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BioRxiv : the Preprint Server For... Jun 2024During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit...
UNLABELLED
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here we analyzed the role of microglia in the synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to ameboid morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially restores ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting their recruitment to synaptic sites early after neuronal injury.
HIGHLIGHTS
Early after transient intraocular pressure elevation: Microglia increase in number, complexity, and process movementMicroglia-synaptic contacts increase in the inner plexiform layerMicroglia-synaptic contacts increase on retinal ganglion cell dendritesMicroglia depletion partially restores ganglion cell function.
PubMed: 38915631
DOI: 10.1101/2024.06.13.598914 -
BioRxiv : the Preprint Server For... Jun 2024To investigate ultra-high-dose rate helium ion irradiation and its potential FLASH sparing effect with the endpoint acute brain injury in preclinical in vivo settings.
PURPOSE
To investigate ultra-high-dose rate helium ion irradiation and its potential FLASH sparing effect with the endpoint acute brain injury in preclinical in vivo settings.
MATERIAL AND METHODS
Raster-scanned helium ion beams were administered to explore and compare the impact of dose rate variations between standard dose rate (SDR at 0.2 Gy/s) and FLASH (at 141 Gy/s) radiotherapy (RT). Irradiation-induced brain injury was investigated in healthy C57BL/6 mice via DNA damage response kinetic studies using nuclear γH2AX as a surrogate for double-strand breaks (DSB). The integrity of the neurovascular and immune compartments was assessed via CD31+ microvascular density and microglia/macrophages activation. Iba1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, together with the expression of inducible nitric oxide synthetase (iNOS).
RESULTS
Helium FLASH RT significantly prevented acute brain tissue injury compared with SDR. This was demonstrated by reduced levels of DSB and structural preservation of the neurovascular endothelium after FLASH RT. Moreover, FLASH RT exhibited reduced activation of neuroinflammatory signals compared with SDR, as detected by quantification of CD68+ iNOS+ microglia/macrophages.
CONCLUSION
To our knowledge, this is the first report on the FLASH-sparing neuroprotective effect of raster scanning helium ion radiotherapy in vivo.
PubMed: 38915610
DOI: 10.1101/2024.06.13.598785 -
BioRxiv : the Preprint Server For... Jun 2024While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life....
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by has the potential to diminish unwanted effects of fumarates while retaining efficacy.
PubMed: 38915544
DOI: 10.1101/2024.06.10.598291 -
Journal of Neuroinflammation Jun 2024Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive...
Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ischemia and macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids and laser photocoagulation have limited effects on RR. The role of retinal inflammation and its contribution to the microvascular damage occurring in RR remain incompletely understood. To explore cellular and vascular events after irradiation, we analyzed their time course at 1 week, 1 month and 6 months after rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes and microglia were rapidly activated, and these markers of retinal inflammation persisted for 6 months after irradiation. This was accompanied by early cell death in the outer retina, which persisted at later time points, leading to retinal thinning. A delayed loss of small retinal capillaries and retinal hypoxia were observed after 6 months, indicating inner blood‒retinal barrier (BRB) alteration but without cell death in the inner retina. Moreover, activated microglial cells invaded the entire retina and surrounded retinal vessels, suggesting the role of inflammation in vascular alteration and in retinal cell death. Radiation also triggered early and persistent invasion of the retinal pigment epithelium by microglia and macrophages, contributing to outer BRB disruption. This study highlights the role of progressive and long-lasting inflammatory mechanisms in RR development and demonstrates the relevance of this rat model to investigate human pathology.
Topics: Animals; Rats; Retina; Disease Models, Animal; Retinal Diseases; Inflammation; Radiation Injuries, Experimental; Radiation Injuries; Male; Microglia
PubMed: 38915029
DOI: 10.1186/s12974-024-03151-2 -
Scientific Reports Jun 2024The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of...
Assessment of cerebrovascular alterations induced by inflammatory response and oxidative-nitrative stress after traumatic intracranial hypertension and a potential mitigation strategy.
The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of diffuse brain swelling or malignant brain herniation during decompressive craniectomy. The microcirculation and venous system are also involved in this process, but the precise mechanisms remain unclear. A physiological model of extremely high intracranial pressure was created in rats. This development triggered the TNF-α/NF-κB/iNOS axis in microglia, and released many inflammatory factors and reactive oxygen species/reactive nitrogen species, generating an excessive amount of peroxynitrite. Subsequently, the capillary wall cells especially pericytes exhibited severe degeneration and injury, the blood-brain barrier was disrupted, and a large number of blood cells were deposited within the microcirculation, resulting in a significant delay in the recovery of the microcirculation and venous blood flow compared to arterial flow, and this still persisted after decompressive craniectomy. Infliximab is a monoclonal antibody bound to TNF-α that effectively reduces the activity of TNF-α/NF-κB/iNOS axis. Treatment with Infliximab resulted in downregulation of inflammatory and oxidative-nitrative stress related factors, attenuation of capillary wall cells injury, and relative reduction of capillary hemostasis. These improved the delay in recovery of microcirculation and venous blood flow.
Topics: Animals; Oxidative Stress; Rats; Intracranial Hypertension; Male; Tumor Necrosis Factor-alpha; Inflammation; Microcirculation; Cerebrovascular Circulation; Rats, Sprague-Dawley; Brain Injuries, Traumatic; Infliximab; Disease Models, Animal; Blood-Brain Barrier; Reactive Oxygen Species; Reactive Nitrogen Species; Microglia
PubMed: 38914585
DOI: 10.1038/s41598-024-64940-6 -
Cell Death Discovery Jun 2024Neuroinflammation caused by microglia and other immune cells plays pivotal role in cerebral ischemia/reperfusion injury and recovery. Modulating microglial polarization...
