RESUMEN
In the subacute Parkinson's disease (PD) mice model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), injection of HMGB1 competitive inhibitor protein HMGB1 A box and the ethyl pyruvate (EP) that inhibit the release of HMGB1 from cells restored the number of dopaminergic neurons and TH+ fibers in the SN and striatum. Our data show that A box up-regulated CD200-CD200R signal of microglia inhibited the activation of microglia mediated by HMGB1, and the production of TNF-α, IL-1ß and IL-6 in vivo and in vitro mixed culture system. Microglia overexpressing CD200R produced less inflammatory chemokines and reduced the loss of TH+ neurons. In addition, HMGB1 A box decreased the level of CCL5 and significantly inhibited the infiltration of almost all T cells including Th17 and the proportion of Th17 in CD4+ T cells. In vitro MPP+ induced model and HMGB1-stimulated mesencephalic cell system activated microglia induced the differentiation of naïve T cells to Th17, and A box significantly inhibited this process. To sum up, our results show that HMGB1 A box targeting HMGB1, which effectively reduces the activation of microglia in MPTP PD model by restoring CD200-CD200R signal inhibit microglia mediated neuroinflammation and the differentiation of T cells to Th17.
Asunto(s)
Proteína HMGB1/antagonistas & inhibidores , Microglía/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Sustancia Negra/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Masculino , Ratones Endogámicos C57BL , Sustancia Negra/inmunología , Linfocitos T/efectos de los fármacos , Células Th17RESUMEN
Neuroinflammation has been reported to be involved in the pathogenesis of Parkinson's disease (PD). Inhibition of microglia-mediated neuroinflammation might be a potential strategy for PD treatment. Biochanin A, is an O-methylated isoflavone, classified as a kind of phytoestrogens due to its chemical structure that is similar to mammalian estrogens. It has been found to possess antifibrotic, antiapoptotic, and antioxidant effects. In the present study, we investigated the neuroprotective effects of biochanin A on lipopolysaccharide (LPS)-induced dopaminergic neurons damage both in vivo and in vitro and the related molecular mechanisms. The results showed that biochanin A treatment for 21 days significantly attenuated the behavioral dysfunction of PD rats, prevented dopaminergic neurons damage, and inhibited activation of microglia in the LPS-induced PD rats. Furthermore, biochanin A decreased the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the serum, and inhibited the phosphorylation of ERK, JNK, p38 in the substantia nigra of PD rats. In vitro test, biochanin A also inhibited primary microglial activation and protected dopaminergic neurons, decreased the content of nitric oxide, IL-1ß, and TNF-α in supernatants, and inhibited the reactive oxygen species production. Taken together, these results suggest that biochanin A exerts protective effects on LPS-induced PD rats, and the mechanisms may be associated with the inhibition of inflammatory response and the MAPK signaling pathway.
Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/inmunología , Genisteína/farmacología , Microglía/efectos de los fármacos , Microglía/inmunología , Fármacos Neuroprotectores/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiparkinsonianos/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Evaluación Preclínica de Medicamentos , Lipopolisacáridos , Masculino , Microglía/patología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Fosforilación/efectos de los fármacos , Distribución Aleatoria , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/enzimología , Sustancia Negra/inmunología , Sustancia Negra/patologíaRESUMEN
Autoantibodies play an important role in central nervous system manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies have shown that the lupus-prone NZM88 strain has major neural deficits and high titers of serum IgG to brain antigens. ELISA was performed to detect the presence of IgG in different brain regions of NZM88 mice and to compare the levels with NZM2758 mice and control strains (NZW and BALB/c). There was a substantial increase of IgG in the substantia nigra (SN) and hypothalamus (HT) of brains from NZM88 mice compared to control NZW and BALB/c mice, whereas NZM2758 mice had more IgG in the cortex. The increased presence of IgG in the NPSLE-prone NZM88 mouse brain was paralleled by increased TNF-alpha and IL-12 in the SN and HT regions; significantly elevated expression of MHC Class-II was also observed in the SN of NZM88 mice and cortex of NZM2758 mice. A co-culture system of dopaminergic neurons and microglia was used to demonstrate that NZM88 sera modifies dopaminergic cell activity only in the presence of microglia and that TNF-alpha is synthesized and released in this co-culture. This study demonstrates a functional link between the autoantibodies, the activation of microglia, and neuronal function associated dopamine production, which is suggested to be causally related to the predominant NPSLE syndromes.
Asunto(s)
Autoanticuerpos/inmunología , Inflamación/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Técnicas de Cocultivo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Dopamina/biosíntesis , Dopamina/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipotálamo/inmunología , Hipotálamo/metabolismo , Inmunoglobulina G/análisis , Inmunoglobulina G/inmunología , Inflamación/metabolismo , Interleucina-12/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central/etiología , Vasculitis por Lupus del Sistema Nervioso Central/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NZB , Neuroglía/citología , Neuroglía/metabolismo , Neuronas/citología , Neuronas/metabolismo , Especificidad de la Especie , Sustancia Negra/inmunología , Sustancia Negra/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Ceruloplasmin (CP) is a 132 kd cuproprotein which, together with transferrin, provides the majority of anti-oxidant capacity in serum. Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well. The present study compared CP immunoreactivity in brain specimens from normal controls and subjects with neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], progressive supranuclear palsy [PSP], and Huntington's disease [HD]) (n = 5 per group). The relative intensity of neuronal CP staining and the numbers of CP-stained neurons per 25x microscope field were determined in hippocampus (CA1, subiculum, and parahippocampal gyrus), parietal cortex, frontal cortex, substantia nigra, and caudate. CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain. Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016). Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls. The numbers of CP-stained neurons per field did not differ between the various neurodegenerative disorders and controls. These results suggest that a modest increase in neuronal CP content is present in the AD brain, and lesser elevations in neuronal CP occur in the other neurodegenerative disorders in this study. Though CP functions as both an acute phase protein and an anti-oxidant in peripheral tissues, whether it does so in the brain remains to be determined.
Asunto(s)
Encéfalo/metabolismo , Ceruloplasmina/inmunología , Ceruloplasmina/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/inmunología , Encéfalo/patología , Núcleo Caudado/inmunología , Núcleo Caudado/metabolismo , Núcleo Caudado/patología , Lóbulo Frontal/inmunología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Enfermedades Neurodegenerativas/inmunología , Neuronas/inmunología , Neuronas/metabolismo , Lóbulo Parietal/inmunología , Lóbulo Parietal/metabolismo , Lóbulo Parietal/patología , Sustancia Negra/inmunología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
The mesolimbic dopaminergic system has been implicated in mediating morphine and electroacupuncture analgesia. In the present study, Fos immunoreactivity was used as a marker of neuronal activity to investigate if electroacupuncture could activate the dopaminergic neurons in the midbrain. Electroacupuncture stimulation significantly increased the number of Fos-positive dopaminergic neurons in the ventral tegmental area (VTA), whereas no significant c-fos expression in the dopaminergic neurons was observed in the substantia nigra (SN). These results indicate that the VTA rather than the SN may play a role in mediating electroacupuncture analgesia.