Decrease Of Dopaminergic Neurons Research Articles

Oxidative stress as the trigger for menthol-induced developmental alterations in zebrafish (Danio rerio) model

Menthol is a natural origin organic compound obtained from the peppermint plant whose effects at the embryonic development level are not completely known. In this work, the effects of an acute exposure (96 h) to menthol were evaluated in zebrafish embryos based on the calculated lethal concentration (LC50, 27.5 mg L−1). The results showed a decreased hatching rate and heart rate as well as a notable increase in malformations and mortality. After menthol exposure, an increased production of reactive oxygen species (ROS) accompanied by an increase in the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and reductase) and a decrease in glutathione-S-transferase and protein carbonyls was detected. At the metabolic level, a decrease in ATPase activity and an increase in lactate dehydrogenase activity were perceived. Furthermore, mitochondrial membrane potential (ΔΨm) was increased after menthol exposure as well as the expression of Nrf2. At the behavioural level, shorter distance, speed, and percentage of active time were observed in menthol-treated larvae. In addition, an increase in the distance to the centre of the well and in the turn angle was observed supporting an anxiety-like behaviour induced by menthol exposure. Furthermore, there was a decrease in dopaminergic neurons and in the activity of the enzyme acetylcholinesterase (AChE) suggesting neurobehavioral impairment. Overall, while further studies are required, menthol compromised the development of zebrafish by mediating early development through the regulation of Nrf2 by mitochondrial ROS production with the consequent teratogenic outcomes.

Cannabidiol (CBD) Consideration in Parkinson Disease

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the decrease in dopaminergic neurons in the brain leading to motor and nonmotor symptoms. With the increased availability of cannabidiol in the United States and interest in the PD community for PD-related symptom management in complementary to pharmacologic treatment, this review provides nurse practitioners with useful information on existing studies and regulatory considerations on the implication of cannabidiol in PD.

Endoplasmic Reticulum Stress Is Associated with the Mesencephalic Dopaminergic Neuron Injury in Stressed Rats.

An increasing number of people are in a state of stress due to social and psychological pressures, which may result in mental disorders. Previous studies indicated that mesencephalic dopaminergic neurons are associated with not only reward-related behaviors but also with stress-induced mental disorders. To explore the effect of stress on dopaminergic neuron and potential mechanism, we established stressed rat models of different time durations and observed pathological changes in dopaminergic neurons of the ventral tegmental area (VTA) through HE and thionine staining. Immunohistochemistry coupled with microscopy-based multicolor tissue cytometry (MMTC) was employed to investigate the number changes of dopaminergic neurons. Double immunofluorescence labelling was used to investigate expression changes of endoplasmic reticulum stress (ERS) protein GRP78 and CHOP in dopaminergic neurons. Our results showed that prolonged stress led to pathological alteration in dopaminergic neurons of VTA, such as missing of Nissl bodies and pyknosis in dopaminergic neurons. Immunohistochemistry with MMTC indicated that chronic stress exposure resulted in a significant decrease in dopaminergic neurons. Double immunofluorescence labelling showed that the endoplasmic reticulum stress protein took part in the injury of dopaminergic neurons. Taken together, these results indicated the involvement of ERS in mesencephalic dopaminergic neuron injury induced by stress exposure.

Effect of benzo(a)pyrene on dopaminergic neurons and α-synuclein in brain and its mechanism involved

