RESUMEN
Parkinson's disease is a neurodegenerative disorder while secondary-parkinsonism can be caused by infectious, inflammatory, traumatic, vascular, hereditary, paraneoplastic, or even induced by drug/metal poisoning. Here we report an uncommon subacute parkinsonism who presented with micrographia and mild cognitive impairment. The CSF examination showed inflammatory profile and positive anti-NMDAR antibody. The patient showed no improvement with levodopa/benserazide administration but satisfactory response to immunotherapy with methylprednisolone. This case indicated that autoimmune etiology should also be considered in parkinsonism to exclude a treatable condition.
Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Autoanticuerpos/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Escritura Manual , Inmunoterapia , Enfermedad de Parkinson Secundaria/inmunología , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Antiparkinsonianos/uso terapéutico , Benserazida/uso terapéutico , Combinación de Medicamentos , Fiebre de Origen Desconocido/etiología , Humanos , Inmunosupresores/uso terapéutico , Levodopa/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Pruebas Neuropsicológicas , Enfermedad de Parkinson Secundaria/diagnóstico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/psicología , Temblor/etiologíaRESUMEN
Rotenone is a mitochondrial complex I inhibitor, which can cause the death of dopaminergic (DA) neurons and Parkinson's disease (PD). Currently, whether metformin has a protective effect on neurotoxicity induced by rotenone is unclear. The purpose of this study was to evaluate the potential protective effect of metformin against rotenone-induced neurotoxicity. PD animal model was established by unilateral rotenone injection into the right substantia nigra (SN) of C57BL/6 mice. The behavioral tests were performed by rotarod test and cylinder test. The numbers of TH-positive neurons and Iba-1 positive microglia in the SN were investigated by immunohistochemical staining. The mRNA levels of proinflammatory cytokines (TNF-α and IL-1ß) and molecules involved in endoplasmic reticulum (ER) stress (ATF4, ATF6, XBP1, Grp78, and CHOP) in the midbrain were detected by Quantitative real-time PCR. This study showed that 50 mg/kg metformin given orally daily, beginning 3 d before rotenone injection and continuing for 4 weeks following rotenone injection, significantly ameliorated dyskinesia, increased the number of TH-positive neurons, and mitigated the activation of microglia in the SN in rotenone-induced PD mice. Furthermore, 50 mg/kg metformin markedly downregulated the expression of proinflammatory cytokines (TNF-α and IL-1ß) and ER stress-related genes (ATF4, ATF6, XBP1, Grp78, and CHOP) in rotenone-induced PD mice. Metformin has a protective effect on DA neurons against rotenone-induced neurotoxicity through inhibiting neuroinflammation and ER stress in PD mouse model.
Asunto(s)
Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Metformina/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Sustancias Protectoras/farmacología , Rotenona/toxicidad , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Inflamación , Interleucina-1beta/metabolismo , Masculino , Metformina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/inmunología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Sustancias Protectoras/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder characterized by the loss of dopaminergic (DA) neurons. Limited understanding of the early molecular pathways associated with the demise of DA neurons, including those of inflammatory exacerbation of neurodegeneration, is a major impediment to therapeutic development. Recent studies have implicated gene-environment interactions in PD susceptibility. We used transcriptomic profiling in a Drosophila PD model in response to paraquat (PQ)-induced oxidative stress to identify pre-symptomatic signatures of impending neuron dysfunction. Our RNAseq data analysis revealed extensive regulation of innate immune response genes following PQ ingestion. We found that PQ exposure leads to the activation of the NF-κB transcription factor, Relish, and the stress signaling factor JNK, encoded by the gene basket in Drosophila. Relish knockdown in the dopaminergic neurons confers PQ resistance and rescues mobility defects and DA neuron loss. Furthermore, PQ-induced toxicity is mediated through the immune deficiency signaling pathway. Surprisingly, the expression of Relish-dependent anti-microbial peptide (AMPs) genes is suppressed upon PQ exposure causing increased sensitivity to Gram-negative bacterial infection. This work provides a novel link between PQ exposure and innate immune system modulation underlying environmental toxin-induced neurodegeneration, thereby underscoring the role of the innate immune system in PD pathogenesis.
