Glial cells and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterised by a massive loss of dopaminergic neurons in the substantia nigra. Yet glial cells may also participate in the pathophysiology of the disease. Indeed, glial cells can produce trophic factors which may stimulate neuronal survival or, alternatively, they could produce toxic compounds which may be involved in neuronal degeneration. This paper reviews the potentially protective or deleterious effects of glial cells in the substantia nigra of patients with Parkinson’s disease.

     

Parkinson’s Disease–Associated Changes in the Expression of Neurotrophic Factors and their Receptors upon Neuronal Differentiation of Human Induced Pluripotent Stem Cells

Journal of Molecular Neuroscience - Parkinson’s disease (PD) is a neurodegenerative pathology resulting from the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN)....     

X-box-binding protein 1-modified neural stem cells for treatment of Parkinson’s disease

X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson’s disease. The survival capacities and differentiation rates of cells expressing the dopaminergic marker tyrosine hydroxylase were higher in X-box-binding protein 1-transfected neural stem cells compared to non-transfected cells. Moreover, dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra were significantly increased, α-synuclein expression was decreased, and neurological behaviors were significantly ameliorated in rats following transplantation of X-box-binding protein 1-transfected neural stem cells. These results indicate that transplantation of X-box-binding protein 1-transfected neural stem cells can promote stem cell survival and differentiation into dopaminergic neurons, increase dopamine and 3,4-dihydroxyphenylacetic acid levels, reduce α-synuclein aggregation in the substantia nigra, and improve the symptoms of Parkinson’s disease in rats.     

Gastrodin inhibits neuroinflammation in rotenone-induced Parkinson's disease model rats

The present study showed that the latency of rats moving on a vertical grid was significantly prolonged,and the number of rats sliding down from the declined plane was increased remarkably,in rotenone-induced Parkinson’s disease model rats compared with control rats.The moving latency recovered to normal levels,but the number of slides was significantly increased at 28 days after model establishment.The slope test is a meaningful approach to evaluate the symptoms of Parkinson’s disease model rats treated with rotenone.In addition,loss of substantia nigral dopaminergic neurons in model rats was observed at 1 day after the model was established,and continued gradually at 14 and 28 days.The expression of tyrosine hydroxylase-positive cells was significantly increased in gastrodin-treated rats at 14 days.Significant numbers of activated microglia cells were observed in model rats at 14 and 28 days;treatment of rats with Madopar at 28 days suppressed microglial activation.Treatment of rats with gastrodin or Madopar at 28 days significantly reduced interleukin-1β expression.The loss of substantia nigral dopaminergic neurons paralleled the microglial activation in Parkinson’s disease model rats treated with rotenone.The inflammatory factors tumor necrosis factor-α and interleukin-1β are involved in the substantia nigral damage.Gastrodin could protect dopaminergic neurons via inhibition of interleukin-1β expression and neuroinflammation in the substantia nigra.     

Noradrenergic Modulation on Dopaminergic Neurons

It is now well accepted that there is a close relationship between noradrenergic and dopaminergic neurons in the brain, especially referring to the modulation of the locus coeruleus–norepinephrine (LC-NE) system on dopamine transmission. The disturbance of this modulation may contribute to neurodegeneration of dopaminergic neurons in Parkinson’s disease. In this article, we briefly review evidence related to such modulation. Firstly, we illustrated the noradrenergic innervation and functional implication for the LC-NE system and nigra–striatum dopaminergic system. Furthermore, we depicted neuroprotective effects of the LC-NE on dopaminergic neurons in vivo and in vitro. Moreover, we present data implicating the potential mechanisms underlying the modulation of the LC-NE system on dopaminergic neurons, in particular the effects of NE as a neurotrophic factor and through its ability to stimulate the expression of other neurotrophic factors, such as the brain-derived neurotrophic factor. Finally, we discussed other mechanisms intrinsic to NE’s effects. A better understanding of the noradrenergic modulation on dopaminergic neurons may be rewarding by significant advances in etiologic study and promising treatment of Parkinson’s disease.     

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson’s disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein α-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated α-synuclein increased in the same regions. VPA treatment counteracted both these α-synuclein alterations. Furthermore, monoubiquitinated α-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of α-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.     

