Editorial

2 pages, 168 KiB

Open AccessEditorial

Neurobiology Research in Parkinson’s Disease

by Takao Yasuhara

Int. J. Mol. Sci. 2020, 21(3), 793; https://doi.org/10.3390/ijms21030793 - 25 Jan 2020

Cited by 4 | Viewed by 4753

In recent years, therapeutic strategies for Parkinson’s disease (PD) have been developing in many different ways [...] Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

Research

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20 pages, 2890 KiB

Open AccessArticle

Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite—Urolithin A—In the Brain

by Małgorzata Kujawska, Michael Jourdes, Monika Kurpik, Michał Szulc, Hanna Szaefer, Piotr Chmielarz, Grzegorz Kreiner, Violetta Krajka-Kuźniak, Przemyslaw Łukasz Mikołajczak, Pierre-Louis Teissedre and Jadwiga Jodynis-Liebert

Int. J. Mol. Sci. 2020, 21(1), 202; https://doi.org/10.3390/ijms21010202 - 27 Dec 2019

Cited by 103 | Viewed by 10080

Abstract

Pomegranate juice is a rich source of ellagitannins (ETs) believed to contribute to a wide range of pomegranate’s health benefits. While a lot of experimental studies have been devoted to Alzheimer disease and hypoxic-ischemic brain injury, our knowledge of pomegranate’s effects against Parkinson’s [...] Read more.

Pomegranate juice is a rich source of ellagitannins (ETs) believed to contribute to a wide range of pomegranate’s health benefits. While a lot of experimental studies have been devoted to Alzheimer disease and hypoxic-ischemic brain injury, our knowledge of pomegranate’s effects against Parkinson’s disease (PD) is very limited. It is suggested that its neuroprotective effects are mediated by ETs-derived metabolites—urolithins. In this study, we examined the capability of pomegranate juice for protection against PD in a rat model of parkinsonism induced by rotenone. To evaluate its efficiency, assessment of postural instability, visualization of neurodegeneration, determination of oxidative damage to lipids and α-synuclein level, as well as markers of antioxidant defense status, inflammation, and apoptosis, were performed in the midbrain. We also check the presence of plausible active pomegranate ETs-derived metabolite, urolithin A, in the plasma and brain. Our results indicated that pomegranate juice treatment provided neuroprotection as evidenced by the postural stability improvement, enhancement of neuronal survival, its protection against oxidative damage and α-synuclein aggregation, the increase in mitochondrial aldehyde dehydrogenase activity, and maintenance of antiapoptotic Bcl-xL protein at the control level. In addition, we have provided evidence for the distribution of urolithin A to the brain. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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17 pages, 5650 KiB

Open AccessArticle

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

by Yuan-Hao Chen, Vicki Wang, Eagle Yi-Kung Huang, Yu-Ching Chou, Tung-Tai Kuo, Lars Olson and Barry J. Hoffer

Int. J. Mol. Sci. 2019, 20(24), 6251; https://doi.org/10.3390/ijms20246251 - 11 Dec 2019

Cited by 18 | Viewed by 3466

Abstract

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson’s disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA [...] Read more.

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson’s disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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16 pages, 4232 KiB

Open AccessArticle

Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease

by Sangwoo Ham, Heejeong Kim, Jin-Ha Yoon, Hyojung Kim, Bo Reum Song, Jeong-Yun Choi, Yun-Song Lee, Seung-Mann Paek, Han-Joo Maeng and Yunjong Lee

Int. J. Mol. Sci. 2019, 20(21), 5481; https://doi.org/10.3390/ijms20215481 - 04 Nov 2019

Cited by 7 | Viewed by 3237

Abstract

The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β [...] Read more.

The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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16 pages, 2714 KiB

Open AccessArticle

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

by Ji Yeon Choi, Jaesuk Yun, Chul Ju Hwang, Hee Pom Lee, Hae Deun Kim, Hyungok Chun, Pil-Hoon Park, Dong Young Choi, Sang-Bae Han and Jin Tae Hong

Int. J. Mol. Sci. 2019, 20(11), 2632; https://doi.org/10.3390/ijms20112632 - 29 May 2019

Cited by 3 | Viewed by 3795

Abstract

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced [...] Read more.

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP⁺; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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Review

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23 pages, 1578 KiB

Open AccessReview

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

by Abdeslam Chagraoui, Marie Boulain, Laurent Juvin, Youssef Anouar, Grégory Barrière and Philippe De Deurwaerdère

Int. J. Mol. Sci. 2020, 21(1), 294; https://doi.org/10.3390/ijms21010294 - 31 Dec 2019

Cited by 63 | Viewed by 8423

Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in [...] Read more.

