minocycline and Parkinson-Disease

The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.

Topics: Alzheimer Disease; Animals; Anti-Bacterial Agents; Doxycycline; Drug Repositioning; Humans; Minocycline; Parkinson Disease; Tetracycline

The prevalence of Parkinson's disease, which affects millions of people worldwide, is increasing due to the aging population. In addition to the classic motor symptoms caused by the death of dopaminergic neurons, Parkinson's disease encompasses a wide range of nonmotor symptoms. Although novel disease-modifying medications that slow or stop Parkinson's disease progression are being developed, drug repurposing, which is the use of existing drugs that have passed numerous toxicity and clinical safety tests for new indications, can be used to identify treatment compounds. This strategy has revealed that tetracyclines are promising candidates for the treatment of Parkinson's disease. Tetracyclines, which are neuroprotective, inhibit proinflammatory molecule production, matrix metalloproteinase activity, mitochondrial dysfunction, protein misfolding/aggregation, and microglial activation. Two commonly used semisynthetic second-generation tetracycline derivatives, minocycline and doxycycline, exhibit effective neuroprotective activity in experimental models of neurodegenerative/ neuropsychiatric diseases and no substantial toxicity. Moreover, novel synthetic tetracyclines with different biological properties due to chemical tuning are now available. In this review, we discuss the multiple effects and clinical properties of tetracyclines and their potential use in Parkinson's disease treatment. In addition, we examine the hypothesis that the anti-inflammatory activities of tetracyclines regulate inflammasome signaling. Based on their excellent safety profiles in humans from their use for over 50 years as antibiotics, we propose the repurposing of tetracyclines, a multitarget antibiotic, to treat Parkinson's disease.

Topics: Anti-Inflammatory Agents; Apoptosis; Doxycycline; Drug Repositioning; Free Radical Scavengers; Humans; Inflammasomes; Minocycline; Mitochondria; Molecular Structure; Neuroprotective Agents; Parkinson Disease; Poly(ADP-ribose) Polymerase Inhibitors; Protease Inhibitors; Protein Aggregates; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Structure-Activity Relationship; Tetracyclines

Parkinson's disease (PD) is a type of motor system disorder that results from the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) of the midbrain. It is one of the most common neurodegenerative disorders, with an incidence that is second only to Alzheimer's disease (AD). Although replacement of dopamine can temporarily alleviate the symptoms of PD patients, it can not prevent the progression of the disease. Increasing evidence has suggested that neuroinflammation significantly contributes to the progress of PD. Therefore, anti-inflammatory therapy could represent a promising neuroprotective intervention with the potential to delay or prevent onset of the disease. This review summarizes several novel potential agents/candidates that might open new avenues for the treatment of PD. In addition to possessing demonstrated anti-inflammatory activities that operate through different molecular mechanisms, these agents exert neuroprotective effects by enhancing the production of neurotrophic factors or interfering with the apoptosis of neurons.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cytoprotection; Diterpenes; Encephalitis; Epoxy Compounds; Glatiramer Acetate; Humans; Microglia; Minocycline; Neuroprotective Agents; Parkinson Disease; Peptides; Phenanthrenes

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by cardinal features of tremor, bradykinesia, rigidity and postural instability. In addition to the motor symptoms patients experience cognitive decline eventually resulting in severe disability. Pathologically PD is characterized by neurodegeneration in the substantia nigra pars compacta (SNc) with intracytoplasmic inclusions known as Lewy bodies. In addition to the SNc there is neurodegeneration in other areas including cerebral cortex, raphe nuclei, locus ceruleus, nucleus basalis of meynert, cranial nerves and autonomic nervous system. Recent evidence supports the role of inflammation in Parkinson's disease. Apoptosis has been shown to be one of the pathways of cell death in PD. Minocycline, a tetracycline derivative is a caspase inhibitor, and also inhibits the inducible nitric oxide synthase which are important for apoptotic cell death. Furthermore, Minocycline has been shown to block microglial activation of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonism animal models and protect against nigrostriatal dopaminergic neurodegeneration. In this review, we present the current experimental evidence for the potential use of tetracycline derivative, minocycline, as a neuroprotective agent in PD.

