Potential neuroprotective effect of ibuprofen,insights from the mice model of Parkinson's disease

BackgroundParkinson's disease (PD) is one of the most common neurodegenerative diseases. An inflammatory reaction seems to be involved in the pathological process in PD. Prospective clinical studies with various nonsteroidal anti-inflammatory drugs (NSAIDs) have shown that ibuprofen decreases the risk of PD. In the present study we investigated the influence of ibuprofen on dopaminergic neuron injury in the mice model of PD.MethodsTwelve-month-old male C57Bl mice were injected with MPTP together with various doses of ibuprofen (10, 30 or 50 mg/kg), administered 1 h before MPTP injection for 7 consecutive days. Evaluation concerned dopamine content in the striatum, tyrosine hydroxylase (TH) protein and α-synuclein expression measured 7 and 21 days post MPTP administration (dpa).ResultsMPTP caused injury to dopaminergic neuron endings in the striatum: dopamine content decreased by about 90% 7 dpa and by 85% 21 dpa; TH protein expression diminished by 21% 7 dpa; α-synuclein level decreased by 10 and 26% 7 and 21 dpa, respectively. Ibuprofen administration to mice treated with MPTP significantly increased the level of dopamine in the striatum 7 and 21 dpa. It also prevented TH protein decrease and increased α-synuclein level 21 dpa.ConclusionsIbuprofen was shown to protect neurons against MPTP-induced injury in the striatum. The possible mechanism of the neuroprotective effect of ibuprofen might be associated with decreased dopamine turnover and cyclooxygenases inhibition resulting in lower reactive oxygen species formation.     

Apomorphine therapy in Parkinson's disease: a review

Motor fluctuations are common and distressing for patients with advanced Parkinson's disease. Subcutaneous apomorphine injections can be an extremely valuable adjunctive therapy. In this review, the authors discuss the history, pharmacology, efficacy, safety and proper administration of apomorphine for treating ‘off’ states in Parkinson's disease, with a focus on intermittent subcutaneous administration.     

Cryptotanshinone protects against oxidative stress in the paraquat-induced Parkinson's disease model

Parkinson's disease (PD) is a common neurodegenerative disorder associated with striatal dopaminergic neuronal loss in the Substantia nigra. Oxidative stress plays a significant role in several neurodegenerative diseases. Paraquat (PQ) is considered a potential neurotoxin that affects the brain leading to the death of dopaminergic neurons mimicking the PD phenotype. Various scientific reports have proven that cryptotanshinone possesses antioxidant and anti-inflammatory properties. We hypothesized that cryptotanshinone could extend its neuroprotective activity by exerting antioxidant effects. This study was designed to evaluate the effects of cryptotanshinone in both cellular and animal models of PQ-induced PD. Annexin V-PI double staining and immunoblotting were used to detect apoptosis and oxidative stress proteins, respectively. Reactive oxygen species kits were used to evaluate oxidative stress in cells. For in vivo studies, 18 B6 mice were divided into three groups. The rotarod data revealed the motor function and immunostaining showed the survival of TH+ neurons in SNpc region. Our study showed that cryptotanshinone attenuated paraquat-induced oxidative stress by upregulating anti-oxidant markers in vitro, and restored behavioral deficits and survival of dopaminergic neurons in vivo, demonstrating its therapeutic potential.     

Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson's disease

Levetiracetam (LEV), a second-generation anti-epileptic drug, is used for treatment of both focal and generalized epilepsy. Growing body of evidence suggests that LEV may have neuroprotective effects. The present study was undertaken to investigate the neuroprotective effects of LEV on rotenone-induced Parkinson's disease (PD) in rats. Twenty-four adult Sprague-Dawley rats were infused with rotenone (3 μg/μl in DMSO) or vehicle (1 μl DMSO) into the left substantia nigra pars compacta (SNc) under stereotaxic surgery. PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly distributed into two groups; Group 1 (n = 8) and Group 2 (n = 8) were administered saline (1 ml/kg/day, i.p.) and LEV (600 mg/kg/day, i.p.) through 21 days, respectively. The effects of LEV treatment were evaluated by behavioral (rotation score), biochemical (brain homovalinic acid level and oxidant/antioxidant status) and immunohistochemical (tyrosine hydroxylase) parameters. Apomorphine-induced rotations in PD rats were significantly suppressed by LEV treatment. While unilateral rotenone lesion induced a dramatic loss of dopaminergic neurons both in the striatum and SNc, LEV treatment significantly attenuated the degenerative changes in dopaminergic neurons. Furthermore, LEV significantly decreased lipid peroxide levels, a marker of lipid peroxidation, and induced glutathione levels, catalase and superoxide dismutase activity in PD rats compared with saline group. We conclude that LEV may have beneficial effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the attenuation of oxidative stress.     

Therapeutic strategy at the crossroad of neuroinflammation and oxidative stress in age-related neurodegenerative diseases

Aging is the greatest risk factor for neurodegenerative diseases in the CNS, including two major age-related neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease. Understanding the biology of aging is pivotal in management of patients with neurodegenerative disorders. Genetically programmed aging and oxidative stress-elicited aging are two mechanisms of aging that are likely intertwined, leading to neurodegenerative damages. It is a commonly accepted that neurodegenerative diseases are the consequences of overproduction of oxidative stress or a result of compromised antioxidative mechanisms regardless of their aetiology. In aged brain, microglia increase in number and switch to a more pro-inflammatory state, providing a basis for greater inflammatory responses to inflammogens. Unfortunately, these unfavorable changes are often coupled with compromised capacity to remove oxidative products, allowing mutual perpetuation of inflammation and oxidative damage. This review highlights roles of microglia-mediated neuroinflammation and oxidative stress and association of these two. The possible novel therapeutic approaches are discussed in the context of focusing only on those possessing anti-inflammatory or antioxidative properties.     

Mitochondrial pathology in Parkinson's disease and implications for therapeutic intervention

Although the ultimate origin and role of mitochondrial pathology in Parkinson's disease (PD) remains controversial, accumulating data suggest that mitochondrial dysfunction is genetic and plays an important role in neurodegeneration. PD mitochondria display abnormal electron transport chain activity, increased reactive oxygen species generation, and abnormal calcium handling. These abnormalities arise, at least in part, from information encoded by mitochondrial DNA. These processes are implicated in current models of neuronal death and validate ongoing efforts to develop mitochondrial‐level pharmacologic interventions for the treatment of this disease.<n>Drug Dev. Res. 46:44–50, 1999. © 1999 Wiley‐Liss, Inc.     

西红花苷防治中枢神经系统疾病的研究进展

西红花苷是西红花中活性成分,具有多种药理作用。西红花苷具有出色的中枢神经系统保护作用,可以多维度、多途径地改善中枢神经系统疾病的神经功能,能抗抑郁、抗癫痫,对帕金森病、阿尔茨海默病、缺血性脑卒中、多发性硬化具有神经保护作用。综述了西红花苷防治中枢神经系统疾病的研究进展,以期提高西红花苷在临床治疗中的转化和应用。     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease

Current drugs used in the treatment of Parkinson''s disease (PD), for example, L-DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long-term use is associated with the appearance of adverse effects such as L-DOPA-induced dyskinesia. Much emphasis has therefore been placed on finding alternative non-dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre-synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD.     

Fatigue in Parkinson's disease

Introduction: Non-motor symptoms of Parkinson's disease (PD) have become increasingly recognized as central to the disease. These include somatic symptoms, such as pain and autonomic dysfunction (bladder dysfunction, constipation, dipahoresis and orthostatic hypotension) and behavioral problems, such as dementia, depression, fatigue, sleep disorders and psychosis. Research on fatigue has focused on its epidemiology with only a single report of a beneficial treatment trial, which used methylphenidate.

Areas covered: This review was made of all articles related to fatigue in Parkinson's disease arising in PUBMED. It will cover the types of fatigue, epidemiology, pathophysiology and treatment of fatigue in PD.