Asunto(s)
Perfilación de la Expresión Génica , Inmunidad Innata , Paraquat/toxicidad , Enfermedad de Parkinson Secundaria , Transducción de Señal/inmunología , Animales , Proteínas de Drosophila , Drosophila melanogaster , Humanos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Transducción de Señal/efectos de los fármacosRESUMEN
We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson's disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine-induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose.
Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Exenatida/administración & dosificación , Incretinas/administración & dosificación , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Animales , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/inmunología , Cuerpo Estriado/patología , Preparaciones de Acción Retardada/administración & dosificación , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Masculino , Oxidopamina/administración & dosificación , Oxidopamina/toxicidad , Enfermedad de Parkinson Secundaria/etiología , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/patología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/inmunología , Sustancia Negra/patología , Resultado del Tratamiento , Tirosina 3-Monooxigenasa/inmunologíaRESUMEN
Microglial NADPH oxidase (Nox2) plays a key role in chronic neuroinflammation and related dopaminergic neurodegeneration in Parkinson's disease (PD). However, the mechanisms behind Nox2 activation remain unclear. Here, we revealed the critical role of complement receptor 3 (CR3), a microglia-specific pattern recognition receptor, in Nox2 activation and subsequent dopaminergic neurodegeneration by using paraquat and maneb-induced PD model. Suppression or genetic deletion of CR3 impeded paraquat and maneb-induced activation of microglial Nox2, which was associated with attenuation of dopaminergic neurodegeneration. Mechanistic inquiry revealed that blocking CR3 reduced paraquat and maneb-induced membrane translocation of Nox2 cytosolic subunit p47phox, an essential step for Nox2 activation. Src and Erk (extracellular regulated protein kinases) were subsequently recognized as the downstream signals of CR3. Moreover, inhibition of Src or Erk impaired Nox2 activation in response to paraquat and maneb co-exposure. Finally, we found that CR3-deficient mice were more resistant to paraquat and maneb-induced Nox2 activation and nigral dopaminergic neurodegeneration as well as motor dysfunction than the wild type controls. Taken together, our results showed that CR3 regulated Nox2 activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway in a two pesticide-induced PD model, providing novel insights into the immune pathogenesis of PD.
Asunto(s)
Neuronas Dopaminérgicas/patología , Antígeno de Macrófago-1/inmunología , NADPH Oxidasa 2/inmunología , Enfermedad de Parkinson Secundaria/patología , Transducción de Señal , Animales , Células Cultivadas , Neuronas Dopaminérgicas/inmunología , Activación Enzimática , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Paraquat , Enfermedad de Parkinson Secundaria/inmunología , Plaguicidas , Ratas Sprague-Dawley , Familia-src Quinasas/inmunologíaRESUMEN
Mutations in the TREM2 gene confer risk for Alzheimer's disease and susceptibility for Parkinson's disease (PD). We evaluated the effect of TREM2 deletion in a 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, measuring neurodegeneration and microglia activation using a combined in vivo imaging and postmortem molecular approach. In wild-type mice, MPTP administration induced a progressive decrease of [11C]FECIT uptake, culminating at day 7. Neuronal loss was accompanied by an increase of TREM2, IL-1ß, and translocator protein (TSPO) transcript levels, [11C]PK11195 binding and GFAP staining (from day 2), and an early and transient increase of TNF-α, Galectin-3, and Iba-1 (from day 1). In TREM2 null (TREM2-/-) mice, MPTP similarly affected neuron viability and microglial cells, as shown by the lower level of Iba-1 staining in basal condition, and reduced increment of Iba-1, TNF-α, and IL-1ß in response to MPTP. Likely to compensate for TREM2 absence, TREM2-/- mice showed an earlier increment of [11C]PK11195 binding and a significant increase of IL-4. Taken together, our data demonstrate a central role of TREM2 in the regulation of microglia response to acute neurotoxic insults and suggest a potential modulatory role of TSPO in response to immune system deficit.
