary response was recorded using an eye tracker. The balance was assessed by using a force plate. Two-way Repeated Measures ANOVA and LSD post-hoc tests were employed to compare pupillary response and Center of Pressure (CoP) displacement across the four conditions and between individuals with PD and healthy controls.Results: Pupillary response was higher in individuals with PD compared to healthy controls (p = 0.009) and increased with more challenging postural conditions in both groups (p < 0.001). The post-hoc analysis demonstrated increased pupillary response in the single balance eyes occluded (p < 0.001), dual task eyes open (p = 0.01), and dual task eyes occluded (p < 0.001) conditions compared to single task eyes open condition.Conclusion: Overall, the PD group had increased pupillary response with increased postural demand compared to the healthy controls. In the future, pupillary response can be a potential tool to understand the neurophysiological underpinnings of falls risk in the PD population.

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The Noradrenergic System in Parkinson’s Disease

Cited by 91 publications

References 207 publications

Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’s Disease?

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

Pupillary Response to Postural Demand in Parkinson’s Disease

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