L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These “false neurotransmitters,” also known for some of them as inducing an “amphetamine-like” mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to “false neurotransmission.” Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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23 pages, 493 KiB

Open AccessReview

Role of MicroRNAs in Parkinson’s Disease

by Suh Yee Goh, Yin Xia Chao, Shaikali Thameem Dheen, Eng-King Tan and Samuel Sam-Wah Tay

Int. J. Mol. Sci. 2019, 20(22), 5649; https://doi.org/10.3390/ijms20225649 - 12 Nov 2019

Cited by 130 | Viewed by 6906

Abstract

Parkinson’s disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular [...] Read more.

Parkinson’s disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood–brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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14 pages, 1376 KiB

Open AccessReview

Animal Models for Parkinson’s Disease Research: Trends in the 2000s

by Kyohei Kin, Takao Yasuhara, Masahiro Kameda and Isao Date

Int. J. Mol. Sci. 2019, 20(21), 5402; https://doi.org/10.3390/ijms20215402 - 30 Oct 2019

Cited by 93 | Viewed by 8114

Abstract

Parkinson’s disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this [...] Read more.

Parkinson’s disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this goal, clarification of the pathology is required. Attempts have been made to emulate human PD and various animal models have been developed over the decades. Neurotoxin models have been commonly used for PD research. Recently, advances in transgenic technology have enabled the development of genetic models that help to identify new approaches in PD research. However, PD animal model trends have not been investigated. Revealing the trends for PD research will be valuable for increasing our understanding of the positive and negative aspects of each model. In this article, we clarified the trends for animal models that were used to research PD in the 2000s, and we discussed each model based on these trends. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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28 pages, 753 KiB

Open AccessReview

The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson’s Disease

by Kai-Jung Lin, Kai-Lieh Lin, Shang-Der Chen, Chia-Wei Liou, Yao-Chung Chuang, Hung-Yu Lin and Tsu-Kung Lin

Int. J. Mol. Sci. 2019, 20(21), 5312; https://doi.org/10.3390/ijms20215312 - 25 Oct 2019

Cited by 78 | Viewed by 8396

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing Lewy body inclusions in the substantia nigra. While the exact pathomechanisms of PD remain unclear, genetic investigations have revealed evidence of the involvement of mitochondrial function, alpha-synuclein (α-syn) aggregation, and the endo-lysosomal system, in disease pathogenesis. Due to the high energy demand of dopaminergic neurons, mitochondria are of special importance acting as the cellular powerhouse. Mitochondrial dynamic fusion and fission, and autophagy quality control keep the mitochondrial network in a healthy state. Should defects of the organelle occur, a variety of reactions would ensue at the cellular level, including disrupted mitochondrial respiratory network and perturbed calcium homeostasis, possibly resulting in cellular death. Meanwhile, α-syn is a presynaptic protein that helps regulate synaptic vesicle transportation and endocytosis. Its misfolding into oligomeric sheets and fibrillation is toxic to the mitochondria and neurons. Increased cellular oxidative stress leads to α-syn accumulation, causing mitochondrial dysfunction. The proteasome and endo-lysosomal systems function to regulate damage and unwanted waste management within the cell while facilitating the quality control of mitochondria and α-syn. This review will analyze the biological functions and interactions between mitochondria, α-syn, and the endo-lysosomal system in the pathogenesis of PD. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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26 pages, 820 KiB

Open AccessReview

Probiotics for Parkinson’s Disease

by Parisa Gazerani

Int. J. Mol. Sci. 2019, 20(17), 4121; https://doi.org/10.3390/ijms20174121 - 23 Aug 2019

Cited by 97 | Viewed by 16867

Abstract

Parkinson’s disease (PD) is a complex neurological disorder classically characterized by impairments in motor system function associated with loss of dopaminergic neurons in the substantia nigra. After almost 200 years since the first description of PD by James Parkinson, unraveling the complexity of [...] Read more.

Parkinson’s disease (PD) is a complex neurological disorder classically characterized by impairments in motor system function associated with loss of dopaminergic neurons in the substantia nigra. After almost 200 years since the first description of PD by James Parkinson, unraveling the complexity of PD continues to evolve. It is now recognized that an interplay between genetic and environmental factors influences a diverse range of cellular processes, reflecting on other clinical features including non-motor symptoms. This has consequently highlighted the extensive value of early clinical diagnosis to reduce difficulties of later stage management of PD. Advancement in understanding of PD has made remarkable progress in introducing new tools and strategies such as stem cell therapy and deep brain stimulation. A link between alterations in gut microbiota and PD has also opened a new line. Evidence exists of a bidirectional pathway between the gastrointestinal tract and the central nervous system. Probiotics, prebiotics and synbiotics are being examined that might influence gut-brain axis by altering gut microbiota composition, enteric nervous system, and CNS. This review provides status on use of probiotics for PD. Limitations and future directions will also be addressed to promote further research considering use of probiotics for PD. Full article

(This article belongs to the Special Issue Neurobiology Research in Parkinson's Disease)

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