Expert opinion: Fatigue is a common and severe problem in Parkinson's disease. Virtually nothing is known about it aside from its epidemiology. It is an area greatly in need of investigation.     

红景天苷防治帕金森病的药理作用研究进展

帕金森病已成为威胁老年人身心健康的主要疾病之一。红景天苷是从红景天中提取的主要活性化合物之一,具有多种药理作用。红景天苷可通过抑制细胞凋亡、增强细胞自噬、降低氧化应激反应、降低炎症反应、促进胶质细胞源性神经营养因子的表达、提高多巴胺转运蛋白的表达以达到防治帕金森病的作用。总结了红景天苷防治帕金森病的药理作用及其作用机制,为红景天苷的临床使用提供参考。     

Individual susceptibility has a major impact on strong association between oxidative stress,defence systems and Parkinson's disease

Oxidative stress plays an important role in the degeneration of dopaminergic neurons, which causes Parkinson's disease (PD). Oxidative stress products, antioxidant and their balance have important roles in the development of oxidative stress-based PD. The impact of reactive oxygen species (ROS) and defence systems can be altered by genetic polymorphisms, and thus the risk of PD may also be affected. We aimed to investigate the possible association of individual susceptibility with the development of oxidative stress-based PD. For this purpose, we measured serum levels of folic acid, homocysteine, Vitamin B6 and B12 that play roles in folate-dependent one-carbon pathway, oxidant or antioxidant enzymes (NADPH oxidase, MnSOD, GPX), 8-OHdG and repair enzymes (OGG1, XRCC1 and MTH1) by ELISA, and analysed related gene polymorphisms by PCR-RFLP. XRCC1, ROS, NADPH and folic acid levels were found to be statistically higher in patients than controls. XRCC1, MnSOD and GPX activities were increased. We observed higher levels of 8-OHdG in patients with MnSOD and XRCC1 mutant genotypes and higher XRCC1 levels in patients with NOX p22 fox mutant genotypes rather than controls. We suggest that routinely clinical validation of major oxidative stress-related biomarkers will be a good approach to manage detrimental effects of PD.     

Unravelling mitochondrial pathways to Parkinson's disease

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson''s disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson''s disease models. However, identification of the recessive genes implicated in Parkinson''s disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson''s disease.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Non-mammalian animal models of Parkinson's disease for drug discovery

Importance of the field: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of predominantly elderly individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. Compounding this problem is the current lack of a truly representative mammalian model of PD. However, a number of non-mammalian models of PD have been created in recent years that hold tremendous promise to accelerate our understanding of the disease as well as to transform the drug discovery process.

Areas covered in this review: This review provides an overview of the various Caenorhabditis elegans and Drosophila genetic models of PD that have been generated to date and discusses the utility of these model systems in the identification of molecules of potential therapeutic value for the PD patient.

What the reader will gain: Readers will appreciate the strengths (and limitations) of C. elegans and Drosophila in modeling salient features of the disease as well as their usefulness in uncovering novel gene–gene interaction and pathways relevant to PD pathogenesis. Readers will also appreciate how technological advancements have allowed the direct evaluation of novel compounds in these living models of PD in a virtually high-throughput manner.

Take home message: Non-mammalian models of PD provide a valuable in vivo platform for drug screening. Unlike cell-based systems, these living models with an intact nervous system allow for a more meaningful evaluation of the neuroprotective properties of genetic and chemical modifiers to be conducted.     