Topics: Animals; Antiparkinson Agents; Apoptosis; Clinical Trials as Topic; Humans; Minocycline; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease

From time to time there have been reports of autoimmune disease succumbing to tetracycline antibiotics, but many have assumed this was due to coincidence, or to some ill-defined 'anti-inflammatory property' of the tetracyclines. But now the inflammation of sarcoidosis has succumbed to antibiotics in two independent studies. This review examines the cell wall deficient (antibiotic resistant) bacteria which have been found in tissue from patients with sarcoidosis. It examines how such bacteria can infect the phagocytes of the immune system, and how they may therefore be responsible for not only sarcoid inflammation, but also for other autoimmune disease. Proof positive of a bacterial pathogenesis for Sarcoidosis includes not only the demonstrated ability of these studies to put the disease into remission, but also the severity of Jarisch-Herxheimer shock resulting from endotoxin release as the microbes are killed. Studies delineating the hormone responsible for phagocyte differentiation in the Th1 immune response, 1,25-dihydroxyvitamin D, are discussed, and its utility as a marker of Th1 immune inflammation is reviewed. Finally, data showing that the behavior of this hormone is also aberrant in rheumatoid arthritis, systemic lupus erythematosus, and Parkinson's, raise the possibility that these diseases may also have a CWD bacterial pathogenesis.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Bacteria; Doxycycline; Forecasting; Humans; Lupus Erythematosus, Systemic; Minocycline; Parkinson Disease; Phagocytes; Sarcoidosis; Secondary Prevention; Tetracyclines; Vitamin D

Topics: Antiparkinson Agents; Clinical Trials as Topic; Creatine; Dopamine Agonists; Double-Blind Method; Humans; Indans; Minocycline; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Multicenter Studies as Topic; Nerve Tissue Proteins; Neuroprotective Agents; Oxepins; Parkinson Disease; Picolinic Acids; Randomized Controlled Trials as Topic; Riluzole; Selegiline; Ubiquinone

Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. The present review summarizes the available data supporting the clinical testing of minocycline for these neurodegenerative disorders. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

Topics: Animals; Apoptosis; Humans; Huntington Disease; Inflammation; Minocycline; Motor Neuron Disease; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease

To assess the predictive value of baseline measures of impairment, disability, and quality of life for the timing of initiation of symptomatic treatment in early Parkinson disease (PD).. Inception cohort analysis.. Ambulatory population from multiple sites in the United States and Canada.. Four hundred thirteen patients with early, untreated PD who participated in 2 double-blind trials that assessed the potential of experimental drugs to serve as disease-modifying agents in PD. Intervention Participants were randomized into treatment groups: creatine (n = 67), minocycline (n = 66), coenzyme Q10 (n = 71), GPI-1485 (n = 71), and placebo (n = 138). Main Outcome Measure Time between baseline assessment and need for the initiation of symptomatic treatment for PD. The following baseline variables were assessed for their relation to the main outcome measure, while adjusting for possible treatment effect: sex; age; level of education; race/ethnicity; disease duration; occupational status; and Unified Parkinson Disease Rating Scale (UPDRS), Medical Outcomes Study Short Form Survey, Modified Rankin Scale, Schwab and England Activities of Daily Living Scale, Total Functional Capacity Scale, 39-item Parkinson Disease Questionnaire, and Geriatric Depression Scale scores. Variables reaching statistical threshold in univariate analyses (alpha = .15) were entered into a multivariable Cox proportional hazards regression model using time to symptomatic treatment as the dependent variable.. Approximately half (48.5%) of the participants reached end point within 12 months. Higher baseline impairment and disability, as determined by UPDRS III (motor section), UPDRS II (activities of daily living section, participant rating), and Modified Rankin Scale scores and level of education were independently associated with an earlier need for symptomatic treatment.. In early PD, greater impairment and disability and higher level of education are independently associated with an earlier need for symptomatic treatment.

