Association of Glial Activation and α-Synuclein Pathology in Parkinson's Disease / 神经科学通报·英文版

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.

Neuroprotective Effect of β-Lapachone in MPTP-Induced Parkinson's Disease Mouse Model: Involvement of Astroglial p-AMPK/Nrf2/HO-1 Signaling Pathways

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether β-Lapachone (β-LAP), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. β-LAP reduced the tyrosine hydroxylase (TH)-immuno-reactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, β-LAP protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether β-LAP induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that β-LAP increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, β-LAP increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). β-LAP also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that β-LAP exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.

Delayed Treatment of Capsaicin Produces Partial Motor Recovery by Enhancing Dopamine Function in MPP⁺-lesioned Rats via Ciliary Neurotrophic Factor

Transient receptor potential vanilloid subtype 1 (TRPV1) on astrocytes prevents ongoing degeneration of nigrostriatal dopamine (DA) neurons in MPP⁺-lesioned rats via ciliary neurotrophic factor (CNTF). The present study determined whether such a beneficial effect of astrocytic TRPV1 could be achieved after completion of injury of DA neurons, rather than ongoing injury, which seems more relevant to therapeutics. To test this, the MPP⁺-lesioned rat model utilized here exhibited approximately 70~80% degeneration of nigrostriatal DA neurons that was completed at 2 weeks post medial forebrain bundle injection of MPP⁺. TRPV1 agonist, capsaicin (CAP), was intraperitoneally administered. CNTF receptor alpha neutralizing antibody (CNTFRαNAb) was nigral injected to evaluate the role of CNTF endogenously produced by astrocyte through TRPV1 activation on DA neurons. Delayed treatment of CAP produced a significant reduction in amphetamine-induced rotational asymmetry. Accompanying this behavioral recovery, CAP treatment increased CNTF levels and tyrosine hydroxylase (TH) activity in the substantia nigra pars compacta (SNpc), and levels of DA and its metabolites in the striatum compared to controls. Interestingly, behavioral recovery and increases in biochemical indices were not reflected in trophic changes of the DA system. Instead, behavioral recovery was temporal and dependent on the continuous presence of CAP treatment. The results suggest that delayed treatment of CAP increases nigral TH enzyme activity and striatal levels of DA and its metabolites by CNTF endogenously derived from CAP-activated astrocytes through TRPV1, leading to functional recovery. Consequently, these findings may be useful in the treatment of DA imbalances associated with Parkinson's disease.

Reinforcement omission effects in rats with bilateral lesions in the substantia nigra pars compacta and ventral tegmental area

Reinforcement omission effects (ROEs) are characterized by higher response rates after reinforcement omission than after reinforcement delivery. This pattern of behavior is interpreted in terms of motivational and attentional processes. Recent studies from our laboratory have shown that the amygdala, nucleus accumbens, and medial prefrontal cortex are involved in ROE modulation. Also, the literature has demonstrated a role of other areas such as substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) in processes related to surprising events, such as prediction error and presentation or omission of an event (exteroceptive stimulus and reinforcement). Since these structures send projections to areas related to ROE modulation such as the amygdala, nucleus accumbens, and prefrontal cortex, the objective of the present study was to determine whether the SNc and VTA also integrate the circuit involved in ROE modulation. Rats were trained on a fixed-interval 12 s with limited-hold 6 s signaled schedule of reinforcement (Pre-lesion training). After acquisition of stable performance, the rats received bilateral neurotoxic lesions of the SNc (Experiment 1) and VTA (Experiment 2). Following postoperative recovery, the rats were submitted to two refresher sessions (Post-lesion training). Subsequently, the training was changed from a 100 to a 50% schedule of reinforcement (Post-lesion testing). In both experiments, the results showed that there was no difference in performance between sham rats and rats with bilateral lesions of the SNc or the VTA.

Astrocyte Specificity and Coverage of hGFAP-CreERT2 Tg(GFAP-Cre/ERT2)13Kdmc Mouse Line in Various Brain Regions