MPTP-Induced Impairment of Cardiovascular Function

Neurotoxicity Research - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra...     

c-Jun N-terminal kinase mediates lactacystin-induced dopamine neuron degeneration

Parkinson disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been proposed that dysfunction of the ubiquitin proteasome system plays an important role in the pathogenesis of Parkinson disease, but the mechanisms underlying ubiquitin proteasome system-related neuron degeneration are unknown. Here, we demonstrate that the proteasome inhibitor lactacystin induces phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, the release of cytochrome c, activation of both caspase-9 and caspase-3, and sequential apoptosis of dopaminergic neurons in vitro. Most of these effects can be attenuated by the JNK inhibitor SP600125. Furthermore, infusion of lactacystin in rats in vivo also leads to phosphorylation of JNK before nigral neuron loss; chronic administration of SP600125 also blocks this loss. These results indicate that JNK is involved in proteasome inhibition-induced dopaminergic neuron degeneration through caspase-3-mediated apoptotic pathways, suggesting that this kinase may be a therapeutic target for the prevention of substantia nigra pars compacta degeneration in Parkinson disease patients.     

Intracerebroventricularly-administered 1-methyl-4-phenylpyridinium ion and brain-derived neurotrophic factor affect catecholaminergic nerve terminals and neurogenesis in the hippocampus,striatum and substantia nigra

Parkinson's disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra.A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) or 1-methyl-4-phenylpyridinium ion(MPP+),which cause the death of dopaminergic neurons.Administration of MPTP or MPP+ results in Parkinson's disease-like symptoms in rodents.However,it remains unclear whether intracerebroventricular MPP+ administration affects neurogenesis in the substantia nigra and subgranular zone or whether brain-derived neurotrophic factor alters the effects of MPP+.In this study,MPP+(100 nmol) was intracerebroventricularly injected into mice to model Parkinson's disease.At 7 days after administration,the number of bromodeoxyuridine(Brd U)-positive cells in the subgranular zone of the hippocampal dentate gyrus increased,indicating enhanced neurogenesis.In contrast,a reduction in Brd U-positive cells was detected in the substantia nigra.Administration of brain-derived neurotrophic factor(100 ng) 1 day after MPP+ administration attenuated the effect of MPP+ in the subgranular zone and the substantia nigra.These findings reveal the complex interaction between neurotrophic factors and neurotoxins in the Parkinsonian model that result in distinct effects on the catecholaminergic system and on neurogenesis in different brain regions.     

Protective effects of kidney-tonifying Chinese herbal preparation on substantia nigra neurons in a mouse model of Parkinson’s disease

The Chinese herbs Herba Epimedii, Fructus Ligustri Lucidi and Rhizoma Polygonati were injected into Parkinson’s disease mice established via intraperitoneal injection of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride. The selective monoamine oxidase B inhibitor selegiline was used as a positive control drug. After successive administration for 4 weeks, Herba Epimedii could downregulate the expression of caspase-3 and increase the brain-derived neurotrophic factor level, as well as increase tyrosine hydroxylase activity in the substantia nigra of Parkinson’s disease mouse models. Rhizoma Polygonati could downregulate the expression of caspase-3 and FasL, and increase neural growth factor and brain-derived neurotrophic factor levels. Fructus Ligustri Lucidi could downregulate caspase-3 expression. Rhizoma Polygonati and Fructus Ligustri Lucidi did not produce obvious effects on tyrosine hydroxylase activity. Herba Epimedii and Fructus Ligustri Lucidi yielded similar effects on apoptosis-promoting factors to those elicited by selegiline. Herba Epimedii and Rhizoma Polygonati significantly increased the levels of neurotrophic factors compared with selegiline. Herba Epimedii significantly increased tyrosine hydroxylase activity compared with selegiline. It is indicated that the kidney-tonifying Chinese herbal preparation can downregulate the expression of apoptosis-promoting factors, increase neurotrophic factors levels in the substantia nigra and striatum, as well as increase tyrosine hydroxylase activity in the substantia nigra of Parkinson’s disease mouse models, thereby exerting a stronger or similar neuroprotective effects compared with selegiline.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Discovery of nigral dopaminergic neurogenesis in adult mice

Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neu-rodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with pop-ular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What’s more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inlfammatory response mouse model. This observation may indicate that neuron loss in Parkinson’s disease results from inhibition of neurogenesis.     

Abnormalities of cerebral oxidative metabolism in animal models of Parkinson disease

Abnormalities of cerebral oxidative metabolism were investigated in "animal models" of Parkinson disease by in situ optical measurements of local cerebral blood volume and cytochrome oxidase redox shifts in rats two weeks after unilateral 6-hydroxydopamine lesions of the substantia nigra with or without interruption of ascending noradrenergic pathways. The data demonstrate oxidative metabolic dysfunction of ipsilateral cerebral hemispheres caused by lesions that involve both dopaminergic and noradrenergic systems but not when dopaminergic neurons only are affected. We speculate that the dementia of Parkinson disease may be more prevalent when degeneration of catecholaminergic systems is widespread and not restricted to the dopaminergic system.     

