Growth Of Dopaminergic Neurons Research Articles

Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.

The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

Exposure of particulate matter (PM10) induces neurodevelopmental toxicity in zebrafish embryos

Particulate matter with 10 μm or less in diameter (PM10) exposure is a major threat to health and environment around the world. Even though a number of clinical and experimental studies have focused on the cardiopulmonary effects of PM10, its impact on neurovascular development and the underlying toxicity is relatively less studied. The present study is therefore undertaken to evaluate the potential toxic effects of PM10 on neurodevelopment and the associated gene expression profiles in the zebrafish embryo/larvae. During 2017–2018, PM10 samples (24 h sampling, 180 sampling days) were collected in an urban downtown site of Jinan, Shandong province, China. To delineate the potential toxic effects of PM10 during neurodevelopment, zebrafish embryos/larvae were exposed to different concentrations viz., 25, 50, 100, 200, and 400 μg/mL of PM10 solution for 24–120 h post-fertilization (hpf) and the effects on the mortality, morphology, swimming behavior, electroencephalogram discharges, growth of dopaminergic neurons, neurovasculature development and gene expression profiles of dopaminergic and neurodevelopment-related genes using qRT-PCR were studied.A significant increase in the mortality rate and morphological abnormalities were observed in 200 μg/mL of the PM10 treated group at 120 hpf. High concentrations (≥100 μg/mL) of PM10 exposure reduced locomotor behavior, caused abnormal electroencephalogram discharges, degeneration of dopaminergic neurons, inhibition of neurovascular development, cerebral hemorrhage, and significant changes in the expression pattern of genes involved in dopaminergic pathway and neurodevelopment such as (th1, dat, drd1, drd2a, drd3, drd4b, syn2a, gap43, α1-tubulin, gfap, map2, elavl3, eno2, neurog1, sox2, shha, and mbp). Taken together, all these parameters collectively imply developmental neurotoxicity and dysfunction of the dopaminergic neurons which provides the first evidence of PM10-induced neurodevelopmental toxicity in the zebrafish embryo/larvae.

Human Amniotic Epithelial Cells Alleviate a Mouse Model of Parkinson's Disease Mainly by Neuroprotective, Anti-Oxidative and Anti-Inflammatory Factors.

Human amniotic epithelial cells (hAECs) have been reported to have neuroprotective roles in Parkinson's disease (PD) animal models. However, the molecular mechanism is not fully understood. The present study was designed to explore the possible mechanism by which hAECs ameliorate PD symptoms and the important paracrine factors produced by hAECs that attribute to the recovery of dopaminergic neurons. Thus, we performed in vivo and in vitro experiments with hAECs in PD models or lesioned dopaminergic neurons, respectively. First, hAECs were transplanted into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and motor deficits were significantly attenuated. Second, the grafts prevented the loss of nigral dopaminergic neurons and promoted the outgrowth of neurites and striatal axon fibers in PD mice. In addition, decreased microglial activation, inflammatory factor levels and MPTP-induced excessive reactive oxygen species (ROS) levels were also observed in hAEC-treated PD mice. In vitro, we found that the conditioned medium (CM) from hAECs promoted the survival of mesencephalic dopaminergic neurons stimulated with 1-methyl-4-phenylpyridine (MPP+) and induced neurite outgrowth. Next, analysis of hAEC-CM with an antibody array of 507 soluble target proteins revealed that the levels of many neurotrophic factors, growth factors, neuronal cell adhesion molecule (NrCAM) and anti-inflammatory factors were evidently high. In addition, antibody neutralization experiments showed that many of these factors contributed to the survival and growth of dopaminergic neurons and neurite outgrowth. More importantly, we found that the anti-inflammatory factor interleukin-1 receptor antagonist (IL-1ra) also augmented the survival of dopaminergic neurons, demonstrating for the first time an anti-oxidative and anti-inflammatory role of hAECs in PD mice, which represents a novel molecular mechanism of hAECs in the treatment of PD. The molecular mechanism of hAECs recovering lesioned dopaminergic neurons and attenuating PD symptoms. First, hAECs secret manyneurotrophic factors, growth factors, and neuronal cell adhesion molecule (NrCAM) which promote the growth of the damaged dopaminergic neurons andtheir neurites. Second, hAECs produce many anti-inflammatory factors and other factors contributing to reducing the activation of microglia andsuppressing the neuroinflammation. Third, hAECs reduce the excessive ROS levels by upregulating some anti-oxidative signals.

Paracrine factors for neurodegenerative disorders: special emphasis on Parkinson's disease.

The progressive loss of dopaminergic neurons in the ventral mesencephalon is the main pathological hallmark of Parkinson's disease (PD). Drugs currently available only alleviate the principal symptomatic motor-related disturbances and their benefit is counteracted by side effects in the long time. While cell replacement strategies for approaching PD by means of intrastriatal implantation of dopaminergic neurons showed some encouraging results in a number of patients this therapeutical approach aims primarily to replenish the lack of dopamine but not halting disease progression. Hence, over the past decades various strategies have been exploited to protect the dopaminergic neurons in the ventral mesencephalon from dying. Of special importance are in this context neurotrophic factors, drugs striving against oxidative stress and bioenergetic supplements. Particularly, several neurotrophic factors have been described to specifically increase the survival and/or growth of dopaminergic neurons in vitro and in vivo, including neurotrophins and glial cell line-derived neurotrophic factor (GDNF) family members.

Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism.

Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson's disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson's disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson's disease.

The rat striatum responds to nigro-striatal degeneration via the increased expression of proteins associated with growth and regeneration of neuronal circuitry.

BackgroundIdiopathic Parkinson’s disease is marked by degeneration of dopamine neurons projecting from the substantia nigra to the striatum. Although proteins expressed by the target striatum can positively affect the viability and growth of dopaminergic neurons, very little is known about the molecular response of the striatum as nigro-striatal denervation progresses. Here, iTRAQ labelling and MALDI TOF/TOF mass spectrometry have been used to quantitatively compare the striatal proteome of rats before, during, and after 6-OHDA induced dopamine denervation.ResultsiTRAQ analysis revealed the differential expression of 50 proteins at 3 days, 26 proteins at 7 days, and 34 proteins at 14 days post-lesioning, compared to the unlesioned striatum. While the denervated striatum showed a reduced expression of proteins associated with the loss of dopaminergic input (e.g., TH and DARPP-32), there was an increased expression of proteins associated with regeneration and growth of neurites (e.g., GFAP). In particular, the expression of guanine deaminase (GDA, cypin) – a protein known to be involved in dendritic branching – was significantly increased in the striatum at 3, 7 and 14 days post-lesioning (a finding verified by immunohistochemistry).ConclusionsTogether, these findings provide evidence to suggest that the response of the normal mammalian striatum to nigro-striatal denervation includes the increased expression of proteins that may have the capacity to facilitate repair and growth of neuronal circuitry.

Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 as a Neuroprotective Agent: Promotion of the Morphological Development of Midbrain Dopaminergic Neurons

A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.

Therapeutic potential of nerve growth factors in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative syndrome which primarily affects dopamine-producing neurons of the substantia nigra, resulting in poverty and slowness of movement, instability of gait and posture, and tremor at rest in individuals with the disease. While symptoms of the disease can be effectively managed for several years with available drugs, the syndrome is progressive and the efficacy of standard drugs wanes with time. One experimental approach to therapy is to use natural and synthetic molecules which promote survival and growth of dopaminergic neurons, so-called 'neurotrophic factors', to stabilise the diminishing population of dopaminergic neurons and stimulate compensation and growth in these cells. In this review, we examine the available evidence on 29 molecules with neurotrophic properties for dopaminergic neurons. The properties of these molecules provide ample reasons for optimism that a neurotrophic strategy can be developed that would provide a significant treatment option for patients with PD. While the search continues for even more specific, potent and long lasting agents, the single greatest challenge is the development of techniques for targeted delivery of these molecules.

Altered Motor Function and Graft Survival Produced by Basic Fibroblast Growth Factor in Rats with 6-OHDA Lesions and Fetal Ventral Mesencephalic Grafts Are Associated with Glial Proliferation

Basic fibroblast growth factor (bFGF) promotes the survival and growth of dopaminergic neurons. We have investigated the effect of treating fetal ventral mesencephalon with bFGF or nerve growth factor (NGF) on the subsequent survival and function of grafted dopaminergic neurons implanted into the striatum of rats with a unilateral 6-hydroxydopamine lesion. Animals implanted with fetal ventral mesencephalon mixed with bFGF, but not with NGF, displayed a more rapid compensation in motor behavior up to 9 weeks after graft implantation. bFGF, but not NGF, produced an increase in the number of tyrosine hydroxylase (TH)-positive neurons, a larger graft volume, and longer neurite outgrowth in comparison to control grafts. bFGF also increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes within the grafts. The increased number of GFAP-positive astrocytes induced by bFGF correlated with the increase in the number of TH-positive neurons, with graft volume and with neurite outgrowth. These findings support the use of bFGF to promote the functional integration of fetal ventral mesencephalon grafts into the denervated host brain and suggest that its action may be indirectly mediated through glial cells.

Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson's disease

The clinical use of fetal neural grafts as an intracerebral source of dopamine for patients with Parkinson's disease has met with limited success. Since basic fibroblast growth factor (bFGF) enhances the survival and growth of dopaminergic neurons in vitro, we explored whether cells genetically modified to produce bFGF would improve the functional efficacy of dopaminergic neurons implanted into rats with experimental Parkinson's disease. Results show that bFGF-producing cells grafted together with fetal dopamine neurons have potent growth-promoting effects on the implanted neurons in vivo. Moreover, rats implanted with such co-grafts display the most pronounced behavioural improvements post-grafting. These findings not only provide insight into the function of bFGF in situ, but also suggest an approach for enhancing the survival and function of dopamine neurons grafted into the damaged brain.