Extracellular microvesicles-derived from microglia treated with unaggregated α-synuclein attenuate mitochondrial fission and toxicity-induced by Parkinsonian toxin MPP
Li Na,Wu Yufeng,Zhu Liangyi,Huang Yang,Liu Zongran,Shi Min,Soltys David,Zhang Jing,Chang Qing
Biochemical and biophysical research communications
Biological functions of extracellular vesicles (EVs) are being discovered to be critical in neurodegenerative disorders, including Parkinson's disease (PD). A previous study using cellular models of PD has suggested that EVs derived from microglia exposed to aggregated α-synuclein (α-Syn) leads to enhanced neurotoxicity. However, the function of EVs derived from microglia not treated with aggregated a-Syn or treated with monomeric α-Syn are unclear. Here, employing a widely used cellular model of PD, i.e. SH-SY5Y cells treated with MPP, a well-established parkinsonian toxicant, we revealed that microglial EVs, when not stimulated by aggregated α-Syn, appeared to be protective, and the mechanisms, though remain to be defined further, appeared to involve mitochondrial dynamics, especially mitochondrial fission.
10.1016/j.bbrc.2019.07.084
Association between SGK1 and α-synuclein in skeletal muscle in an MPTP-induced Parkinson's disease model.
Neuroscience letters
Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the substantia nigra and it is known to involve the accumulation of α-synuclein (α-syn), which is a neuroprotein that promotes degeneration of dopaminergic neurons. Serum/glucocorticoid-related kinase 1 (SGK1) is involved in the physiological and pathological processes in neurons. The aim of this study was to examine the relationship between SGK1 and α-syn expression in muscle tissue of a PD model and in C2C12 cells. Western blotting, immunohistochemistry, and immunofluorescence microscopy confirmed reduced SGK1 and increased α-syn expression in skeletal muscle of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared to the control group. To determine the relationship between SGK1 and α-syn, SGK1 small interfering RNA (siRNA) knockdown was performed in C2C12 cells, which showed that suppression of SGK1 levels resulted in increased α-syn expression. The main finding of our study is that reduction of SGK1 expression contributes to the pathogenesis of PD by increasing the expression of α-syn in skeletal muscle of MPTP-treated mice and C2C12 cells. This study confirms that decreased SGK1 induces increased α-syn expression in skeletal muscle, which suggests that maintaining SGK1 expression may improve PD symptoms.
10.1016/j.neulet.2023.137464
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models.
EMBO molecular medicine
Astrocytes and microglia are brain-resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro-inflammatory properties of glia by suppressing the intracellular NFκB-, NLRP3-inflammasome-, and CGAS-STING-mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti-inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD-associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia-mediated neuroinflammation.
10.15252/emmm.202013076
Acute levodopa intake and associated cortisol decrease in patients with Parkinson disease.
Müller Thomas,Muhlack Siegfried
Clinical neuropharmacology
Levodopa application improves motor symptoms in patients with Parkinson disease (PD). Levodopa induces lower cortisol plasma levels and decreases serotonergic activity in certain brain areas of fish. The objectives of this study were to perform repeat cortisol concentration measurements before and after the administration of soluble levodopa/benserazide (dose, 200 mg) in 32 patients with PD during an interval of 150 minutes. The cortisol concentrations significantly decreased after levodopa intake, particularly in the patients with more advanced stage of PD, but not in the less affected patients. There were significantly lower cortisol levels in the patients at the advanced stage of PD compared with those of the earlier patients with PD, particularly at -30, 0, and 90 minutes before/after levodopa application. Significant inverse relations were found between the cortisol levels and the Unified Parkinson Disease Rating Scale total score, particularly at 60 and 90 minutes after levodopa intake. Neurodegeneration occurs in striatal regions and in the brain stem of patients with PD. The 5-HT-containing neuronal terminals of the brain stem hypothetically mediate the cortisol level decrease after levodopa intake because these cells contain an important fraction of amino acid decarboxylase. Therefore, this compartment may be the site of enzymatic conversion of superfluous, exogenous levodopa to dopamine. Consequently, short-term levodopa administration also leads to levodopa uptake in these 5-HT-metabolizing neurons, which interferes with the 5-HT synthesis and may cause a decrease of 5-HT levels. These lower 5-HT levels reduce the hypothalamic function and, via the corticotropin axis, the subsequent peripheral cortisol release. Thus, levodopa-induced cortisol decrease may be related to PD progression.