Astrocyte is the most abundant cell type in the central nervous system and its importance has been increasingly recognized in the brain pathophysiology. To study in vivo function of astrocyte, astrocyte-specific gene-targeting is regarded as a powerful approach. Especially, hGFAP-CreERT2, which expresses tamoxifen-inducible Cre recombinase under the human GFAP promoter, has been developed and characterized from several research groups. However, one of these mouse lines, [Tg(GFAP-Cre/ERT2)13Kdmc] from Ken McCarthy group has not been quantitatively analyzed, despite its frequent use. Here, we performed comprehensive characterization of this mouse line with quantitative analysis. By crossing this mouse line with Ai14 (RCL-tdTomato), a very sensitive Cre reporter mouse line, we visualized the Cre-expressing cells in various brain regions. For quantitative analysis, we immunostained S100β as an astrocytic marker and NeuN, tyrosine hydroxylase or calbindin as a neuronal marker in different brain regions. We calculated ‘astrocyte specificity’ as the proportion of co-labelled S100β and tdTomato positive cells in the total number of tdTomato positive cells and the ‘astrocyte coverage’ as the proportion of co-labelled S100β and tdTomato positive cells in the total number of S100β positive cells. Interestingly, we found varying degree of astrocyte specificity and coverage in each brain region. In cortex, hypothalamus, substantia nigra pars compacta and cerebellar Purkinje layer, we observed high astrocyte specificity (over 89%) and relatively high astrocyte coverage (over 70%). In striatum, hippocampal CA1 layer, dentate gyrus and cerebellar granule layer, we observed high astrocyte specificity (over 80%), but relative low astrocyte coverage (50–60%). However, thalamus and amygdala showed low astrocyte specificity (about 65%) and significant neuron specificity (over 30%). This hGFAP-CreERT2 mouse line can be useful for genetic modulations of target gene either in gain-of-function or loss-of-function studies in the brain regions with high astrocyte specificity and coverage. However, the use of this mouse line should be restricted to gain-of-function studies in the brain regions with high astrocyte specificity but low coverage. In conclusion, hGFAP-CreERT2 mouse line could be a powerful tool for gene-targeting of astrocytes in cortex, striatum, hippocampus, hypothalamus, substantia nigra pars compacta and cerebellum, but not in thalamus and amygdala.

Presynaptic Dysfunction by Familial Factors in Parkinson Disease / 대한배뇨장애요실금학회지

Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer disease. The loss of specific brain area, the substantia nigra pars compacta is known as a major etiology, however it is not fully understood how this neurodegeneration is initiated and what precisely causes this disease. As one aspect of pathophysiology for PD, synaptic dysfunction (synaptopathy) is thought to be an earlier appearance for neurodegeneration. In addition, some of the familial factors cumulatively exhibit that these factors such as α-synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced kinase 1, and DJ-1 are involved in the regulation of synaptic function and missense mutants of familial factors found in PD-patient show dysregulation of synaptic functions. In this review, we have discussed the physiological function of these genetic factors in presynaptic terminal and how dysregulation of presynaptic function by genetic factors might be related to the pathogenesis of Parkinson disease.

Non-Motor Symptom Burdens Are Not Associated with Iron Accumulation in Early Parkinson's Disease: a Quantitative Susceptibility Mapping Study

BACKGROUND: Quantitative susceptibility mapping (QSM) has been used to measure iron accumulation in the deep nuclei of patients with Parkinson's disease (PD). This study examined the relationship between non-motor symptoms (NMSs) and iron accumulation in the deep nuclei of patients with PD. METHODS: The QSM data were acquired from 3-Tesla magnetic resonance imaging (MRI) in 29 patients with early PD and 19 normal controls. The Korean version of the NMS scale (K-NMSS) was used for evaluation of NMSs in patients. The patients were divided into high NMS and low NMS groups. The region-of-interest analyses were performed in the following deep nuclei: red nucleus, substantia nigra pars compacta, substantia nigra pars reticulata, dentate nucleus, globus pallidus, putamen, and head of the caudate nucleus. RESULTS: Thirteen patients had high NMS scores (total K-NMSS score, mean = 32.1), and 16 had low NMS scores (10.6). The QSM values in the deep were not different among the patients with high NMS scores, low NMS scores, and controls. The QSM values were not correlated linearly with K-NMSS total score after adjusting the age at acquisition of brain MRI. CONCLUSION: The study demonstrated that the NMS burdens are not associated with iron accumulation in the deep nuclei of patients with PD. These results suggest that future neuroimaging studies on the pathology of NMSs in PD should use more specific and detailed clinical tools and recruit PD patients with severe NMSs.

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs / Neuroinflamação na patofisiologia da doença de Parkinson e evidências terapêuticas de drogas antiinflamatórias

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.

A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. Nesta revisão, foram abordadas evidências de envolvimento do processo inflamatório e uma possível utilidade terapêutica de drogas antiinflamatórias na DP.

