C3/C3aR inhibition alleviates GMH-IVH-induced hydrocephalus by preventing microglia-astrocyte interactions in neonatal rats

Tang, Jun; Jila, Shiju; Luo, Tao; Zhang, Bo; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

doi:10.1016/j.neuropharm.2021.108927

Cited by 12 publications

(7 citation statements)

References 47 publications

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“…Complement C3 binds to its responding receptors and plays an important role in the pathological mechanisms of immune defense, inflammation and neuropsychiatric diseases. It has been shown that the role of complement C3 is closely related to microglial activation [29], as its receptor C3aR is a specific pattern recognition receptor for microglia [18]. According to these findings, our study showed that the levels of C3 and C3aR were significantly upregulated in response to chronic stress.…”

Section: Discussionsupporting

confidence: 68%

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

et al. 2022

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Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

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Section: Discussionsupporting

confidence: 68%

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

et al. 2022

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“…The anaphylatoxins C3a and C5a cause chemotaxis of neutrophils and mast cells, which can release oxygen radicals and lysosomal proteases ( 30 , 31 ). Moreover, astrocytes upregulate and release C3, which binds to C3aR in microglia, promoting neuroinflammation and hydrocephalus after germinal matrix hemorrhage ( 32 ). However, few studies have explored the role of other complement components in the pathological process after ICH.…”

Section: Discussionmentioning

confidence: 99%

“…In visceral pain, minocycline, which repressed microglial activation, suppressed transcription of C1q and CR3, and ultimately repressed C1q/C3-CR3-mediated synaptic engulfment in the amygdala, reduced visceral hypersensitivity ( 15 ). Furthermore, minocycline can decrease both the number of C3 + /GFAP + astrocytes and C3aR + /Iba-1 + microglia after germinal matrix hemorrhage ( 32 ). Consistently, we revealed that minocycline exerted neuroprotection, alleviated oxidative stress, and downregulated C1q and CR3 expression.…”

Section: Discussionmentioning

confidence: 99%

Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment

et al. 2022

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AimThe complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined.MethodsThere were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined.ResultsThere were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1.ConclusionsThe complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.

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“…C3a then binds to the C3aR receptor on microglia, promoting their activation and C1q production, thereby causing local injury to neurons [ 38 , 43 , 53 ]. Based on this finding, various other groups have exploited this pathway to study astrocyte-microglia interactions in status epilepticus [ 40 ], hydrocephalus [ 39 ], depression [ 36 ], white matter injury [ 41 ], and prion disease [ 42 ].…”

Section: Astrocyte-derived Molecules Regulating Microglial Function I...mentioning

confidence: 99%

Bidirectional Communication Between Microglia and Astrocytes in Neuroinflammation

Bhusal

Lee

Suk

2023

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Neuroinflammation is a common feature of diverse nervous system pathologies. In many instances, it begins at an early stage of the disease, paving the way for further exacerbations. The main drivers of neuroinflammation are brain-resident glial cells, such as microglia and astrocytes. Microglia are the primary responders to any insult to the brain parenchyma, translating the signals into diverse molecules. These molecules derived from microglia can regulate the stimuli-dependent reactivity of astrocytes. Once activated, astrocytes in turn, can control microglia phenotypes. Recent evidence indicates that the crosstalk between these glial cells plays an important role in delaying or accelerating neuroinflammation and overall disease progression. To date, various molecules have been recognized as key mediators of the bidirectional communication between microglia and astrocytes. The current review aims to discuss the novel molecules identified recently, which play a critical role in interglial crosstalk, highlighting their therapeutic potential.

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C3/C3aR inhibition alleviates GMH-IVH-induced hydrocephalus by preventing microglia-astrocyte interactions in neonatal rats

Cited by 12 publications

References 47 publications

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment

Bidirectional Communication Between Microglia and Astrocytes in Neuroinflammation

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