Topics: Activities of Daily Living; Adult; Aged; Antiparkinson Agents; Creatine; Disability Evaluation; Disease Management; Drug Administration Schedule; Endpoint Determination; Female; Humans; Male; Middle Aged; Minocycline; Mobility Limitation; Neuropsychological Tests; Parkinson Disease; Predictive Value of Tests; Severity of Illness Index; Surveys and Questionnaires; Tacrolimus; Time Factors; Ubiquinone

Creatine and minocycline were prioritized for testing in Phase II clinical trials based on a systematic evaluation of potentially disease modifying compounds for Parkinson disease (PD).. To test whether creatine and minocycline alter the course of early PD relative to a predetermined futility threshold for progression of PD in a randomized, double-blind, Phase II futility clinical trial. Agents that do not perform better than the futility threshold are rejected as futile and are not considered for further study.. Participants had a diagnosis of PD within 5 years, but did not require medications for the management of symptoms. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline to either the time when there was sufficient disability to warrant symptomatic therapy for PD or 12 months, whichever came first. Subjects were randomized 1:1:1 to receive creatine 10 g/day, minocycline 200 mg/day, or matching placebo. The futility threshold was set as a 30% reduction in UPDRS progression based on the placebo/tocopherol arm of the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. p values < or = 0.1 indicate futility.. Two hundred subjects were randomized to the three groups. Neither creatine (p = 0.96) nor minocycline (p = 0.66) could be rejected as futile based on the DATATOP futility threshold. The rate of progression for the calibration placebo group fell outside the 95% CI for the DATATOP historical control. In a sensitivity analysis, based on the threshold derived from the calibration placebo group, again neither drug could be rejected as futile. Tolerability was 91% in the creatine group and 77% in the minocycline group. Common adverse events included upper respiratory symptoms (26%), joint pain (19%), and nausea (17%).. Both creatine and minocycline should be considered for definitive Phase III trials to determine if they alter the long term progression of Parkinson disease (PD). Additional factors must be weighed before selecting agents for Phase III trials, including safety, tolerability, activity, cost, and availability of these two agents in comparison with other agents currently in development for PD.

Topics: Aged; Anti-Bacterial Agents; Creatine; Disabled Persons; Double-Blind Method; Female; Humans; Male; Middle Aged; Minocycline; Parkinson Disease

Prior studies indicated the involvement of neuroinflammation in the dopaminergic neurodegeneration in mice of paraquat (PQ)-induced Parkinson's disease (PD), but the underlying mechanisms remain to be elucidated. The present study explored whether microglia-mediated inflammation disrupted blood-brain barrier (BBB) and its related mechanism. C57BL/6 mice were injected intraperitoneally with PQ, twice a week for six weeks, following with or without minocycline (intraperitoneal injection, once every two days). The microglial activation, BBB permeability, expression of tight junctions (TJs) proteins and matrix metalloproteinase (MMP), as well as the loss of dopaminergic neurons and neurological deficits assessment, were evaluated. Minocycline efficiently restrained nigral microglial activation induced by PQ in mice. PQ-induced increase of EB content in the brain and excessive expression of zonula occludin-1 (ZO-1), claudin-5 and occludin were significantly dampened by minocycline treatment. Inhibition of microglial activation by minocycline greatly ameliorated the loss of dopaminergic neurons and neurological dysfunctions in PQ-exposed mice. Also, microglial inactivation downregulated the expression of MMP-2/9 in PQ-lesioned mice. These findings suggested the potential protection of suppressing microglia-mediated neuroinflammation against dopaminergic neurodegeneration through attenuating BBB disruption in a mouse of PQ-induced PD, and MMP-2/9 might involve in the contribution, which needs to be verified in future study.

Topics: Animals; Blood-Brain Barrier; Dopaminergic Neurons; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neuroinflammatory Diseases; Occludin; Paraquat; Parkinson Disease; Permeability