Asunto(s)
Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Eliminación de Gen , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Degeneración Nerviosa/genética , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/patología , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Regulación hacia Arriba , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/patología , Degeneración Nerviosa/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunologíaRESUMEN
The objectives of this study were to determine the behavioral and molecular responses in the adult zebrafish (Danio rerio) central nervous system (CNS) following a dietary exposure to the pesticide dieldrin. Zebrafish were fed pellets spiked with 0.03, 0.15, or 1.8µg/g dieldrin for 21days. Behavioral analysis revealed no difference in exploratory behaviors or those related to anxiety. Transcriptional networks for T-cell aggregation and selection were decreased in expression suggesting an immunosuppressive effect of dieldrin, consistent with other studies investigating organochlorine pesticides. Processes related to oxidative phosphorylation were also differentially affected by dieldrin. Quantitative proteomics (iTRAQ) using a hybrid quadrupole-Orbitrap identified 226 proteins that were different following one or more doses. These proteins included ATP synthase subunits (mitochondrial) and hypoxia up-regulated protein 1 which were decreased and NADH dehydrogenases (mitochondrial) and signal recognition particle 9 which were up-regulated. Thus, proteins affected were functionally associated with the mitochondria and a protein network analysis implicated Parkinson's disease (PD) and Huntington's disease as diseases associated with altered proteins. Molecular networks related to mitochondrial dysfunction and T-cell regulation are hypothesized to underlie the association between dieldrin and PD. These data contribute to a comprehensive transcriptomic and proteomic biomarker framework for pesticide exposures and neurodegenerative diseases. BIOLOGICAL SIGNIFICANCE: Dieldrin is a persistent organochlorine pesticide that has been associated with human neurodegenerative disease such as Parkinson's disease. Dieldrin is ranked 18th on the 2015 U.S. Agency for Toxic Substances and Disease Registry and continues to be a pesticide of concern for human health. Transcriptomics and quantitative proteomics (ITRAQ) were employed to characterize the molecular networks in the central nervous system that are altered with dietary exposure to dieldrin. We found that transcriptional and protein networks related to the immune system, mitochondria, and Parkinson's disease were preferentially affected by dieldrin. The study provides new insight into the mechanisms of dieldrin neurotoxicity that may explain, in part, the association between this pesticide and increased risks to neurodegeneration. These data contribute in a significant way to developing a molecular framework for pesticide induced neurotoxicity.
Asunto(s)
Sistema Nervioso Central , Dieldrín/toxicidad , Mitocondrias , Proteínas Mitocondriales , Plaguicidas/toxicidad , Proteínas de Pez Cebra , Pez Cebra , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Mitocondrias/inmunología , Mitocondrias/metabolismo , Proteínas Mitocondriales/inmunología , Proteínas Mitocondriales/metabolismo , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/inmunología , Síndromes de Neurotoxicidad/inmunología , Síndromes de Neurotoxicidad/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/metabolismo , Pez Cebra/inmunología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/inmunología , Proteínas de Pez Cebra/metabolismoRESUMEN
Pramipexole is a dopamine (DA) agonist (D2 subfamily receptors) that widely use in the treatment of Parkinson's diseases. Some epidemiological and genetic studies propose a role of inflammation in the pathophysiology of Parkinson's disease. To our knowledge, there is no study regarding the anti-inflammatory activity of pramipexol. Therefore, the aim of the study was to investigate anti-inflammatory effect of pramipexol. Anti-inflammatory effects of pramipexole were studied in three well-characterized animal models of inflammation, including carrageenan- or formalin-induced paw inflammation in rats, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. The animals received pramipexol (0.25, 0.5 and 1 mg/kg, I.P.) 30 min before subplantar injection of carrageenan or formalin. Pramipexol (0.5 and 1 mg/kg) was also injected 30 min before topical application of TPA on the ear mice. Serum malondialdehyde (MDA) levels were evaluated in the carrageenan test. Finally, pathological examination of the inflamed tissues was carried out. Pramipexole significantly inhibited paw inflammation 1, 2, 3 and 4 h after carrageenan challenge compared with the control group (p < .001). Pramipexol also showed considerable anti-inflammatory activity against formalin-evoked paw edema over a period of 24 h (p < .001). TPA-induced ear edema was markedly decreased by pramipexol (p < .001). The pathological evaluation of the paws and ears revealed that pramipexole reduced tissue injury, neutrophil infiltration, and subcutaneous edema. Pramipexole did not alter the increased serum levels of MDA due to carrageenan injection. These data clearly indicate that pramipexol possesses significant anti-inflammatory activity. It seems that its antioxidants do not play an important role in these effects.