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.Key Words: adeno-associated virus, bone morphogenetic protein, dopaminergic neurons, growth/differentiation factor 5, neurodegeneration, neuroprotection, neurotrophic factor, Parkinson''s disease, Smad signaling, α-synuclein     

Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson’s disease rats

Previous studies found that iron accumulates in the substantia nigra of Parkinson’s disease patients. However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson’s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.     

帕金森小鼠多巴胺能神经元轴突变性研究

目的建立1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的大龄(32～36 w)小鼠帕金森病慢性模型,探讨其多巴胺能神经元轴突变性在帕金森病发病机制中的作用。方法应用免疫组织化学染色、Fluoro-Jade C染色等方法,观察MPTP诱导的小鼠黑质多巴胺能神经元轴突变性与胞体凋亡的时效性关系。结果慢性MPTP腹腔注射大龄小鼠可诱导产生典型且稳定的帕金森病症状,并可引起黑质-纹状体多巴胺能神经元的凋亡与轴突变性,但轴突变性在发生时间上早于细胞凋亡。结论轴突变性在帕金森病发病机制中起着十分重要的作用,帕金森病可能与神经元-轴突-神经胶质细胞网络损伤密切相关。     

Anti-apoptotic effect ofShudipingchan granule in the substantia nigra of rat models of Parkinson’s disease

Levodopa is the gold-standard treatment for Parkinson’s disease. However, although it alleviates the clinical symptoms, it cannot delay the progressive apoptosis of dopaminergic neurons or prevent motor complications in the long term. In the present study, we investigated the effect ofShudipingchan granule on neuronal apoptosis in a rat model of Parkinson’s disease, established by injecting 6-hydroxydopamine into the substantia nigra pars compacta and ventral tegmental area. We then administered levodopa (20 mg/kg intraperitoneally, twice daily) with or withoutShudipingchan granule (7.5 mL/kg intragastrically, twice daily), for 4 weeks. hTe long-term use of levodopa accel-erated apoptosis of nigral cells and worsened behavioral symptoms by activating the extracellular signal-regulated kinase pathway and downstream apoptotic factors. However, administration ofShudipingchan granule with levodopa reduced expression of phosphorylated extracellular signal-regulated kinase 1/2 and Bax, increased tyrosine hydroxylase and Bcl-2, reduced apoptosis in the substantia nigra, and markedly improved dyskinesia. hTese ifndings suggest thatShudipingchan granule suppresses neuronal apoptosis by inhibiting the hyper-phosphorylation of extracellular signal-regulated kinase and downregulating expression of anti-apoptotic genes.Shudipingchan granule, used in combination with levodopa, can effectively reduce the symptoms of Parkinson’s disease.     

Post-Mortem Studies of Neurturin Gene Therapy for Parkinson's Disease: Two Subjects with 10 Years CERE120 Delivery

Background

Neurturin is a member of the glial cell line-derived neurotrophic factor family of neurotrophic factors and has the potential to protectdegenerating dopaminergic neurons.

Objective

Here, we performed post-mortem studies on two patients with advanced Parkinson's disease that survived 10 years following AAV-neurturin gene (Cere120) delivery to verify long-term effects of trophic factor neurturin.

Methods

Cere120 was delivered to the putamen bilaterally in one case and to the putamen plus substantia nigra bilaterally in the second. Immunohistochemistry was used to examine neurturin, Rearranged during transfection(RET), phosphor-S6, and tyrosine hydroxylase expressions, inflammatory reactions, and α-synuclein accumulation.

Results

In both patients there was persistent, albeit limited, neurturin expression in the putamen covering 1.31% to 5.92% of the putamen. Dense staining of tyrosine hydroxylase-positive fibers was observed in areas that contained detectable neurturin expression. In substantia nigra, neurturin expression was detected in 11% of remaining melanin-containing neurons in the patient with combined putamenal and nigral gene delivery, but not in the patient with putamenal gene delivery alone. Tyrosine hydroxylase positive neurons were 66% to 84% of remaining neuromelanin neurons in substantia nigra with Cere120 delivery and 23% to 24% in substantia nigra without gene delivery. More RET and phosphor-S6 positive neurons were observed in substantia nigra following nigral Cere120. Inflammatory and Lewy pathologies were similar in substantia nigra with or without Cere120 delivery.

Conclusions

This study provides evidence of long-term persistent transgene expression and bioactivity following gene delivery to the nigrostriatal system. Therefore, future efforts using gene therapy for neurodegenerative diseases should consider means to enhance remaining dopamine neuron function and stop pathological propagation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.