10.1097/01.WNF.0000240954.72186.91
Cortisol levels, motor, cognitive and behavioral symptoms in Parkinson's disease: a systematic review.
Soares Nayron Medeiros,Pereira Gabriela Magalhães,Altmann Vivian,de Almeida Rosa Maria Martins,Rieder Carlos R M
Journal of neural transmission (Vienna, Austria : 1996)
Parkinson's disease (PD) is a progressive and multifactorial neurodegenerative disease. It has been suggested that a dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) occurs in PD. Furthermore, this dysregulation may be involved in triggering, exacerbation or progression of disease. The objective of this study was to systematically review the literature regarding cortisol levels and their relation with motor, cognitive and behavioral symptoms in patients with PD. A systematic search was performed in PubMed and Embase databases, according to PRISMA norms. Twenty-one studies were included, which evaluated baseline levels of cortisol and motor, cognitive, behavioral symptoms, drugs administration or deep brain stimulation to PD treatment. Sample size ranged from 7 to 249 individuals. In 14 studies that assessed cortisol levels in PD patients, seven showed elevation of cortisol levels. In relation to symptomatology, high levels of cortisol were associated with worst functional scores evaluated by UPDRS, depression and behavior in risk preference. Medication interactions showed an influence on the regulation of cortisol release, mainly, conventional drugs used in the PD's treatment, such as levodopa. The results found in this review point to a possible relationship between cortisol levels and symptoms in PD, indicating that an HPA axis dysfunction related to cortisol level occurs in PD.
10.1007/s00702-018-1947-4
Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.
Li Si-Yue,Wang Ya-Li,Liu Wen-Wen,Lyu Dong-Jun,Wang Fen,Mao Cheng-Jie,Yang Ya-Ping,Hu Li-Fang,Liu Chun-Feng
Chinese medical journal
BACKGROUND:Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. METHODS:The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. RESULTS:L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01). CONCLUSIONS:In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.
10.4103/0366-6999.204920
Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease.
Schoffer Kerrie L,Henderson Robert D,O'Maley Karen,O'Sullivan John D
Movement disorders : official journal of the Movement Disorder Society
There is limited evidence for the treatment of orthostatic hypotension in idiopathic Parkinson's disease. The objective of this study was to determine the efficacy of three treatments (nonpharmacological therapy, fludrocortisone, and domperidone). Phase I assessed the compliance, safety, and efficacy of nonpharmacological measures. Phase II was a double-blind randomized controlled crossover trial of the two medications. Primary outcome measures consisted of the orthostatic domain of the Composite Autonomic Symptom Scale (COMPASS-OD), a clinical global impression of change (CGI), and postural blood pressure testing via bedside sphygmomanometry (Phase I) or tilt table testing (Phase II). For the 17 patients studied, nonpharmacological therapy did not significantly alter any outcome measure. Both medications improved the CGI and COMPASS-OD scores. There was a trend towards reduced blood pressure drop on tilt table testing, with domperidone having a greater effect.
10.1002/mds.21428
The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson's Disease.
Brain sciences
The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.
10.3390/brainsci12121695
Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids.