Asunto(s)
Antiinflamatorios/farmacología , Benzotiazoles/farmacología , Animales , Carragenina/toxicidad , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/patología , Pramipexol , Ratas , Ratas Wistar , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder in which dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) region are selectively destroyed. Sonic hedgehog (Shh) has been well known to play a key role in a variety of processes such as embryogenesis, cell proliferation and protection, and tissue repair during inflammation. However, the evidences for the innate role of Shh in adult brain injury are presently lacking and studies have been needed to unveil the importance of Shh in the process of neurodegeneration. Here, we investigated the role of Shh in the pathologic progress of Parkinson's disease in MPTP-induced animal model system. Interestingly, we observed that Shh expression was gradually increased in MPTP affected SNpc region. Activated microglia exclusively expressed SHH in vivo and we could recapitulate Shh induction in activated cultured primary microglia cells. Using the SHH responsive Cre-loxP binary genetic reporter transgenic mouse system, we also found that most of the cell types except for oligodendrocyte in the SNpc region reacted to the SHH by MPTP injection. Taken together, activated microglia induced Shh expression and most neural cells except oligodendrocyte responded to microglia-derived SHH in MPTP-treated SN. These results suggest that SHH in activated microglia by MPTP-injection might be involved in the innate processes of recovery from neurotoxin induced injury in the PD animal model system.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Proteínas Hedgehog/genética , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/patología , Regulación hacia Arriba , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas Hedgehog/análisis , Proteínas Hedgehog/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Lipopolisacáridos/inmunología , Masculino , Ratones Endogámicos C57BL , Microglía , Enfermedad de Parkinson Secundaria/inmunología , Sustancia Negra/inmunología , Sustancia Negra/metabolismoRESUMEN
Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson's disease and Huntington's disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson's disease, Huntington's disease, Alzheimer's disease, and other amyloidoses.
Asunto(s)
Amiloide/inmunología , Amiloidosis/tratamiento farmacológico , Cognición/efectos de los fármacos , Epítopos/inmunología , Actividad Motora/efectos de los fármacos , Anticuerpos de Cadena Única/farmacología , Amiloidosis/inmunología , Amiloidosis/patología , Amiloidosis/fisiopatología , Animales , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/inmunología , Enfermedad de Huntington/fisiopatología , Masculino , Ratones , Ratones Mutantes , Actividad Motora/inmunología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/fisiopatología , Anticuerpos de Cadena Única/inmunologíaRESUMEN
The cannabinoid (CB2) receptor type 2 has been proposed to prevent the degeneration of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. However, the mechanisms underlying CB2 receptor-mediated neuroprotection in MPTP mice have not been elucidated. The mechanisms underlying CB2 receptor-mediated neuroprotection of dopamine neurons in the substantia nigra (SN) were evaluated in the MPTP mouse model of Parkinson's disease (PD) by immunohistochemical staining (tyrosine hydroxylase, macrophage Ag complex-1, glial fibrillary acidic protein, myeloperoxidase (MPO), and CD3 and CD68), real-time PCR and a fluorescein isothiocyanate-labeled albumin assay. Treatment with the selective CB2 receptor agonist JWH-133 (10 µg kg(-1), intraperitoneal (i.p.)) prevented MPTP-induced degeneration of dopamine neurons in the SN and of their fibers in the striatum. This JWH-133-mediated neuroprotection was associated with the suppression of blood-brain barrier (BBB) damage, astroglial MPO expression, infiltration of peripheral immune cells and production of inducible nitric oxide synthase, proinflammatory cytokines and chemokines by activated microglia. The effects of JWH-133 were mimicked by the non-selective cannabinoid receptor WIN55,212 (10 µg kg(-1), i.p.). The observed neuroprotection and inhibition of glial-mediated neurotoxic events were reversed upon treatment with the selective CB2 receptor antagonist AM630, confirming the involvement of the CB2 receptor. Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.