To analyze the effect of benzopyrene on the decrease of dopaminergic neurons, and the increase and aggregation of α-synuclein, which are the pathological features of Parkinson's disease, and to explore its possible mechanisms. Eight-month-old transgenic mice with human SNCA gene were randomly divided into a BaP-exposed group and a control group. BaP and solvent corn oil were injected intraperitoneally to BaP-exposed group and control group respectively, once a day for 60 days. The motor dysfunction of mice was tested by rotarod test. The effects of BaP on the decrease of dopaminergic neurons and increase and aggregation of α-synuclein were observed by immunohistochemistry and Western blot experiments respectively, and the expression of related mRNA was detected by quantitative real-time PCR (qRT-PCR). Twenty genes were tested in the study, mainly related to neurotransmitter transporter (2 genes), neurotransmitter receptor function (10 genes), cellular autophagy (5 genes), and α-synuclein aggregation and degradation (3 genes). After BaP exposure, the movement time of the mice in the rotarod test was significantly reduced (P<0.05). The substantia nigra dopami-nergic neurons in the mice were significantly reduced, which was 62% of the control group (P<0.05), and the expression of α-synuclein in the midbrain increased, which was 1.36 times that of the control group (P<0.05). After BaP exposure, mRNA expressions of 14 genes in the midbrain of the mice were significantly down-regulated (P<0.05). Alpha-synuclein degradation and cell autophagy (5 genes), neuron transporters (2 genes), and neurotransmitter receptor functions (5 genes) were involved. The expression of one gene, Synphilin-1, was significantly up-regulated (P<0.01), which was related to α-synuclein aggregation. BaP exposure not only inhibited function of neurotransmitter receptor and dopamine transporter, but also interfered cell autophagy, thereby hindering the degradation of α-synuclein, which could lead to decrease of dopaminergic neurons in substantia nigra and increase and aggregation of α-synuclein in midbrain, as the significant pathology of Parkinson's disease. Therefore, BaP exposure may increase the risk of Parkinson's disease.

Neuroprotective and Neurotherapeutic Effects of Tetrahedral Framework Nucleic Acids on Parkinson's Disease in Vitro.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a series of progressive motor disorders. PD is caused by dysfunction of basal ganglia, decrease of dopaminergic neurons in substantia nigra, and abnormal accumulation of Lewy bodies and Lewy neurites. Antiparkinsonian agents, which are currently used for treatment of PD, exhibit unsatisfactory effects on disease control. In recent years, tetrahedral framework nucleic acids (TFNAs) have been considered as multifunctional nanomaterials, and their scope of application has been extended to a wide range of areas. In previous studies, TFNAs were shown to exert positive effects on various cell types in processes such as cell proliferation, cell differentiation, and apoptosis. In the present study, we explored the role of TFNAs in the treatment and prevention of PD in vitro and elucidated its underlying mechanisms of action. On the basis of the experiments conducted, we demonstrated that TFNAs could inhibit and repair the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of PC12 cells through decreasing the accumulation of α-synuclein, one of the characteristic biomarkers of PD. Genes and proteins related to the AKT/PI3K signaling and mitochondrial apoptotic pathways were examined to further support this finding. Most importantly, TFNAs exhibited unexpected neuroprotective and neurorestorative effects on PC12 cells, providing a novel approach for reducing the neuropathological changes caused by PD.

Protective effects of DA-9805 on dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity in the models of Parkinson’s disease

With the elderly population rapidly growing, the prevalence of Parkinson’s disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 μg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD.

Longitudinal characterization of cognitive and motor deficits in an excitotoxic lesion model of striatal dysfunction in non-human primates

As research progresses in the understanding of the molecular and cellular mechanisms underlying neurodegenerative diseases like Huntington's disease (HD) and expands towards preclinical work for the development of new therapies, highly relevant animal models are increasingly needed to test new hypotheses and to validate new therapeutic approaches. In this light, we characterized an excitotoxic lesion model of striatal dysfunction in non-human primates (NHPs) using cognitive and motor behaviour assessment as well as functional imaging and post-mortem anatomical analyses.NHPs received intra-striatal stereotaxic injections of quinolinic acid bilaterally in the caudate nucleus and unilaterally in the left sensorimotor putamen. Post-operative MRI scans showed atrophy of the caudate nucleus and a large ventricular enlargement in all 6 NHPs that correlated with post-mortem measurements. Behavioral analysis showed deficits in 2 analogues of the Wisconsin card sorting test (perseverative behavior) and in an executive task, while no deficits were observed in a visual recognition or an episodic memory task at 6 months following surgery. Spontaneous locomotor activity was decreased after lesion and the incidence of apomorphine-induced dyskinesias was significantly increased at 3 and 6 months following lesion. Positron emission tomography scans obtained at end-point showed a major deficit in glucose metabolism and D2 receptor density limited to the lesioned striatum of all NHPs compared to controls. Post-mortem analyses revealed a significant loss of medium-sized spiny neurons in the striatum, a loss of neurons and fibers in the globus pallidus, a unilateral decrease in dopaminergic neurons of the substantia nigra and a loss of neurons in the motor and dorsolateral prefrontal cortex.Overall, we show that this robust NHP model presents specific behavioral (learning, execution and retention of cognitive tests) and metabolic functional deficits that, to the best of our knowledge, are currently not mimicked in any available large animal model of striatal dysfunction. Moreover, we used non-invasive, translational techniques like behavior and imaging to quantify such deficits and found that they correlate to a significant cell loss in the striatum and its main input and output structures. This model can thus significantly contribute to the pre-clinical longitudinal evaluation of the ability of new therapeutic cell, gene or pharmacotherapy approaches in restoring the functionality of the striatal circuitry.

