The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia

Higaki, Hiromi; Choudhury, Mohammed E.; Kawamoto, Chisato; Miyamoto, Keisuke; Islam, Afsana; Ishii, Yurika; Miyanishi, Kazuya; Tamano, Haruna; Seo, Naoto; Sugimoto, Keishi; Takahashi, Hiroyuki; Yano, Hajime; Tanaka, Junya

doi:10.1016/j.neuint.2016.06.013

Cited by 16 publications

(35 citation statements)

References 44 publications

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“…The synthetic glucocorticoid Dex has a strong suppressive effect on activated microglial cells as shown in this study and elsewhere (Carrillo-de Sauvage et al, 2013;Higaki et al, 2016;Tanaka et al, 1997). dose Dex administration did not cause significant changes in DA turnover in the striatum, although an increased turnover rate of DA has been considered a probable mechanism for the compensation (Bezard et al, 2003;Perez et al, 2008) The most critical point for the hypothesis shown in Figure 8 is that activated microglia in the SNr selectively eliminates glutamatergic synapses from the hyperactive STN in the indirect pathway, but not the GABArgic synapses from the striatum in the direct pathway.…”

Section: Discussionsupporting

confidence: 87%

“…The synthetic glucocorticoid Dex has a strong suppressive effect on activated microglial cells as shown in this study and elsewhere (Carrillo‐de Sauvage et al, ; Higaki et al, ; Tanaka et al, ). Dex inhibits Glu‐stimulated phagocytosis and mRNA expression for microglial activation‐related factors in vitro.…”

Section: Discussionsupporting

confidence: 87%

“…Glu enhanced the expression of mRNA encoding the microglial markers Iba1, CD11b, and CX3CR1 (Liu et al, ) (Figure Ga–Gc). Glu also increased mRNA encoding F4/80 (Lin et al, ), CD68 (Sugimoto et al, ), matrix metalloproteinase 2 (MMP2) (Lively and Schlichter, ), cathepsin S (Hayashi et al, ; Lively and Schlichter, ), and interferon regulatory factor 1 (IRF1) (Higaki et al, ) (Figure Gd–Gh), which have been suggested to participate in phagocytosis, migration, modulation of synapses, or activation of microglia, respectively. Dex abolished the stimulatory effects of Glu on mRNA expression.…”

Section: Resultsmentioning

confidence: 99%

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Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Aono

Choudhury

Higaki

et al. 2017

Glia

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Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Aono

Choudhury

Higaki

et al. 2017

Glia

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“…These results suggest that circadian changes in NA contents may be correlated with the circadian changes in microglial activity. NA suppresses expression of IRF1, a proinflammatory transcription factor for microglia (Higaki et al, ; Ishii et al, ). The NA effects were mimicked by knockdown of IRF1, suggesting that NA causes circadian changes of microglial function, at least partly, by regulating IRF1 expression.…”

Section: Discussionmentioning

confidence: 99%

Phagocytic elimination of synapses by microglia during sleep

Choudhury

Miyanishi

Tamano

et al. 2019

Glia

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Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG‐E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3‐ or MFG‐E8‐bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate‐induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine‐depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG‐E8, while increasing the sleeping period. A NA precursor l‐threo‐dihydroxyphenylserine abolished the reserpine‐induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.

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“…As BBB breakdown is not apparent in PD, infiltration of leukocytes, including monocytes, is not often seen. In PD pathophysiology, dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) in the mesencephalon primarily undergo degeneration, leading to microglial activation in the vicinity of the degenerating neurons [42][43][44] . The activated microglia release potentially neurotoxic substances, such as either reactive oxygen/nitrogen species or glutamate [45,46] .…”

Section: Response Of Microglia In Brain Pathology In the Absence Of Bmentioning

confidence: 99%

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

Tanaka¹

2020

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How to cite this article: Tanaka J. Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system. Neuroimmunol Neuroinflammation 2020;7:73-91. http://dx. AbstractResident microglia in the central nervous system (CNS) are activated rapidly in response to even minor pathologic changes in the CNS, releasing various cytokines, growth factors, reactive oxygen species and other bioactive substances, in addition to eliminating synapses and degenerating cells through phagocytosis. Monocytes in circulation invade the inflamed brain tissues and develop into macrophages that also produce several bioactive substances and engage in phagocytosis. This article introduces methods for distinguishing microglia and macrophages. The pathophysiological roles of resident microglia and macrophages are discussed in animal models with neuroinflammation in the brain either with or without disruption of the blood-brain barrier. Both cell types have ameliorating and aggravating effects on the pathologic CNS, and their different roles are addressed in this article. Furthermore, this article compares the effects of some pharmacological interventions to induce phenotypic cellular changes for improved outcomes of the pathologic CNS.

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The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia

Cited by 16 publications

References 44 publications

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Phagocytic elimination of synapses by microglia during sleep

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

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