Tanaka J,Fujita H,Matsuda S,Toku K,Sakanaka M,Maeda N
Glia
Effects of steroid hormones on the regulation of function and morphology of microglial cells were investigated using the cultured cells isolated from forebrain of newborn rats. Cortisol, corticosterone, and aldosterone at 100 nM caused a strong shrinkage of microglial cells cultured in a serum-supplemented medium. However, cholesterol, pregnenolone, testosterone, estradiol, and dehydroepiandrosterone did not exhibit any significant effects. The corticosteroids also inhibited the GM-CSF-mediated ramification of microglia in a serum-free medium. An anti-glucocorticoid agent RU38486 abolished the effects of corticosteroids on the microglial morphology, suggesting the presence of functional glucocorticoid receptor (GR) in microglial cells. The presence of GR was confirmed by immunoblotting with an antibody to the receptor. Cytokines GM-CSF and interleukin-3 altered the level of GR expression. Binding experiments with [3H]-corticosterone demonstrated the presence of not only GR but also mineralocorticoid receptor (MR): the dissociation constants (Kd) and the number of binding sites (Bmax) were 0.8 nM and 15 fmol/mg protein for MR and 5.0 nM and 73 fmol/mg protein for GR, respectively. The pure glucocorticoid RU28362 and dexamethasone at 20 nM (but not aldosterone and corticosterone at the same concentration) inhibited proliferation of microglial cells, as revealed by PCNA immunocytochemistry. RU28362 inhibited the activities of inducible nitric oxide synthase and acid phosphatase at concentrations higher than 1 nM. Aldosterone and corticosterone exhibited the similar inhibitory effect at 100 nM, and this inhibition was completely overcome by RU38486. On the other hand, corticosterone and aldosterone at concentrations lower than 1 nM enhanced the activities of both enzymes. The antimineralocorticoid agent spironolactone eliminated the stimulatory effects of corticosterone on the enzyme activities. In accordance with these biochemical results, electron microscopic observations revealed that glucocorticoids enhanced the formation of lysosomal vacuolation in microglial cells and aldosterone increased the number and size of lysosomes. In conclusion, it is suggested that GR and MR mediated the opposite effects of corticosterone on the functions of microglial cells; the hormone acted as an inhibitor through GR and as an stimulator through MR.
Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation.
de Pablos Rocío M,Herrera Antonio J,Espinosa-Oliva Ana M,Sarmiento Manuel,Muñoz Mario F,Machado Alberto,Venero José L
Journal of neuroinflammation
BACKGROUND:Parkinson's disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson's disease. METHODS:To achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations. RESULTS:Data showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson's disease. This effect was dependent on glucocorticoids. CONCLUSIONS:Our data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson's disease.
10.1186/1742-2094-11-34
Inflammation in Parkinson's disease: role of glucocorticoids.
Herrero María-Trinidad,Estrada Cristina,Maatouk Layal,Vyas Sheela
Frontiers in neuroanatomy
Chronic inflammation is a major characteristic feature of Parkinson's disease (PD). Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules e.g., TNF-α, iNOS, IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Recent genetic studies point to the role of immune system in the etiology of PD, thus in combination with environmental factors, both peripheral and CNS-mediated immune responses could play important roles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are known to mediate chronic inflammation, the roles of other immune-competent cells are less well understood. Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis. Glucocorticoids (GCs) released from adrenal glands upon stimulation of HPA axis, in response to either cell injury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both through direct transcriptional action on target genes and by indirectly inhibiting transcriptional activities of transcriptional factors such as NF-κB, AP-1 or interferon regulatory factors. In PD patients, the HPA axis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GR function in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucial effect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover, GCs are also known to regulate human brain vasculature as well as blood brain barrier (BBB) permeability, any dysfunction in their actions may influence infiltration of cytotoxic molecules resulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor actions is likely important in dopamine neuron degeneration through establishment of chronic inflammation.
10.3389/fnana.2015.00032
Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism.
Ros-Bernal Francisco,Hunot Stéphane,Herrero Maria Trinidad,Parnadeau Sebastien,Corvol Jean-Christophe,Lu Lixia,Alvarez-Fischer Daniel,Carrillo-de Sauvage María Angeles,Saurini Françoise,Coussieu Christiane,Kinugawa Kiyoka,Prigent Annick,Höglinger Günter,Hamon Michel,Tronche François,Hirsch Etienne C,Vyas Sheela
Proceedings of the National Academy of Sciences of the United States of America
Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.