FSD-C10抑制MPTP诱导的帕金森病小鼠氧化应激及炎性反应研究

目的 研究口服FSD-C10对帕金森病（Parkinson's disease,PD）小鼠的治疗作用,并探讨其相关机制。方法 小鼠随机分为正常组、PD组和FSD-C10组（50 mg·kg^-1）,旷场行为学测试评估小鼠移动的总距离、休息时间、穿格次数;Western blotting检测脑组织酪氨酸羟化酶（tyrosine hydroxylase,TH）、ROCKⅡ;比色法检测脑组织过氧化氢酶（catalase,CAT）、还原型谷胱甘肽（glutathione,GSH）、丙二醛和一氧化氮（nitric oxide,NO）;ELISA检测脑组织肿瘤坏死因子（tumor necrosis factor-α,TNF-α）、白介素-1β（interleukin-1β,IL-1β）及白介素-6（interleukin-6,IL-6）。结果 与正常组比较,PD组小鼠移动的总距离、穿格次数降低（P<0.01）,休息时间延长（P<0.01）,TH表达降低（P<0.05）,ROCKⅡ表达增高（P<0.05）,CAT活力下降（P<0.05）,GSH含量降低（P<0.01）,丙二醛含量升高（P<0.05）,TNF-α、IL-1β、IL-6及NO升高（P<0.05或P<0.01）。与PD组比较,FSD-C10组小鼠移动的总距离、穿格次数增加（P<0.05）,休息时间缩短（P<0.01）,TH表达增高（P<0.05）,ROCKⅡ表达降低（P<0.05）,CAT活力增加（P<0.01）,GSH含量升高（P<0.01）,丙二醛含量降低（P<0.01）,TNF-α、IL-1β、IL-6及NO下降（P<0.01）。结论 口服FSD-C10可以改善PD小鼠的行为学表现,对PD有明确的治疗作用,其作用机制可能与恢复氧化-抗氧化体系平衡、减少炎性因子分泌相关。     

Neurotrophic factors as a therapeutic target for Parkinson's disease

Background: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. Objective: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. Methods: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: ‘Parkinson's disease’, ‘Neurotrophic factors’, ‘BDNF’ (Brain-derived neurotrophic factor), ‘GDNF’ and ‘Neurturin’. Original articles were reviewed, and relevant citations from these articles were also appraised. Conclusion: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.     

苯海索联合司来吉兰治疗帕金森病的临床研究

目的探讨盐酸苯海索片联合盐酸司来吉兰片治疗帕金森病的临床疗效。方法选取2017年5月—2018年11月在郑州大学第五附属医院诊治的帕金森病患者82例,根据用药的差别分为对照组(41例)和治疗组(41例)。对照组口服盐酸司来吉兰片,5 mg/次,若控制不佳可增至10 mg/次;治疗组在对照组的基础上口服盐酸苯海索片,开始1～2 mg/d,然后每3～5天增加2 mg,至疗效最好而又不出现副反应为止,最大剂量10 mg/d,分3～4次服用。两组患者均经12周治疗。观察两组患者临床疗效,同时比较治疗前后两组患者MoCA、MMSE、SPOCA-AUT、UPDRS和PDQ-39评分,以及血清白细胞介素-1β(IL-1β)、YKL40、胱抑素C(Cys-C)、可溶性肿瘤坏死因子受体-1(s TNFR-1)、脂联素(APN)、尿酸(UA)、一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)、对氧磷脂酶1(PON1)和循环谷胱甘肽过氧化物酶(CGP)水平。结果治疗后,对照组临床有效率为80.49%,显著低于治疗组的97.56%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者MoCA评分显著升高(P0.05),MMSE、SPOCA-AUT、UPDRS和PDQ-39评分均显著降低(P0.05),且治疗组患者这些评分改善程度更明显(P0.05)。治疗后,两组患者血清IL-1β、YKL40、Cys-C、s TNFR-1水平均明显下降(P0.05),APN、UA水平显著升高(P0.05),且治疗组患者这些血清学指标改善更明显(P0.05)。治疗后,两组患者血清NOS、SOD、PON1、CGP水平均显著升高(P0.05),且治疗组比对照组升高更明显(P0.05)。结论盐酸苯海索片联合盐酸司来吉兰片治疗帕金森病效果显著,可有效促进患者认知功能、神经功能、运动功能及生活质量的改善。     

Safinamide in the treatment of Parkinson's disease

Importance of the field: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage.

Areas covered in this review: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound – safinamide, which has both dopaminergic and non-dopaminergic actions – might address these.

What the reader will gain: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced ‘OFF’ time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD.

Take home message: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.