Mild hyperbaric oxygen: mechanisms and effects.

Adequate oxygen supply by exposure to mild hyperbaric oxygen at appropriately high atmospheric pressure (1266-1317hPa) and increased oxygen concentration (35-40% oxygen) has a possibility of improving the oxidative metabolism in cells and tissues without barotrauma and excessive production of reactive oxygen species. Therefore, metabolic syndrome and lifestyle-related diseases, including type 2 diabetes and hypertension, in rats were inhibited and/or improved by exposure to mild hyperbaric oxygen. It accelerated the growth-induced increase in oxidative capacity of the skeletal muscle in rats and inhibited the age-related decrease in oxidative capacity of the skeletal muscle in mice. A decrease in dopaminergic neurons in the substantia nigra of mice with Parkinson's disease was inhibited by exposure to mild hyperbaric oxygen. This review describes the beneficial effects of exposure to mild hyperbaric oxygen on some metabolic diseases and their perspectives.

Mild hyperbaric oxygen inhibits the decrease of dopaminergic neurons in the substantia nigra of mice with MPTP-induced Parkinson’s disease

We examined whether exposure to mild hyperbaric oxygen inhibits the decrease of dopaminergic neurons in the substantia nigra of a neurotoxic animal model with Parkinson’s disease. Mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and probenecid twice a week were divided into two groups: mice with mild hyperbaric oxygen and those without. The mice with mild hyperbaric oxygen were exposed to 1317hPa with 45% oxygen for 3h, three times a week. The decrease in dopaminergic neurons of mice with Parkinson’s disease was inhibited by 11 weeks of exposure to mild hyperbaric oxygen. We conclude that exposure to mild hyperbaric oxygen is effective in preventing the progression of Parkinson’s disease.

Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice

MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum.

Protective effects of PEP-1-Catalase on stress-induced cellular toxicity and MPTP-induced Parkinson's disease

Parkinson’s disease (PD) is a neurodegenerative disability caused by a decrease of dopaminergic neurons in the substantia nigra (SN). Although the etiology of PD is not clear, oxidative stress is believed to lead to PD. Catalase is antioxidant enzyme which plays an active role in cells as a reactive oxygen species (ROS) scavenger. Thus, we investigated whether PEP-1-Catalase protects against 1-methyl-4-phenylpyridinium (MPP+) induced SH-SY5Y neuronal cell death and in a 1-methyl-4-phenyl-1,2,3,6-trtrahydropyridine (MPTP) induced PD animal model. PEP-1-Catalase transduced into SH-SY5Y cells significantly protecting them against MPP+-induced death by decreasing ROS and regulating cellular survival signals including Akt, Bax, Bcl-2, and p38. Immunohistochemical analysis showed that transduced PEP-1-Catalase markedly protected against neuronal cell death in the SN in the PD animal model. Our results indicate that PEP-1-Catalase may have potential as a therapeutic agent for PD and other oxidative stress related diseases. [BMB Reports 2015; 48(7): 395-400]

Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H) transduction of dopaminergic neurons in vivo.

Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα). It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson’s disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD.

An enteric nervous system progenitor cell implant promotes a behavioral and neurochemical improvement in rats with a 6-OHDA-induced lesion

The enteric nervous system (ENS) of mammals is derived from neural crest (NC) cells during embryogenesis and at the beginning of postnatal life. However, neural progenitor cells from the ENS (or ENSPC) are also found in the adult intestine and can be used for neuronal regeneration in diseases that lead to a loss of cell population, such as Parkinson's disease (PD), in which there is a decrease of dopaminergic neurons. The objective of this study was to evaluate the capacity of ENSPC to restore damaged nervous tissue and to show that they are functional for a behavioral and neurochemical recovery. We found that animals with ENSPC implants exhibited a motor recovery of 35% vs. the lesion group. In addition, DA levels were partially restored in 34%, while Homovanillic acid (HVA) levels remained at 21% vs. the group with a 6-Hydroxydopamine (6-OHDA)-induced lesion, suggesting that ENSPC represent a possible alternative in the study of cell transplants and the preservation of functional dopaminergic neurons in PD.