[Comparison of the intranasal and intraperitoneal injection of MPTP on density of dark neurons in pars compacta of substantia nigra in animal model of Parkinson's disease]

Background and Objective: Parkinson disease [PD] is the second most common neurologic disorder that results following degeneration of dopaminergic neurons in the pars compacta of substintia nigra [SNc]. The 1-methyl-1,2,3,6-tetrahydropiridine [MPTP] is a chemical neurotoxin that widely used in animal models of PD. This study was carried out to evaluate the numerical density of dark neurons [DNs] in the SNc in mice subjected to intraperitoneal and intranasal injection of different doses of MPTP

Methods: In this experimental study, 90 male adult BALB/c mice were randomly allocated int four experimental groups including: group 1 [MPTP was injected via i.p. at the dose of 20mg/kg per 2 hours for 4 times], group 2 [MPTP was injected via i.p. at the dose of 30mg/kg for 5 consecutive days], group 3 [MPTP was injected via i.n. at a single dose of 1mg/kg], group 4 [MPTP was injected via i.n. at a single dose of 1mg/kg], four sham and one normal groups. 20 days after the final injection, the animal's brain were removed and stained by toluidine blue. Numerical density of DNs was counted

Results: Intranasal injection of MPTP significantly increased density of dark neurons in the pars compacta of substintia nigra in compare to intraperitoneally injection of MPTP [P<0.05]

Conclusion: Intranasal injection of MPTP is more effective manner to induce degeneration of neurons in substintia nigra in animal model of Parkinson's disease

Sex differences in dopaminergic neurons of substantia nigra pars compacta of adult and aged rats: a histological and immunohistochemical study

Substantia nigra pars compacta [SNC] is the main source of dopaminergic [DA] input to the striatum. Parkinson's disease is a neurodegenerative disease affecting DA neurons in SNC, with a higher incidence in men. To study the effect of sex on the structure of DA neurons in adult and aged rat SNC. The brains of 22 adult [11 males and 11 females] and 22 aged [11 males and 11 females] albino rats were processed for histological and immunohistochemical examination of DA neurons in the right SNC. Golgi-Cox staining of adult male SNC neurons showed more varicosities and less extension of their dendrites than adult female SNC. Adult male SNC showed a nonsignificant increase in tyrosine hydroxylase-positive neurons than adult female SNC. Aging-related changes were more marked in aged male rats. Aged SNC showed decreased packing density of neurons, some of which appeared irregular and deeply stained. A reduction in Nissl staining was observed. Golgi-Cox staining showed a marked decrease in extension and branching of the dendrites with loss of spines. Ultrastructurally, accumulation of lipofuscin pigment, membranous whorls, dilated Golgi bodies, decreased rough endoplasmic reticulum, and destroyed cristae of mitochondria were observed. A significant reduction in tyrosine hydroxylase-positive neurons was evident in aged SNC. Sex differences in DA neurons of SNC were more apparent in aged rats, with more degenerative changes in the aged male group, which may underlie the predisposition of males to Parkinson's disease

Meta-analysis of rasagiline as monotherapy in early Parkinson's disease

INTRODUCTION: Parkinson's disease (PD) is a second most common neurodegenerative disorder which affects 1 % to 2% of people older than 60 years and is characterized by cardinal features of bradykinesia, rigidity, and rest tremor (2). Most of the motor disability experienced by patients results from progressive loss of dopaminergic neurons of the Substantia Nigra pars compacta (SNpc). However, recent studies have shown that PD is also associated with extensive non-dopaminergic pathology. Recent trend in the treatment of PD include development of new drugs that will not only address the symptom relief but will also ameliorate the progression of dopaminergic neuron degeneration (3).OBJECTIVE: To assess the evidence from randomized controlled trials the effects of Rasagiline compared with placebo in the treatment of patients with Parkinson's diseaseDESIGN: Meta-analysis of 3 randomized trials identified through Medline/Pubmed and Cochrane Library. Summary of the outcome variables was computed using difference of two means of the United Parkinson's disease rating scale (UPDRS) score and their corresponding standard error of the means under fixed effects models. The chi-square test was done to test heterogeneity. Statistical analysis was done using Revman version 5.RESULTS: The sample size of the studies ranged from 13 to 595 patients. The mean age of the trial participants were in the 60s with a relatively narrow standard deviation. All studies were randomized and placebo controlled. The main outcome measure was change in the UPDRS score from baseline. The mean difference between Rasagiline 1 mg and placebo is -3.06 (95% CI -3.81, -2.31) and Rasagiline 2mg and placebo is -3.17 (95% CI -3.92, -2.42). The overall effect was statistically significant (z=8.01; pCONCLUSION: Based on this meta-analysis, Rasagiline is effective as monotherapy in early Parkinson's disease.