10.1073/pnas.1017820108
Relevance of chronic stress and the two faces of microglia in Parkinson's disease.
Herrera Antonio J,Espinosa-Oliva Ana M,Carrillo-Jiménez Alejandro,Oliva-Martín María J,García-Revilla Juan,García-Quintanilla Alberto,de Pablos Rocío M,Venero José L
Frontiers in cellular neuroscience
This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson's disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD.
10.3389/fncel.2015.00312
Can stress trigger Parkinson's disease?
Djamshidian Atbin,Lees Andrew J
Journal of neurology, neurosurgery, and psychiatry
In this manuscript we summarize the role of chronic stress as a potential trigger factor for Parkinson's disease. Underlying mechanisms and stress-induced changes to the neuronal networks have been highlighted. Examples of stress induced reversible symptoms that resemble parkinsonism in humans and in animal models raise the question whether emotional stress can cause striatal degeneration in susceptible patients. A Pubmed literature review searching for the terms 'Stress', 'Distress and Parkinson's disease', 'Emotional Distress and Parkinson's disease', 'Stress and Parkinson's disease', 'Prodromal Parkinson's disease', 'Non motor symptoms and Parkinson's disease', 'Paradoxical kinesia', 'Psychogenic parkinsonism', 'Functional somatic syndromes', 'Chronic fatigue syndrome', 'Irritable bowel syndrome', 'Fibromyalgia', 'Dopamine and fibromyalgia', 'Dopamine and chronic fatigue syndrome' and 'Dopamine and irritable bowel syndrome' was carried out until April 2013. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this viewpoint.
10.1136/jnnp-2013-305911
Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson's disease.
Růžička Filip,Jech Robert,Nováková Lucie,Urgošík Dušan,Bezdíček Ondřej,Vymazal Josef,Růžička Evžen
Psychoneuroendocrinology
Considering the functional organization of the subthalamic nucleus (STN), we hypothesized that subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease might have a differential impact on the hypothalamic-pituitary-adrenal axis in relation to the position of active stimulating contact within the STN. In addition, we searched for any STN-DBS-related morning plasma cortisol changes in association with postoperative anxiety and weight gain. A plasma cortisol measurement was performed on the day of initiation of bilateral STN-DBS and repeated after 1 and 17 months in twenty patients with advanced Parkinson's disease. The body weight change and anxiety scores following the implantation were assessed as well. The electrode positions in the STN were determined on T1-weighted magnetic resonance images. After initiation of stimulation, cortisol levels significantly decreased and the cortisol changes after 1 and 17 months strongly correlated with the position of active contact in the subthalamic area. Patients with at least one contact located more medially in the STN experienced a significantly greater decrease of cortisol than those with one or both active contacts more laterally. Furthermore, the lower cortisol levels were strongly associated with higher trait anxiety and weight gain. These changes mimicked the effects of chronic stress and suggest the disturbing impact of STN-DBS on limbic and motivational systems.
10.1016/j.psyneuen.2014.12.001
[Experience using veroshpiron in the combined therapy of parkinsonism].
Vartanian K Z,Karimova M Kh
Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia : 1952)
The authors found changes in the function of the adrenals in parkinsonism, which were expressed in the form of elevated excretion of aldosterone and diminished excretion of hydrocortisone. The use of veroshpiron led to a certain normalization of adrenal function and to activation of the sympatho-adrenal system. The study of the clinical efficacy of veroshpiron administered for 20 days in a daily dose of 50-100 mg to 56 patients with parkinsonism showed improvement of a varying degree in 87.5% of patients. A 20-day course of veroshpiron resulted in regression of approximately 1/3 of the main symptoms of parkinsonism with the improvement persisting for several months.
[Effect of veroshpiron on hormone level in patients with Parkinson's disease].
