Long-term cognitive deficits after traumatic brain injury associated with microglia activation

Saba, Esber S.; Karout, Mona; Nasrallah, Leila; Kobeissy, Firas; Darwish, Hala; Khoury, Samia J.

doi:10.1016/j.clim.2021.108815

Cited by 19 publications

(16 citation statements)

References 69 publications

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“…While the relative expression levels of these six transcripts for the various cell types in the different tissue sources are not known, it is important to note that neurons are not present within the optic nerve. Although the microglia markers we examined are also macrophage markers, macrophages are unlikely to have been present in any of the tissues we analyzed, as macrophage invasion into the nervous system typically occurs only after more severe injuries (Anyaegbu et al, 2021;Saba et al, 2021).…”

Section: Qpcr and Nanostring Studies Qpcr Studiesmentioning

confidence: 99%

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: Qpcr and Nanostring Studies Qpcr Studiesmentioning

confidence: 99%

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

et al. 2021

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“…Injuries sustained in military circumstances are a well‐documented risk factor for PTSD, 30 with injury severity 31 also a substantial risk factor. Traumatic brain injury suffered by patients with maxillofacial injuries may be overlooked, 12 and it has been linked to long‐term cognitive and psychiatric outcomes, 32,33 as potentially observed in the current cohort.…”

Section: Discussionmentioning

confidence: 89%

Traumatic maxillofacial injuries: Patterns, outcomes, and long‐term follow‐up of a military cohort

Tsur

Talmy

Radomislensky³

et al. 2022

Dental Traumatology

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Background/Aims: Maxillofacial trauma poses a distinct challenge on the modern battlefield, and data on its long-term implications are scarce. The aim of this study was to investigate maxillofacial injury characteristics, outcomes, and complications along the continuum of care among hospitalized military personnel from the pre-hospital setting through long-term rehabilitation. Materials and Methods: A registry-based study was undertaken of three national trauma and rehabilitation registries: The Israel Defense Forces Trauma Registry (IDF-TR), which records pre-hospital data. The Israeli National Trauma Registry for inhospital data and the Israel Ministry of Defense Rehabilitation Department (MOD-RD) registry contain long-term disability data. The cohort comprised IDF soldiers who suffered maxillofacial injuries between 1997 and 2020.Results: A total of 672 patients with maxillofacial injuries were included in the study, and 6.4% of all trauma admissions were related to maxillofacial injuries. Of these, 366 (54%) were injured in non-military (NMC) circumstances, and 306 (46%) were wounded in military circumstances (MC). The mechanisms of injury were mainly traffic-related among the NMC group compared with an explosion in the MC group.Maxillofacial fractures were frequently associated with traumatic brain injuries with higher rates in the NMC group than in the MC group (55% vs. 30%, p < .001). In a multivariate analysis, zygomatic and orbital fractures were associated with higher odds of concomitant head injury. The most common categories of long-term disability included central nervous system disorders, skull injuries, epilepsy, hearing impairment, ophthalmologic conditions, and post-traumatic stress disorder.Conclusions: Maxillofacial injuries are often associated with concomitant traumatic brain injury. Long-term disabilities associated with these injuries included the central nervous system, hearing, ophthalmologic impairments, and post-traumatic stress disorder.

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“…Functional impairment of microglia is closely related to cognitive impairment. Acute brain trauma leads to impaired cognitive function, and this impairment is accompanied by microglia activation, which is positively correlated with impaired cognitive function ( Saba et al, 2021 ). After the intraperitoneal injection of lipopolysaccharide, a significant increase in activated microglia was observed in the hippocampal region of mice with impaired cognitive function.…”

Section: Introductionmentioning

confidence: 99%

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting

Wang

Xie

Niu

et al. 2023

Front. Cell. Neurosci.

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IntroductionHypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated.MethodsCX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected.ResultsIn this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis.DiscussionThe current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.

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Long-term cognitive deficits after traumatic brain injury associated with microglia activation

Cited by 19 publications

References 69 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

Traumatic maxillofacial injuries: Patterns, outcomes, and long‐term follow‐up of a military cohort

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting

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