Developmental switch in the effects of TNFα on ventral midbrain dopaminergic neurons

The cytokine tumour necrosis factor-alpha (TNFα) has been implicated in the pathogenesis of neurodegenerative conditions as well as in the establishment of neural networks during development. This study investigated the in vitro effects of TNFα on embryonic dopaminergic neurons of the ventral mesencephalon. TNFα treatment enhanced the number of dopaminergic neurons in cultures derived from E12.5 mice embryos in a dose-dependent manner. In order to achieve this effect TNFα signalled via NF-κB. This enhancement in cell number was found to be due to TNFα promoting the differentiation of dopaminergic neurons rather than to an increase in cell survival. In contrast, TNFα-treated cultures derived from E14 or E16 mice demonstrated a decrease in dopaminergic neurons, and this loss was negated by pharmacological inhibition of caspases. The data presented demonstrate that during embryonic development, dopaminergic ventral mesencephalic neurons switch their in vitro response to TNFα from neurotrophic to neurotoxic. This is the first report of a population of neurons exhibiting this switch in TNFα responsiveness during neurodevelopment.

Comparison between the decrease of dopamine transporter and that of L‐DOPA uptake for detection of early to advanced stage of Parkinson's disease in animal models

Early diagnosis of Parkinson's disease (PD) is important for the potential application of neuroprotective therapies. The purpose of this study was to assess the detection of the early changes of PD by either imaging the dopamine transporter (DAT) or uptake of l-3,4-dihydroxyphenylalanine (l-DOPA). An early to advanced stage model of PD was induced in rats by stereotaxic injection of 1–10 μg 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta. Using adjacent sections of the same animals, the binding of [I-125]beta-CIT, which labels DAT and the uptake of [C-14]l-DOPA, were evaluated 4 weeks after induction of the lesion. Any decrease in dopaminergic neurons was evaluated by in situ hybridization histochemistry (ISH) by detection of DAT mRNA-positive neurons. In addition, the expression levels of DAT, dopa decarboxylase (DDC), and vesicular monoamine transporter (VMAT2) in each neuron were studied with ISH. Our results show a decrease in both [I-125]beta-CIT binding and [C-14]l-DOPA uptake in parallel with a decrease in DA neurons from early to advanced stage models of PD. The decrease in [C-14]l-DOPA uptake was smaller than that in [I-125]beta-CIT binding in the same animal (P < 0.0001). Expression levels of DAT, DDC, and VMAT2 mRNAs were also decreased with the progression of the disease. Although ISH failed to detect the origin of the discrepancy between [I-125]beta-CIT and [C-14]l-DOPA levels, it was concluded that [C-14]l-DOPA levels underestimated the decrease of dopaminergic neurons and that [I-125]beta-CIT levels more precisely reflected the decrease. Synapse 31:178–185, 1999. © 1999 Wiley-Liss, Inc.

Apoptosis in substantia nigra following developmental striatal excitotoxic injury.

We have previously observed that an axon-sparing injury to the developing striatum induced by the excitotoxin quinolinate results in a decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the adult. This decrease occurs in the absence of direct injury to the SNpc. As the striatum is a major target for the SNpc dopaminergic system, we have hypothesized that a decrease in the size of the striatal target during development may result in an induced regressive event in the SNpc, similar to what has been described for many developing neural systems with peripheral targets. We have examined by morphologic and biochemical means the time course and character of cell death in SN following a unilateral striatal lesion with quinolinate in immature rats. The striatal lesion is associated with an induced cell death event in the ipsilateral SN, observed first in SNpc and then in SN pars reticulata. The morphologic characteristics of the dying cells were typical of apoptosis. Immunostaining for tyrosine hydroxylase indicated that some of the apoptotic cells in the SNpc were dopaminergic. We conclude that developmental striatal excitotoxic injury is associated with induced apoptotic cell death in SN.