Karimova M Kh,Vartanian K Z,Petelin L S,Kubatiev A A
Klinicheskaia meditsina
Blood hormones and urinary excretion of corticosteroids were measured in 39 parkinsonian patients receiving chemotherapy with adjuvant 3-week course of verospiron (50-100 mg/day). The latter promoted normalization of endocrine and clinical statuses in the majority of the patients. It is suggested that the response may be obtained via neuropeptide systems of the brain.
THE EFFECTS OF HYDROCORTISONE ON SYNAPTIC PROCESSES IN PARKINSON'S DISEASE UNDERLYING THE POTENTIAL THERAPEUTIC STRATEGIES.
Georgian medical news
The study was carried out electrophysiological effects of hydrocortisone for protection on the prelimbic cortex (PrL) neurons in rats, particularly in response to high-frequency stimulation (HFS) of the Caudate-Putamen nuclear complex (CPu) on the models of Parkinson's disease (PD). The study involved 19 rats of the Albino line, each weighing 250 gr. The rats were divided into three experimental groups: intact, rotenone model of Parkinson's disease (PD), and rats with PD but treated with hydrocortisone for protection. Extracellular recording was conducted to measure the impulse activity of single neurons in the prelimbic cortex (PrL) particularly in response to high-frequency stimulation (HFS) of the Caudate-Putamen nuclear complex (CPu) on the models of PD and PD treated with hydrocortisone for protection. In rats with the PD model, there was a decrease in post-stimulus synaptic depressor tetanic effects compared to the norm. This means that the ability of synapses to depress their activity after stimulation was reduced in PD. Conversely, excitatory effects increased in PD rats compared to the norm. This indicates an increase in the excitatory response of neurons in the PD model. When hydrocortisone was applied in PD rats, the frequency of impulse activity dropped sharply, even falling below the levels observed in the normal condition. This indicates that hydrocortisone treatment mitigated the heightened neural activity induced by PD, possibly returning it to a more normal state. Overall, these findings suggest that PD alters synaptic responses and neural activity in the PrL, and hydrocortisone treatment seems to reverse some of these effects.
Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model.
The Journal of neuroscience : the official journal of the Society for Neuroscience
UNLABELLED:Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD. SIGNIFICANCE STATEMENT:The immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant extent infiltrated in the neurodegenerating area of the brain. Specially designed liposomes targeted for the CD163 receptor were loaded with glucocorticoids and injected peripherally to modify the infiltrated CD163 cells toward an anti-inflammatory profile. This modification of the CD163 population resulted in a distinctive microglial response that correlated with decreased dopaminergic cell death and better motor performance.
10.1523/JNEUROSCI.1636-16.2016
Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model.
Ham Sangwoo,Lee Yun-Il,Jo Minkyung,Kim Hyojung,Kang Hojin,Jo Areum,Lee Gum Hwa,Mo Yun Jeong,Park Sang Chul,Lee Yun Song,Shin Joo-Ho,Lee Yunjong
Scientific reports
Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.
10.1038/s41598-017-00614-w
Plasma profiles of adrenocorticotropic hormone, cortisol, growth hormone and prolactin in patients with untreated Parkinson's disease.
Bellomo G,Santambrogio L,Fiacconi M,Scarponi A M,Ciuffetti G
Journal of neurology
Plasma profiles of prolactin, growth hormone, adrenocorticotropic hormone (ACTH) and cortisol were evaluated in a group of untreated patients with idiopathic Parkinson's disease and a group of healthy age-matched controls. Plasma integrated concentrations of all hormones except prolactin were significantly lower in the patients as compared with the controls; however, prolactin nocturnal peak concentration was significantly elevated in the patients; nocturnal growth hormone levels were significantly reduced in the Parkinson group; ACTH and cortisol plasma concentrations were also consistently lower during most of the day in the patients with Parkinson's disease. These data confirm the presence of a hypothalamic disturbance in patients with idiopathic Parkinson's disease, which can affect pituitary function.
Renin-aldosterone system in Parkinson's disease.
Barbeau A,Gillo-Joffroy L,Boucher R,Nowaczynski W,Genest J
Science (New York, N.Y.)