Asunto(s)
Barrera Hematoencefálica/patología , Neuronas Dopaminérgicas/patología , Enfermedad de Parkinson Secundaria/patología , Receptor Cannabinoide CB2/inmunología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Barrera Hematoencefálica/inmunología , Citocinas/análisis , Citocinas/inmunología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Proteína Ácida Fibrilar de la Glía/análisis , Proteína Ácida Fibrilar de la Glía/inmunología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Neuroprotección , Enfermedad de Parkinson Secundaria/inmunología , Sustancia Negra/inmunología , Sustancia Negra/patologíaRESUMEN
Parkinson's disease is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. Recent data showed that growth factors mediate neuroprotection in rodent models of Parkinson's disease, modulating pro-inflammatory processes. Based on our recent studies showing that plasma rich in growth factors (PRGF-Endoret) mediates neuroprotection as inflammatory moderator in Alzheimer's disease, in the present study we examined the effects of plasma rich in growth factors (PRGF-Endoret) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse as a translational therapeutic approach for Parkinson's disease. We found substantial neuroprotection by PRGF-Endoret in our model of Parkinson's disease, which resulted in diminished inflammatory responses and improved motor performance. Additionally, these effects were associated with robust reduction in nuclear transcription factor-κB (NF-κB) activation, and nitric oxide (NO), cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) expression in the substantia nigra. We propose that PRGF-Endoret can prevent dopaminergic degeneration via an NF-κB-dependent signaling process. As the clinical safety profile of PRGF-Endoret is already established, these data suggest that PRGF-Endoret provides a novel neuroprotective strategy for Parkinson's disease.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Neuronas Dopaminérgicas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , FN-kappa B/inmunología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Administración Intranasal , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/inmunología , Sustancia Negra/patologíaRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease. Although its pathogenesis is still unclear, increasing evidence suggests that mitochondrial dysfunction induced by environmental toxins, such as mitochondrial complex I inhibitors, plays a significant role in the disease process. The microglia in PD brains are highly activated, and inflammation is also an essential element in PD pathogenesis. However, the means by which these toxins activate microglia is still unclear. In the present study, we found that rotenone, a mitochondrial complex I inhibitor, could directly activate microglia via the nuclear factor kappa B (NF-κB) signaling pathway, thereby inducing significantly increased expression of inflammatory cytokines. We further observed that rotenone induced caspase-1 activation and mature IL-1ß release, both of which are strictly dependent on p38 mitogen-activated protein kinase (MAPK). The activation of p38 is associated with the presence of reactive oxygen species (ROS) produced by rotenone. Removal of these ROS abrogated the activation of the microglia. Therefore, our data suggest that the environmental toxin rotenone can directly activate microglia through the p38 MAPK pathway.
