Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses

Wang, Jin; Hou, Ying; Zhang, Lixia; Liu, Min; Zhao, Jianshuai; Zhang, Zhen; Ma, Yulong; Hou, Wugang

doi:10.1007/s12035-020-02171-2

Cited by 91 publications

(57 citation statements)

References 41 publications

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“…This, however, does not seem to be true, as demonstrated by our previous experiments showing that the contrast sensitivity deficit resulting from focal cranial air blast was not rescued by an ER-β agonist in combination with an ER-α antagonist, nor did an ER-β antagonist block the improvement in contrast sensitivity produced by raloxifene (Honig et al, 2019). Moreover, the possibility that raloxifene's antagonism at ER-α could be anti-inflammatory is inconsistent with the recent finding that 17β-estradiol exerts antiinflammatory effects by acting as an agonist at ER-α receptors in adult male mice after an impact producing more severe injury (Wang et al, 2021).…”

Section: Considerations For Human Usementioning

confidence: 84%

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

et al. 2021

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Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades. We previously found that treatment with the CB2 inverse agonist SMM-189 after mild TBI in mice produced by focal cranial blast rescues visual deficits and the optic nerve axon loss that would otherwise result. We have further shown that raloxifene, which is Food and Drug Administration (FDA)-approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields similar benefit in this TBI model through its modulation of microglia. As many different traumatic events produce TBI in humans, it is widely acknowledged that diverse animal models must be used in evaluating possible therapies. Here we examine the consequences of TBI created by blunt impact to the mouse head for visual function and associated pathologies and assess raloxifene benefit. We found that mice subjected to impact TBI exhibited decreases in contrast sensitivity and the B-wave of the electroretinogram, increases in light aversion and resting pupil diameter, and optic nerve axon loss, which were rescued by daily injection of raloxifene at 5 or 10 mg/ml for 2 weeks. Raloxifene treatment was associated with reduced M1 activation and/or enhanced M2 activation in retina, optic nerve, and optic tract after impact TBI. Our results suggest that the higher raloxifene dose, in particular, may be therapeutic for the optic nerve by enhancing the phagocytosis of axonal debris that would otherwise promote inflammation, thereby salvaging less damaged axons. Our current work, together with our prior studies, shows that microglial activation drives secondary injury processes after both impact and cranial blast TBI and raloxifene mitigates microglial activation and visual system injury in both cases. The results thus provide a strong basis for phase 2 human clinical trials evaluating raloxifene as a TBI therapy.

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Section: Considerations For Human Usementioning

confidence: 84%

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

et al. 2021

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“…It has been demonstrated that an inflammatory response was closely associated with neuronal apoptosis following TBI. 25,26 Activation of NF-κB mediates production of pro-inflammatory F I G U R E 3 Effects of sirtinol on neuronal survival 24 h after TBI (A, B) The apoptotic index was determined by the TUNEL assay 1 d after TBI. (C) Brain water content and neurological function were assessed after TBI.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 alleviates neuroinflammation‐induced apoptosis after traumatic brain injury

Guan

Wang

Wu³

et al. 2021

J Cellular Molecular Medi

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The pathophysiological features of traumatic brain injury (TBI) include primary brain injuries, which are difficult to predict, and secondary brain injury. 1,2 Over the course of TBI, neuronal apoptosis occurs through a complex sequence of pathological events that involve several contributing factors, such as excitotoxicity, excitotoxic damage, mitochondrial dysfunction and autophagy. 3 Among these events, inflammation is an important factor that aggravates nerve injury during the process of secondary insult. Although the exact mechanisms responsible for the occurrence of neuronal insult and their final degeneration are equivocal, vast literature suggests an important role of neuroinflammation. 4,5 Cytokine signalling and inflammasome are linked to the 'redox-sensitive' master transcriptional regulator nuclear factor-kappa B (NF-κB). Indeed, activation of NF-κB causes an increase in the interleukin (IL)-1 level, which promotes the cascade of inflammatory factors in microglia (ie TNFα) and astrocytes (ie IL-6). 6,7 Accordingly, restrained activation of NF-κB reduces the neuroinflammatory process, which can prevent neuronal apoptosis. 8 Sirtuin 1 (SIRT1), also known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-1, contributes to cellular regulation (reaction to stressors and longevity). 9 It is a highly conserved and well-characterized NAD-dependent class III histone deacetylase in mammalian cells. Numerous studies have demonstrated that SIRT1 plays a central role in the regulation of different biological processes, such as mitochondrial biogenesis, oxidation and inflammation. [10][11][12] SIRT1 is activated in many central nervous system diseases, such as subarachnoid haemorrhage and Parkinson's disease. 13 In addition, it has been reported that it is an important

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“…4J ). Although some reports have shown that caspase8 participates in the processing of pro-Il-1β under certain conditions [ 24 , 25 ]. the data suggest that Pgam5 facilitates the Asc-dependent pro-Il-1β processing via caspase1-associated inflammasome that is independent of Rip3/caspase8 pathway in LPS + ATP-stimulated microglia.…”

Section: Resultsmentioning

confidence: 99%

“…Microglia are the primary mediators of the innate immune response in CNS, and the proinflammatory cytokines released by microglia, such as Il-1β and Tnf-α, are important assessment indices of microglia polarization and pro-inflammatory after TBI [ 24 ]. Indeed, inhibiting microglia activation-mediated inflammation is suggested to improve the neurological outcomes post-TBI [ 25 ]. In this study, we have investigated the molecular mechanism of Pgam5 after TBI.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

et al. 2021

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Traumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1β. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1β secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1β-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.

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Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses

Cited by 91 publications

References 41 publications

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

Sirtuin 1 alleviates neuroinflammation‐induced apoptosis after traumatic brain injury

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

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