Low blood pressure is frequent in the akinetic form of Parkinson's disease. A low renin activity in plasma as well as a low rate of aldosterone secretion is demonstrated in these patients. Renin activity in the plasma is further decreased by treatment with L-dihy-droxyphenylalanine, thus partially accouinting for the hypotensive episodes seen with this form of therapy.
10.1126/science.165.3890.291
Chronic corticosterone aggravates behavioral and neuronal symptomatology in a mouse model of alpha-synuclein pathology.
Burtscher Johannes,Copin Jean-Christophe,Rodrigues João,Kumar Senthil T,Chiki Anass,Guillot de Suduiraut Isabelle,Sandi Carmen,Lashuel Hilal A
Neurobiology of aging
Debilitating, yet underinvestigated nonmotor symptoms related to mood/emotion, such as depression, are common in Parkinson's disease. Here, we explore the role of depression and of the amygdala, a brain region robustly linked to mood/emotion, in synucleinopathy. We hypothesized that mood/emotional deficits might accelerate Parkinson's disease-linked symptomatology, including the formation of α-synuclein pathology. We combined elevated corticosterone treatment, modeling chronic stress and depression, with a model of seeded α-synuclein pathology in mouse striatum and assessed behavioral parameters with a focus on mood/emotion, and neuropathology. We report behavioral resilience against α-synuclein proteinopathy in the absence of additional insults, potentially based on hormesis/conditioning mechanisms. Elevated corticosterone, however, reversed α-synuclein pathology-induced behavioral adaptations and was associated with increased dopaminergic cell loss as well as aggravated α-synuclein pathology in specific brain regions, such as the entorhinal cortex. These findings point to elevated glucocorticoids as a risk factor for Parkinson's disease progression and highlight the potential of glucocorticoid level reducing strategies to slow down disease progression in synucleinopathy.
10.1016/j.neurobiolaging.2019.08.007
Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease.
Brain : a journal of neurology
Parkinson's disease is a neurodegenerative disorder with uncertain aetiology and ill-defined pathophysiology. Activated microglial cells in the substantia nigra (SN) are found in all animal models of Parkinson's disease and patients with the illness. Microglia may, however, have detrimental and protective functions in this disease. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of Parkinson's disease. Central lipopolysaccharide injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor signs and shifted microglial activation towards a pro-inflammatory phenotype with increased interleukin-1beta (IL-1beta) secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, chronic systemic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 directly exacerbated 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide was a downstream molecule of IL-1 action and partially responsible for the exacerbation of neurodegeneration observed. Thus, IL-1 exerts its exacerbating effect on degenerating dopaminergic neurons by direct and indirect mechanisms. This work demonstrates an unequivocal association between IL-1 overproduction and increased disease progression, pointing to inflammation as a risk factor for Parkinson's disease and suggesting that inflammation should be efficiently handled in patients to slow disease progression.
10.1093/brain/awn101
Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease: A Drug-wide Association Study.
Neurology
BACKGROUND AND OBJECTIVES:The incidence rate of Parkinson disease (PD) has been increasing rapidly during the past years. Yet, no treatments exist to prevent or slow the progression of the disease. Moreover, we are unable to detect early disease stages during which intervention with disease-modifying therapies is most likely to succeed. The objective of this study was to perform an agnostic drug-wide association study estimating the association between the use of any of the drugs prescribed in Norway and the subsequent risk of PD. METHODS:This registry-based cohort study use data from the entire Norwegian population between 2004 and 2019 linked to the Norwegian Prescription Registry, with more than 600 million individual prescriptions. Drug classes were screened according to Anatomical Therapeutic Chemical codes at level 2, corresponding to therapeutic subgroups. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the associations between drug classes and PD risk. All values were corrected for multiple testing using the false discovery rate. In addition, we conducted sensitivity analyses of exposure definition as well as time-lag and dose-response analyses. RESULTS:The study population comprised 3,223,672 individuals, 15,849 of whom developed PD during the follow-up. We identified 31 drug classes that were statistically significantly associated with PD risk in Norway during the follow-up. Drugs acting on the renin-angiotensin system (HR 0.92, 95% CI 0.89-0.95), corticosteroids for systemic use (0.88, 95% CI 0.84-0.93), and vaccines (0.89, 95% CI 0.82-0.96) were associated with a decreased risk of PD even up to 10 years before PD onset. Drug classes used to treat symptoms related to prodromal signs of PD, such as constipation, urological issues, and depression, were associated with an increased risk of subsequent diagnosis of PD with HRs of 1.6 (95% CI 1.49-1.73), 1.48 (1.42-1.53), and 1.94 (1.87-2.01), respectively. DISCUSSION:This drug-wide study identified 31 drug classes that were associated with the PD risk change. It reveals the links of renin-angiotensin system medications, vaccines, and corticosteroids with PD risk and suggests that monitoring drug usage using pharmacoepidemiology may allow identifying individuals with prodromal PD.