L-Dopa, while treating motor symptoms of Parkinson's disease, can lead to debilitating L-Dopa-induced dyskinesias, limiting its use. To investigate the causative relationship between neuro-inflammation and dyskinesias, we assessed if striatal M1 and M2 microglia numbers correlated with dyskinesia severity and whether the anti-inflammatories, minocycline and indomethacin, reverse these numbers and mitigate against dyskinesia. In 6-OHDA lesioned mice, we used stereology to assess numbers of striatal M1 and M2 microglia populations in non-lesioned (naïve) and lesioned mice that either received no L-Dopa (PD), remained non-dyskinetic even after L-Dopa (non-LID) or became dyskinetic after L-Dopa treatment (LID). We also assessed the effect of minocycline/indomethacin treatment on striatal M1 and M2 microglia and its anti-dyskinetic potential via AIMs scoring. We report that L-Dopa treatment leading to LIDs exacerbates activated microglia numbers beyond that associated with the PD state; the severity of LIDs is strongly correlated to the ratio of the striatal M1 to M2 microglial numbers; in non-dyskinetic mice, there is no M1/M2 microglia ratio increase above that seen in PD mice; and reducing M1/M2 microglia ratio using anti-inflammatories is anti-dyskinetic. Parkinson's disease is associated with increased inflammation, but this is insufficient to underpin dyskinesia. Given that L-Dopa-treated non-LID mice show the same ratio of M1/M2 microglia as PD mice that received no L-Dopa, and, given minocycline/indomethacin reduces both the ratio of M1/M2 microglia and dyskinesia severity, our data suggest the increased microglial M1/M2 ratio that occurs following L-Dopa treatment is a contributing cause of dyskinesias.

Topics: Animals; Anti-Inflammatory Agents; Antiparkinson Agents; Corpus Striatum; Dyskinesias; Indomethacin; Inflammation; Levodopa; Mice; Microglia; Minocycline; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley

Neurodegenerative diseases are still a challenge for effective treatments. The high cost of approved drugs, severity of side effects, injection site pain, and restrictions on drug delivery to the Central Nervous System (CNS) can overshadow the management of these diseases. Due to the chronic and progressive evolution of neurodegenerative disorders and since there is still no cure for them, new therapeutic strategies such as the combination of several drugs or the use of existing drugs with new therapeutic applications are valuable strategies. Tetracyclines are traditionally classified as antibiotics. However, in this class of drugs, doxycycline and minocycline exhibit also anti-inflammatory effects by inhibiting microglia/macrophages. Hence, they have been studied as potential agents for the treatment of neurodegenerative diseases. The results of in vitro and in vivo studies confirm the effective role of these two drugs as anti-inflammatory agents in experimentally induced models of neurodegenerative diseases. In clinical studies, satisfactory results have been obtained in Multiple sclerosis (MS) but not yet in other disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or Amyotrophic lateral sclerosis (ALS). In recent years, researchers have developed and evaluated nanoparticulate drug delivery systems to improve the clinical efficacy of these two tetracyclines for their potential application in neurodegenerative diseases. This study reviews the neuroprotective roles of minocycline and doxycycline in four of the main neurodegenerative disorders: AD, PD, ALS and MS. Moreover, the potential applications of nanoparticulate delivery systems developed for both tetracyclines are also reviewed.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anti-Bacterial Agents; Doxycycline; Drug Delivery Systems; Humans; Minocycline; Nanoparticle Drug Delivery System; Neurodegenerative Diseases; Parkinson Disease

Studies indicate that mutant α-synuclein (mαSyn) is involved in the pathogenesis of Parkinson's disease (PD). The mαSyn expression leads to the loss of dopaminergic neurons in the substantia nigra (SN) and consequent motor dysfunctions. Additionally, studies found that PD was accompanied by extensive neuroinflammation of SN. However, it remains unclear as to whether microglia participate in the mαSyn pathology. This issue is addressed by using AAV-mα-Syn (A30P-A53T) to overexpress the human mαSyn in the SN in view of establishing the PD model. Subsequently, minocycline (Mino) was used to inhibit microglia activity, and an interleukin-1 receptor (IL-1R1) antagonist was used to hinder the IL-1R1 function. Finally, immunohistochemistry was used to analyze phosphorylated αSyn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. mαSyn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological αSyn 12 weeks after AAV injection. The data demonstrated that inhibiting microglial activation or hindering IL-1R1 reversed the persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system, and development of Lewy body pathology caused by human mαSyn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.