Curcumol ameliorates neuroinflammation after cerebral ischemia-reperfusion injury via affecting microglial polarization and Treg/Th17 balance through Nrf2/HO-1 and NF-κB signaling.
Neuroinflammation caused by microglia and other immune cells plays pivotal role in cerebral ischemia/reperfusion injury and recovery. Modulating microglial polarization or Treg/Th17 balance from pro-inflammatory phenotype to anti-inflammatory phenotype are promising strategies for the treatment of cerebral ischemia. Curcumol has potential to fight against oxidative stress and inflammation, but whether it has protective effect in cerebral ischemia is uncertain. In the present study, cerebral ischemia was induced in C57BL/6 mice via middle cerebral artery occlusion (MCAO). MCAO mice were treated with curcumol for 7 days, then post-stroke ischemic injury, neurological deficits, microglial polarization and brain leukocyte infiltration were evaluated by TTC staining, behavioural tests, flow cytometry, western blot and immunofluorescence. We found that poststroke administration of curcumol reduced infarct volume, attenuated neuronal damage and inflammation, and improved motor function recovery of MCAO mice. Curcumol skewed microglial polarization toward anti-inflammatory phenotype in MCAO mice in vivo or after oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. In addition, curcumol reduced local T cell infiltration in ischemic brain of MCAO mice and impaired Treg/Th17 balance. Curcumol inhibited ROS production and regulated Nrf2/HO-1 and NF-κB signaling in microglia. Finally, inhibiting Nrf2/HO-1 signaling or activating NF-κB signaling abrogated the influence of curcumol on microglial polarization. In conclusion, curcumol treatment reduced brain damage and neuroinflammation via modulating anti-inflammatory microglial polarization and Treg/Th17 balance through Nrf2/HO-1 and NF-κB signaling. Curcumol might be a promising treatment strategy for stroke patients.
PubMed: 38914581
DOI: 10.1038/s41420-024-02067-3 -
Journal of Applied Biomedicine Jun 2024Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory...
Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory activity of RSV in traumatic brain injury (TBI) in mice associated with endoplasmic reticulum stress (ERS). After establishing three experimental groups (sham, TBI, and TBI+RSV), we explored the results of RSV after TBI on ERS and caspase-12 apoptotic pathways. The expression levels of C/EBP homologous protein (CHOP), glucose regulated protein 78kD (GRP78), caspase-3, and caspase-12 in cortical brain tissues were assessed by western blotting. The qPCR analysis was also performed on mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in cortical brain tissue. In addition, the expression of GRP78 in microglia (ionized calcium binding adaptor molecule 1; Iba-1) and neurons (neuronal nuclei; NeuN) was identified by immunofluorescence staining. The neurological function of mice was assessed by modified neurological severity scores (mNSS). After drug treatment, the expression of CHOP, GRP78, caspase-3 and caspase-12 decreased, and qPCR results showed that TNF-α and IL-1β were down-regulated. Immunofluorescence staining showed down-regulation of Iba-1+/GRP78+ and NeuN+/GRP78+ cells after RSV treatment. The mNSS analysis confirmed improvement after RSV treatment. RSV improved apoptosis by downregulating the ERS signaling pathway and improved neurological prognosis in mice with TBI.
Topics: Animals; Brain Injuries, Traumatic; Resveratrol; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Mice; Male; Apoptosis; Prognosis; Neuroprotective Agents; Neurons; Interleukin-1beta; Caspase 12; Heat-Shock Proteins; Tumor Necrosis Factor-alpha; Mice, Inbred C57BL; Cell Death; Microglia; Transcription Factor CHOP
PubMed: 38912865
DOI: 10.32725/jab.2024.008 -
Frontiers in Neuroscience 2024There is a well-established link between physical activity and brain health. As such, the effectiveness of physical exercise as a therapeutic strategy has been explored... (Review)
Review
There is a well-established link between physical activity and brain health. As such, the effectiveness of physical exercise as a therapeutic strategy has been explored in a variety of neurological contexts. To determine the extent to which physical exercise could be most beneficial under different circumstances, studies are needed to uncover the underlying mechanisms behind the benefits of physical activity. Interest has grown in understanding how physical activity can regulate microglia, the resident immune cells of the central nervous system. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise.
PubMed: 38911597
DOI: 10.3389/fnins.2024.1420322 -
International Journal of Nanomedicine 2024Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the...
PURPOSE
Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration.
METHODS
MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated.
RESULTS
Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life.
CONCLUSION
MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.
Topics: Animals; Liposomes; Administration, Intranasal; Ischemic Stroke; Rats; Male; Ginsenosides; Blood-Brain Barrier; Macrophages; Drug Delivery Systems; Rats, Sprague-Dawley; Tissue Distribution; Brain; Biomimetic Materials; Saponins; Mice
PubMed: 38911498
DOI: 10.2147/IJN.S458656 -
Dementia and Geriatric Cognitive... 2024Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary...
INTRODUCTION
Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary microgliopathy is a disorder where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric disease. Triggering receptor expressed on myeloid cells (), TYRO protein tyrosine kinase binding protein () and colony-stimulating factor 1 receptor () are genes implicated in primary microgliopathy. The clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia (FTD), Alzheimer's dementia (AD), and so on. It becomes imperative to establish the diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aimed to describe a case series of subjects with dementia harbouring novel genes of primary microgliopathy, along with their clinical, neuropsychological, cognitive profile and radiological patterns.
METHODS
The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES).
RESULTS
A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of , , and and two variants of uncertain significance in were identified as cause of primary microgliopathy. and presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD.
CONCLUSION
WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in , , and with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.
PubMed: 38910897
DOI: 10.1159/000538145