10.1212/WNL.0000000000207899
Alpha-synuclein-induced stress sensitivity renders the Parkinson's disease brain susceptible to neurodegeneration.
Acta neuropathologica communications
A link between chronic stress and Parkinson's disease (PD) pathogenesis is emerging. Ample evidence demonstrates that the presynaptic neuronal protein alpha-synuclein (asyn) is closely tied to PD pathogenesis. However, it is not known whether stress system dysfunction is present in PD, if asyn is involved, and if, together, they contribute to neurodegeneration. To address these questions, we assess stress axis function in transgenic rats overexpressing full-length wildtype human asyn (asyn BAC rats) and perform multi-level stress and PD phenotyping following chronic corticosterone administration. Stress signaling, namely corticotropin-releasing factor, glucocorticoid and mineralocorticoid receptor gene expression, is also examined in post-mortem PD patient brains. Overexpression of human wildtype asyn leads to HPA axis dysregulation in rats, while chronic corticosterone administration significantly aggravates nigrostriatal degeneration, serine129 phosphorylated asyn (pS129) expression and neuroinflammation, leading to phenoconversion from a prodromal to an overt motor PD phenotype. Interestingly, chronic corticosterone in asyn BAC rats induces a robust, twofold increase in pS129 expression in the hypothalamus, the master regulator of the stress response, while the hippocampus, both a regulator and a target of the stress response, also demonstrates elevated pS129 asyn levels and altered markers of stress signalling. Finally, defective hippocampal stress signalling is mirrored in human PD brains and correlates with asyn expression levels. Taken together, our results link brain stress system dysregulation with asyn and provide evidence that elevated circulating glucocorticoids can contribute to asyn-induced neurodegeneration, ultimately triggering phenoconversion from prodromal to overt PD.
10.1186/s40478-024-01797-w
Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease.
Hopfner Franziska,Wod Mette,Höglinger Günter U,Blaabjerg Morten,Rösler Thomas W,Kuhlenbäumer Gregor,Christensen Kaare,Deuschl Günther,Pottegård Anton
Neurology
OBJECTIVE:To verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively. METHODS:We obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries. RESULTS:We included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use. CONCLUSION:We confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk.
10.1212/WNL.0000000000007694
Adrenal medullary transplantation into the brain for treatment of Parkinson's disease: clinical outcome and neurochemical studies.