Asunto(s)
Contaminantes Ambientales/toxicidad , Sistema de Señalización de MAP Quinasas , Microglía/efectos de los fármacos , Enfermedad de Parkinson/patología , Rotenona/toxicidad , Animales , Línea Celular , Núcleo Celular/metabolismo , Contaminantes Ambientales/farmacología , Humanos , Quinasa I-kappa B/metabolismo , Inflamasomas/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía/inmunología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Enfermedad de Parkinson Secundaria/metabolismo , Rotenona/farmacología , Factor de Transcripción ReIA/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Animal models of Parkinson's disease (PD) have been widely used to investigate the pathogenesis of this neurodegenerative disorder which is typically associated with the specific and largely disordered protein α-synuclein (α-syn). In the current study, the nasal vector was used to deliver α-syn aggregates to the brain. Both α-syn oligomers and its fibrils were firstly characterized using atomic force microscopy and the thioflavin T binding assay. The toxic oligomers alone (0.48 mg/kg) or their 50:50 combination with fibrils (in a total dose of 0.48 mg/kg) were then given intranasally for ten days in mice and PD-mimetic symptoms as well as humoral immunity to these species and dopamine (DA) were evaluated simultaneously. Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen. In contrast, using ELISA, high levels of serum autoantibodies to α-syn monomeric, oligomeric and fibrillar conformers as well as DA were observed in both treatment groups reflecting immune system activation and this substantiates previous clinical studies in Parkinson's disease patients. Thus, nasal administration of α-syn amyloidogenic species may be a potential experimental PD model which results not only in motor deficits but also incitement of humoral protection to mimic the disease. Such a paradigm may be exploitable in the quest for potential therapeutic strategies and further studies are warranted.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dopamina/inmunología , Actividad Motora/efectos de los fármacos , alfa-Sinucleína/farmacología , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/inmunología , Rigidez Muscular/inmunología , Enfermedad de Parkinson Secundaria/inmunología , Vacunación , alfa-Sinucleína/administración & dosificaciónRESUMEN
Although there is growing evidence for a role of the innate immune response in Parkinson's disease, the nature of any humoral response in dopaminergic degeneration is uncertain. Here we report on a protracted N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of dopaminergic death that potentially allows a more full adaptive humoral response to develop. Rag2 mutant mice that lack the full adaptive response (deficient in both T and B cells) are resistant to dopaminergic death and behavioral deficiencies in this model. These mice are resensitized after reconstitution with WT splenocytes. To more directly provide evidence for humoral/IgG involvement, we show that deficiency of Fcγ receptors, which are critical for activation of macrophages/microglia by binding to IgGs, is also protective in this protracted model. FcγR-deficient mice display improved behavior and impaired microglial activation. Interestingly, however, Rag2 mutant but not FcγR-deficient mice are resistant to a more standard N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine paradigm where death is more rapid. Taken together, these data indicate that, provided sufficient time, the humoral arm of the adaptive immune system can play a critical functional role in modulating the microglial response to dopaminergic degeneration and suggest that this humoral component may participate in degeneration in Parkinson's disease.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Neurotoxinas/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Receptores de IgG/inmunología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Muerte Celular/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Intoxicación por MPTP/genética , Intoxicación por MPTP/inmunología , Intoxicación por MPTP/metabolismo , Ratones , Ratones Noqueados , Neurotoxinas/farmacología , Enfermedad de Parkinson Secundaria/genética , Receptores de IgG/genética , Receptores de IgG/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Parkinsonian patients and animal models of PD show inflammatory phenomena such as microglial activation and cytokine production that could modulate the progression of the disease, since they play a crucial role in the degenerative process. Since acute phase proteins (APPs) are involved in a number of homeostatic alterations and inflammatory processes, we analyzed the levels of APPs in primates before and after treatment with MPTP. A significant increase in C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (HP) levels after MPTP treatment. These results demonstrate that MPTP induces a systemic generalized inflammatory reaction after specific dopaminergic neurotoxicity insult, suggesting that the inflammatory process in Parkinsonism may affect other immune-inflammatory responses outside the brain.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Proteínas de Fase Aguda/metabolismo , Dopaminérgicos , Enfermedad de Parkinson Secundaria/inmunología , Animales , Proteína C-Reactiva/metabolismo , Haptoglobinas/metabolismo , Inflamación/sangre , Macaca fascicularis , Masculino , Enfermedad de Parkinson Secundaria/sangre , Enfermedad de Parkinson Secundaria/inducido químicamente , Proteína Amiloide A Sérica/metabolismoAsunto(s)
