TLR4 pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Rosa, Juliana M.; Farré‐Alins, Víctor; Ortega, María Cristina; Navarrete, Marta; López-Rodríguez, Ana Belén; Palomino-Antolín, Alejandra; Fernández-López, Elena; Sol, Virginia Vila-del; Decouty, Céline; Narros-Fernández, Paloma; Clemente, Diego; Egea, Javier

doi:10.1111/bph.15488

Cited by 42 publications

(27 citation statements)

References 67 publications

(155 reference statements)

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“…Astrocytes and microglia are considered key players in the initiation of an inflammatory response after injury [ 28 ]. Astrocytosis occurs in concert with neuronal degeneration [ 29 , 30 ] and has been noted in rodents, primarily in the cortex, within the first 24 h [ 31 ] and up to 12 months after TBI [ 32 ]. In the present study, TBI-induced astrocyte activation in the brain tissue was reduced in S1R-/- mice, suggesting that S1R deficiency prevents development of neurodegenerative processes in brain tissue 12 months postinjury.…”

Section: Discussionmentioning

confidence: 99%

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Stelfa

Vāvers

Švalbe

et al. 2021

IJMS

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Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.

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Section: Discussionmentioning

confidence: 99%

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Stelfa

Vāvers

Švalbe

et al. 2021

IJMS

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“…Indeed, prior studies have reported that astrocytes adopt a reactive state and are recruited to inflammatory sites largely in response to microglial signaling, implying that microgliosis precedes astrogliosis and thus may upstage astrogliosis at early timepoints. However, the weaker astrogliosis could also be explained by the VL's relative resilience as a putative first order nucleus, or by technical idiosyncrasies (e.g., differences in antibody efficacy) (Rosa et al, 2021;Zhang et al, 2010).…”

Section: Secondary Thalamic Inflammation Is Determined By Cortical Co...mentioning

confidence: 99%

Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity

Necula

Cho

et al. 2021

J of Comparative Neurology

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While cortical injuries, such as traumatic brain injury (TBI) and neocortical stroke, acutely disrupt the neocortex, most of their consequent disabilities reflect secondary injuries that develop over time. Thalamic neuroinflammation has been proposed to be a biomarker of cortical injury and of the long‐term cognitive and neurological deficits that follow. However, the extent to which thalamic neuroinflammation depends on the type of cortical injury or its location remains unknown. Using two mouse models of focal neocortical injury that do not directly damage subcortical structures—controlled cortical impact and photothrombotic ischemic stroke—we found that chronic neuroinflammation in the thalamic region mirrors the functional connections with the injured cortex, and that sensory corticothalamic regions may be more likely to sustain long‐term damage than nonsensory circuits. Currently, heterogeneous clinical outcomes complicate treatment. Understanding how thalamic inflammation depends on the injury site can aid in predicting features of subsequent deficits and lead to more effective, customized therapies.

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“…Furthermore, UTI also can inhibit hippocampus endoplasmic reticulum stress and apoptosis after acute paraquat poisoning 16 . Anti-apoptosis, anti-neuroinflammation and antioxidative stress of UTI in central nervous system diseases also were confirmed 10 , 17 , 18 .…”

Section: Discussionmentioning

confidence: 62%

“…Toll-like receptor 4 (TLR4), an innate immune receptor of bacterial endotoxins, is then accumulated to activate the nuclear factor kappa B (NF-κB) signalling transduction pathway, which was reported to be directly involved in inflammation and apoptosis in the epilepsy model 16 , myocardial infarction model 17 and TBI 18 . As the brain tissue consumes more oxygen than most organs, ROS generation increases under oxidative stress after TBI 18 , subarachnoid haemorrhage 19 or ischaemia-reperfusion injury 20 . Therefore, further studies of new potential drug targets in oxidative stress and apoptosis by targeting the TLR4/NF-κB/p65 signalling pathway are warranted.…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis

Feng

Chen

et al. 2022

Acta Cir. Bras.

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Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1β (IL-1β), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.

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TLR4 pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Abstract: TLR4-pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Cited by 42 publications

References 67 publications

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity

Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis

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