Mayo Clinic proceedings
Transplantation of adrenal medulla into the caudate nucleus as treatment for Parkinson's disease was performed in eight patients. Although our previous 6-month follow-up revealed early modest improvement, an extension of that follow-up to 1 year disclosed no additional gains in any patient. At the end of 1 year, only one patient could be categorized as moderately improved; three patients were mildly improved, and four patients were unimproved. The rationale for transplanting adrenal medulla was to reestablish a physiologic source of dopamine to the striatum. We measured cerebrospinal fluid (CSF) and plasma catecholamines and metabolites before and after transplantation. Conjugated dopamine (the predominant form of dopamine found in the CSF) and homovanillic acid (the major dopamine metabolite) were modestly and inconsistently increased in the CSF. Conjugated and free epinephrine and norepinephrine, as well as 3-methoxy-4-hydroxyphenylglycol concentrations were not increased in CSF after graft placement, an indication that the adrenal chromaffin cells were no longer producing high levels of these nondopamine catecholamines and metabolites. CSF cortisol concentrations were not increased after transplantation, compared with values from controls, consistent with low numbers of functioning adrenal cortical cells contaminating the graft (or poor survival). Posttransplantation CSF did not induce a neurotrophic effect in cell cultures of 15-day embryonic rat dorsal root ganglion or PC12 (rat pheochromocytoma) cell lines. Survival of samples of patients' adrenal medullary tissue for 2 weeks in tissue culture attested to the viability of the graft at the time of transplantation. The relative concentrations of dopamine to epinephrine or norepinephrine increased in these cultured adrenal medullary cells, presumably because of loss of the glucocorticoid influence on catecholamine synthesis. A wide variety of factors could have contributed to our failure to replicate the earlier impressive results of adrenal-to-brain transplantation reported by others. Continued transplantation studies in animal models of parkinsonism are necessary for better elucidation of these factors.
10.1016/s0025-6196(12)62532-4
Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour.
Djamshidian Atbin,O'Sullivan Sean S,Papadopoulos Andrew,Bassett Paul,Shaw Karen,Averbeck Bruno B,Lees Andrew
Journal of neurology, neurosurgery, and psychiatry
OBJECTIVE:To investigate salivary cortisol samples in patients with Parkinson's disease (PD) with and without impulsive compulsive behaviours (ICB) during a risk task. METHODS:Salivary cortisol levels were measured in 13 PD patients without ICB (PD-ICB) and in 15 PD patients with ICB (PD+ICB) before, after medication and throughout the day, and were compared with results with 14 healthy controls. All participants also performed a gambling task to assess risk taking behaviour. RESULTS:Significantly higher diurnal cortisol levels were found in the PD-ICB group compared with healthy controls but no differences were seen between the PD+ICB and the control group. Increased cortisol levels were significantly correlated with increased risk taking in PD+ICB patients but no interaction was found in the PD-ICB group. CONCLUSIONS:The findings are in keeping with previous studies which have linked low cortisol levels with antisocial behaviour. The higher cortisol levels during the risk task in the PD+ICB group are consistent with reports in pathological gamblers during gambling and addicts during drug abuse. The results support the hypothesis that cortisol plays an important role in risk taking in ICBs.
10.1136/jnnp.2011.245746
Association between Decreased SGK1 and Increased Intestinal α-Synuclein in an MPTP Mouse Model of Parkinson's Disease.
International journal of molecular sciences
Parkinson's disease (PD) is a globally common progressive neurodegenerative disease resulting from the loss of dopaminergic neurons in the brain. Increased α-synuclein (α-syn) is associated with the degeneration of dopaminergic neurons and non-motor symptoms like gastrointestinal disorders. In this study, we investigated the association between serum/glucocorticoid-related kinase 1 (SGK1) and α-syn in the colon of a PD mouse model. SGK1 and α-syn expression patterns were opposite in the surrounding colon tissue, with decreased SGK1 expression and increased α-syn expression in the PD group. Immunofluorescence analyses revealed the colocation of SGK1 and α-syn; the PD group demonstrated weaker SGK1 expression and stronger α-syn expression than the control group. Immunoblotting analysis showed that Na/K pump ATPase α1 expression levels were significantly increased in the PD group. In SW480 cells with SGK1 knockdown using SGK1 siRNA, decreasing SGK1 levels corresponded with significant increases in the expression levels of α-syn and ATPase α1. These results suggest that SGK1 significantly regulates Na/K pump ATPase, influencing the relationship between electrolyte balance and fecal formation in the PD mouse model. Gastrointestinal disorders are some of the major prodromal symptoms of PD. Therefore, modulating SGK1 expression could be an important strategy for controlling PD.
10.3390/ijms242216408