Topics: alpha-Synuclein; Animals; Behavior, Animal; Corpus Striatum; Dopamine; Dopaminergic Neurons; Humans; Lewy Bodies; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Motor Activity; Mutation; Nerve Degeneration; Parkinson Disease; Receptors, Interleukin-1 Type I; Substantia Nigra

Parkinson's disease is a common, debilitating, neurodegenerative disorder for which the current gold standard treatment, levodopa (L-DOPA) is symptomatic. There is an urgent, unmet need for neuroprotective or, ideally, neuro-restorative drugs. We describe a 6-hydroxydopamine (6-OHDA) zebrafish model to screen drugs for neuroprotective and neuro-restorative capacity. Zebrafish larvae at two days post fertilization were exposed to 6-OHDA for three days, with co-administration of test drugs for neuroprotection experiments, or for 32 h, with subsequent treatment with test drugs for neuro-restoration experiments. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized by tyrosine hydroxylase immuno-histochemistry. Exposure to 6-OHDA for either 32 h or 3 days induced similar, significant locomotor deficits and neuronal loss in 5-day-old larvae. L-DOPA (1 mM) partially restored locomotor activity, but was neither neuroprotective nor neuro-restorative, mirroring the clinical situation. The calcium channel blocker, isradipine (1 µM) did not prevent or reverse 6-OHDA-induced locomotor deficit or neuronal loss. However, both the tetracycline analog, minocycline (10 µM), and the monoamine oxidase B inhibitor, rasagiline (1 µM), prevented the locomotor deficits and neuronal loss due to three-day 6-OHDA exposure. Importantly, they also reversed the locomotor deficit caused by prior exposure to 6-OHDA; rasagiline also reversed neuronal loss and minocycline partially restored neuronal loss due to prior 6-OHDA, making them candidates for investigation as neuro-restorative treatments for Parkinson's disease. Our findings in zebrafish reflect preliminary clinical findings for rasagiline and minocycline. Thus, we have developed a zebrafish model suitable for high-throughput screening of putative neuroprotective and neuro-restorative therapies for the treatment of Parkinson's disease.

Topics: Adrenergic Agents; Analysis of Variance; Animals; Disease Models, Animal; Dopaminergic Neurons; Drug Administration Schedule; Embryo, Nonmammalian; Indans; Isradipine; Levodopa; Locomotion; Minocycline; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Time Factors; Tyrosine 3-Monooxygenase; Zebrafish

We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91(phox-/-) 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91(phox-/-) 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91(phox-/-) 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91(phox-/-)-lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91(phox-/-) 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91(phox-/-) 6-OHDA lesioned mice, a likely mechanism whereby gp91(phox-/-) 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.

Topics: Animals; Apomorphine; Corpus Striatum; Disease Models, Animal; Dopaminergic Neurons; Inflammation; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Minocycline; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 2; NADPH Oxidases; Nerve Degeneration; NF-kappa B; Oxidopamine; Parkinson Disease; Substantia Nigra; Tumor Necrosis Factor-alpha

Topics: Acne Vulgaris; Humans; Male; Middle Aged; Minocycline; Parkinson Disease; Skin Diseases; Treatment Outcome

The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration.. Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-α infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples.. Here, we demonstrate that differences in the chronicity of TNF-α application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-α treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced.. We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control.

Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Brain; Disease Models, Animal; Mice; Minocycline; Neural Stem Cells; Neurogenesis; Oligodendroglia; Oxidopamine; Parkinson Disease; Tumor Necrosis Factor-alpha

Parkinson's disease is a neurodegenerative disorder which is in most cases of unknown etiology. Mutations of the Park-2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK-KO) mice have abnormalities that resemble the clinical syndrome. We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK-KO and wild-type (WT) mice with rotenone (ROT). ROT (0.025-0.1 microm) produced a dose-dependent selective reduction of tyrosine hydroxylase-immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule-associated protein 2 in PK-KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone (Boc-D-FMK). PK-KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK-KO than in WT cultures. Indomethacin, a cyclo-oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT-induced apoptosis but did not change tyrosine hydroxylase-immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor N-nitro-L-arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal-regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT-naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK-KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK-KO mice were more susceptible than WT to ROT and the combined effects of Park-2 suppression and ROT reproduced the c

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Cells, Cultured; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Genetic Predisposition to Disease; Immunity, Innate; Male; Mice; Mice, Knockout; Mice, Transgenic; Microglia; Minocycline; NADPH Oxidases; Neurons; Neuroprotective Agents; Parkinson Disease; Rotenone; Substantia Nigra; Tyrosine 3-Monooxygenase; Ubiquitin-Protein Ligases; Uncoupling Agents

Topics: Brain; Creatine; Dopamine; Humans; Minocycline; Parkinson Disease