Autoanticuerpos/inmunología , Ganglios Basales/inmunología , Trastornos Distónicos/etiología , Esclerosis Múltiple Crónica Progresiva/complicaciones , Enfermedad de Parkinson Secundaria/etiología , Adulto , Atrofia , Encéfalo/patología , Trastornos Distónicos/inmunología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Hipocinesia/etiología , Esclerosis Múltiple Crónica Progresiva/inmunología , Enfermedad de Parkinson Secundaria/inmunología , Embarazo , Complicaciones del Embarazo/inmunología , Trastornos Puerperales/etiología , Trastornos Puerperales/inmunologíaRESUMEN
Vascular parkinsonism (VP) is characterized by predominantly lower body involvement with gait impairment and postural instability, often without tremor, and by relative levodopa unresponsiveness. Neuroimaging studies demonstrate multiple infarcts or ischemic changes in periventricular white matter. Anticardiolipin antibodies (ACLA) are associated with hypercoagulable states and increased stroke risk. Review of our Movement Disorders Clinic records identified 44 individuals with a diagnosis of VP. ACLA have been obtained in 22 of these patients (mean age, 78.3 years; mean Mini-Mental Status Exam score, 25.8). Gait disturbance was the initial clinical feature in 82% of the patients, and levodopa responsiveness was present in 18% of those treated. In 9 of the 22 (40.9%), ACLA immunoglobulin G was positive. No significant differences in clinical features or risk factors (hypertension, diabetes, coronary artery disease, and clinical stroke) were evident between ACLA+ and ACLA- groups. Since the presence of ACLA in individuals with stroke is usually treated by full-scale anticoagulation with warfarin, our findings raise the question whether such treatment should also be used in persons with VP who are ACLA positive.
Asunto(s)
Anticuerpos Anticardiolipina/inmunología , Enfermedad de Parkinson Secundaria/inmunología , Anciano , Antiparkinsonianos/uso terapéutico , Encéfalo/irrigación sanguínea , Encéfalo/patología , Isquemia Encefálica/patología , Circulación Cerebrovascular/fisiología , Trastornos del Conocimiento/diagnóstico , Femenino , Marcha , Humanos , Levodopa/uso terapéutico , Extremidad Inferior/fisiopatología , Masculino , Pruebas Neuropsicológicas , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/fisiopatología , Postura , Factores de RiesgoRESUMEN
A 49-year-old man had mild parkinsonism after being stung by a wasp, a member of the Hymenoptera order. His clinical course was stable for 6 months after which his condition rapidly progressed to a severe akinetic-rigid syndrome with evidence, on a magnetic resonance imaging brain scan, of marked destruction of the basal ganglia. The symptoms did not respond to standard antiparkinsonian medications. Repeated courses of plasmapheresis followed by monthly intravenous infusions of immunoglobulin and long-term administration of azathioprine halted and appeared to partially reverse his deterioration. The literature on the neurologic, particularly the extrapyramidal, manifestations of stings by insects of the Hymenoptera order is reviewed and the possible pathophysiological mechanisms of injury are discussed. Hymenoptera stings should be included in the differential diagnosis of acute and chronic extrapyramidal syndromes.
Asunto(s)
Mordeduras y Picaduras de Insectos/complicaciones , Enfermedad de Parkinson Secundaria/etiología , Avispas , Animales , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Ganglios Basales/inmunología , Ganglios Basales/patología , Corteza Cerebral/inmunología , Diagnóstico Diferencial , Humanos , Mordeduras y Picaduras de Insectos/inmunología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Enfermedad de Parkinson Secundaria/diagnóstico , Enfermedad de Parkinson Secundaria/inmunologíaRESUMEN
A 37 year woman developed neuroleptic induced parkinsonism that persisted long after the drug had been discontinued. This prompted a study of the effect of an eight week course of haloperidol (HAL) followed by two week withdrawal, on dopaminergic neurons of the substantia nigra in rats. Animals treated with HAL showed a highly significant 32%-46% loss of tyrosine hydroxylase (TH) immunoreactive neurons in the substantia nigra, and 20% contraction of the TH stained dendritic arbour. Neuroleptic drug induced downregulation of nigral dopaminergic neurons may help to explain the persistent parkinsonism found in many patients after withdrawal of medication.