Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain

Background: Parkinson's Disease results from a loss of dopaminergic neurons, and reduced levels of the neurotransmitter dopamine. Parkinson's Disease treatments involve increasing dopamine levels through administration of L-DOPA, which can cross the blood brain barrier and be converted to dopamine in the brain. The toxicity of dopamine has previously studied but there has been little study of L-DOPA toxicity. Methods: We have compared the toxicity of dopamine and L-DOPA in the yeasts, Saccharomyces cerevisiae and Candida glabrata by cell viability assays, measuring colony forming units. Results: L-DOPA and dopamine caused time-dependent cell killing in Candida glabrata while only dopamine caused such effects in Saccharomyces cerevisiae. The toxicity of L-DOPA is much lower than dopamine. Conclusion: Candida glabrata exhibits high sensitivity to L-DOPA and may have advantages for studying the cytotoxicity of L-DOPA.

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Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms22031059 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1059

Author(s):

Bodo C. Melnik

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Dopaminergic Neurons ◽

Vagal Nerve ◽

Β Cells ◽

Pancreatic Β Cells ◽

The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

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Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Pharmaceutics ◽

10.3390/pharmaceutics13040508 ◽

2021 ◽

Vol 13 (4) ◽

pp. 508

Author(s):

Sara Silva ◽

António J. Almeida ◽

Nuno Vale

Keyword(s):

Side Effects ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Pharmacokinetic Profile ◽

The Elderly ◽

Motor Symptoms ◽

Administration Routes ◽

Pharmaceutical Therapy ◽

Drug Pharmacokinetic ◽

The Brain

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

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A bimodal probe for fluorescence and synchrotron X-ray fluorescence imaging of dopaminergic neurons in brain

Chemical Communications ◽

10.1039/d1cc06475d ◽

2022 ◽

Author(s):

Meiling Yan ◽

Tingting Zuo ◽

Jichao Zhang ◽

Yiyang Wang ◽

Ying Zhu ◽

...

Keyword(s):

Fluorescence Imaging ◽

Immunoglobulin G ◽

Dopaminergic Neurons ◽

X Ray ◽

Erythrosine B ◽

The Brain

A bimodal probe, erythrosine B (EB) conjugated immunoglobulin G complex (EB/IgG), has been developed for fluorescence and synchrotron X-ray fluorescence (SXRF) imaging of dopaminergic neurons in the brain.

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Parkinson's Disease

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch012 ◽

2019 ◽

pp. 252-273 ◽

Cited By ~ 1

Author(s):

Vaibhav Walia ◽

Ashish Gakkhar ◽

Munish Garg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Older Patients ◽

Neurodegenerative Disorder ◽

Progressive Loss ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Biomolecules ◽

10.3390/biom10030391 ◽

2020 ◽

Vol 10 (3) ◽

pp. 391 ◽

Cited By ~ 6

Author(s):

Margaux Teil ◽

Marie-Laure Arotcarena ◽

Emilie Faggiani ◽

Florent Laferriere ◽

Erwan Bezard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Clinical Trials ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Curative Treatment ◽

Preclinical Studies ◽

Cytoplasmic Inclusions ◽

The Many ◽

The Brain

Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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iPS models of Parkin and PINK1

Biochemical Society Transactions ◽

10.1042/bst20150010 ◽

2015 ◽

Vol 43 (2) ◽

pp. 302-307 ◽

Cited By ~ 8

Author(s):

Aleksandar Rakovic ◽

Philip Seibler ◽

Christine Klein

Keyword(s):

Dopaminergic Neurons ◽

Induced Pluripotent Stem Cell ◽

Therapeutic Agents ◽

Axonal Outgrowth ◽

Disease Mechanisms ◽

The Central Nervous System ◽

Degenerative Disorder ◽

Induced Pluripotent ◽

Druggable Targets ◽

The Brain

Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the unique possibility of studying disease mechanisms in human tissue that was otherwise not accessible, such as the brain. Of particular interest are the monogenetic forms of PD as they closely resemble the more common ‘idiopathic’ PD and, through the mutated protein, provide a clear research target in iPSC-derived neurons. Recessively inherited Parkin and PTEN-induced putative kinase 1 (PINK1) mutations have been investigated in this context and the present review describes the first insights gained from studies in iPSC-derived dopaminergic neurons, which comprise abnormalities in mitochondrial and dopamine homoeostasis, microtubular stability and axonal outgrowth. These new models of PD have a high translational potential that includes the identification of druggable targets, testing of known and novel therapeutic agents in the disease-relevant tissue using well-defined read-outs and potential regenerative approaches.

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The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2011.0387 ◽

2012 ◽

Vol 367 (1607) ◽

pp. 3264-3275 ◽

Cited By ~ 75

Author(s):

Melina Reisenberg ◽

Praveen K. Singh ◽

Gareth Williams ◽

Patrick Doherty

Keyword(s):

Dopaminergic Neurons ◽

Cannabinoid Receptors ◽

Homology Modelling ◽

Detailed Examination ◽

The Body ◽

Adult Brain ◽

And Migration ◽

Regulatory Loop ◽

Translational Mechanisms ◽

The Brain

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB 1 and CB 2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB 1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity—however, key insights can be gleaned by homology modelling against other α/β hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

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Ethanol induced increase of fibroblast growth factor 2 mRNA content in emotiogenic brain structures of rats

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20206605419 ◽

2020 ◽

Vol 66 (5) ◽

pp. 419-422

Author(s):

M.I. Airapetov ◽

S.O. Eresco ◽

A.A. Lebedev ◽

E.R. Bychkov ◽

P.D. Shabanov

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Dopaminergic Neurons ◽

Mrna Level ◽

Brain Structures ◽

Fibroblast Growth Factor 2 ◽

Fibroblast Growth ◽

Mrna Content ◽

The Brain

We studied the effects of acute, subacute, and chronic alcohol treatment of rats on the content of fibroblast growth factor 2 (FGF2) mRNA in various brain structures. Results suggest a possible role of FGF2 in the functioning of dopaminergic neurons in the midbrain. In our experiment, ethanol treatment of rats was accompanied by an increase in the FGF2 mRNA level in the emotiogenic structures of the brain. This effect was blocked by pretreatment of animals with chlorpromazine. This suggests FGF2 involvement in the mechanisms of alcohol dependence and can be considered as a possible diagnostic and therapeutic target in alcoholism.

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