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Molecular Neurobiology Mar 2023Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as... (Review)
Review
Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.
Topics: Humans; Microglia; Neuroinflammatory Diseases; Retrospective Studies; Sepsis; Sepsis-Associated Encephalopathy; Brain Injuries
PubMed: 36445634
DOI: 10.1007/s12035-022-03148-z -
Frontiers in Pharmacology 2022Stroke, including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH), remains a leading cause of mortality globally. Different stroke subtypes...
Stroke, including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH), remains a leading cause of mortality globally. Different stroke subtypes have similar detrimental effects in multiple fields of health. Previous research has shown that metformin plays a neuroprotective role in experimental animal models of stroke; however, a preclinical quantitative analysis on the ability of metformin to treat stroke is still lacking. This meta-analysis evaluates the efficacy of metformin in improving stroke prognosis in rodent models of stroke. Relevant preclinical trials were retrieved from PubMed, EMBASE, and the Web of Science. The neurological score (NS), brain water content (BWC), infarct size, rotarod test, TUNEL, neuron quantity, microglia quantity, and p-AMPK levels were compared between a control group and a metformin group using the standardized mean difference (SMD) and corresponding confidence interval (CI). Quality was assessed with SYRCLE's risk of bias tool. Fifteen articles published from 2010 to 2022 were included in the meta-analysis. The metformin group had statistically significant differences compared to the control group in the following aspects: NS (SMD -1.45; 95% CI -2.32, -0.58; = 0.001), BWC (SMD -3.22; 95% CI -4.69, -1.76; < 0.0001), infarct size (SMD -2.90; 95% CI -3.95, -1.85; < 0.00001), rotarod test (SMD 2.55; 95% CI 1.87, 3.23; < 0.00001), TUNEL (SMD -3.63; 95% CI -5.77, -1.48; = 0.0009), neuron quantity (SMD 3.42; 95% CI 2.51, 4.34; < 0.00001), microglia quantity (SMD -3.06; 95% CI -4.69, -1.44; = 0.0002), and p-AMPK levels (SMD 2.92; 95% CI 2.02, 3.82; < 0.00001). Furthermore, sensitivity analysis and stratified analysis were conducted for heterogeneous outcome indicators. Overall, metformin treatment improves severe outcomes triggered by stroke. Despite the limitations intrinsic to animal studies, this systematic review may provide a vital reference for future high-quality preclinical trials and clinical use.
PubMed: 36408248
DOI: 10.3389/fphar.2022.1009169 -
Neural Plasticity 2022Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have shown great therapeutic potential in cerebral ischemia-reperfusion injury (CIRI). In... (Meta-Analysis)
Meta-Analysis
Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have shown great therapeutic potential in cerebral ischemia-reperfusion injury (CIRI). In this study, we firstly performed a systematic review to evaluate the efficacy of MSCs-derived sEV for experimental cerebral ischemia/reperfusion injury. 24 studies were identified by searching 8 databases from January 2012 to August 2022. The methodological quality was assessed by using the SYRCLE 's risk of bias tool for animal studies. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 9 in a total of ten points. Meta-analyses showed that MSCs-derived sEVs could effectively alleviate neurological impairment scores, reduced the volume of cerebral infarction and brain water content, and attenuated neuronal apoptosis. Additionally, the possible mechanisms of MSCs-derived sEVs for attenuating neuronal apoptosis were inhibiting microglia-mediated neuroinflammation. Thus, MSCs-derived sEVs might be regarded as a novel insight for cerebral ischemic stroke. However, further mechanistic studies, therapeutic safety, and clinical trials are required. Systematic review registration. PROSPERO CRD42022312227.
Topics: Animals; Rodentia; Mesenchymal Stem Cells; Extracellular Vesicles; Reperfusion Injury; Brain Ischemia; Stroke
PubMed: 36338577
DOI: 10.1155/2022/3933252 -
Frontiers in Molecular Neuroscience 2022Molecular neuroimaging studies provide mounting evidence that neuroinflammation plays a contributory role in the pathogenesis of major depressive disorder (MDD). This...
Molecular neuroimaging studies provide mounting evidence that neuroinflammation plays a contributory role in the pathogenesis of major depressive disorder (MDD). This has been the focus of a number of positron emission tomography (PET) studies of the 17-kDa translocator protein (TSPO), which is expressed by microglia and serves as a marker of neuroinflammation. In this meta-analysis, we compiled and analyzed all available molecular imaging studies comparing cerebral TSPO binding in MDD patients with healthy controls. Our systematic literature search yielded eight PET studies encompassing 238 MDD patients and 164 healthy subjects. The meta-analysis revealed relatively increased TSPO binding in several cortical regions (anterior cingulate cortex: Hedges' = 0.6, 95% CI: 0.36, 0.84; hippocampus: = 0.54, 95% CI: 0.26, 0.81; insula: = 0.43, 95% CI: 0.17, 0.69; prefrontal cortex: = 0.36, 95% CI: 0.14, 0.59; temporal cortex: = 0.39, 95% CI: -0.04, 0.81). While the high range of effect size in the temporal cortex might reflect group-differences in body mass index (BMI), exploratory analyses failed to reveal any relationship between elevated TSPO availability in the other four brain regions and depression severity, age, BMI, radioligand, or the binding endpoint used, or with treatment status at the time of scanning. Taken together, this meta-analysis indicates a widespread ∼18% increase of TSPO availability in the brain of MDD patients, with effect sizes comparable to those in earlier molecular imaging studies of serotonin transporter availability and monoamine oxidase A binding.
PubMed: 36226319
DOI: 10.3389/fnmol.2022.981442 -
Frontiers in Neuroscience 2022Neuroinflammation is a response that involves different cell lineages of the central nervous system, such as neurons and glial cells. Among the non-pharmacological...
BACKGROUND
Neuroinflammation is a response that involves different cell lineages of the central nervous system, such as neurons and glial cells. Among the non-pharmacological interventions for neuroinflammation, photobiomodulation (PBM) is gaining prominence because of its beneficial effects found in experimental brain research. We systematically reviewed the effects of PBM on laboratory animal models, specially to investigate potential benefits of PBM as an efficient anti-inflammatory therapy.
METHODS
We conducted a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: photobiomodulation, low-level laser therapy, brain, neuroinflammation, inflammation, cytokine, and microglia. Data search was limited from 2009 to June 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The initial systematic search identified 140 articles. Among them, 54 articles were removed for duplication and 59 articles by screening. Therefore, 27 studies met the inclusion criteria.
RESULTS
The studies showed that PBM has anti-inflammatory properties in several conditions, such as traumatic brain injury, edema formation and hyperalgesia, ischemia, neurodegenerative conditions, aging, epilepsy, depression, and spinal cord injury.
CONCLUSION
Taken together, these results indicate that transcranial PBM therapy is a promising strategy to treat brain pathological conditions induced by neuroinflammation.
PubMed: 36203812
DOI: 10.3389/fnins.2022.1006031 -
Forensic Science, Medicine, and... Dec 2022Clinical features of COVID-19 range from mild respiratory symptoms to fatal outcomes. Autopsy findings are important for understanding COVID-19-related pathophysiology... (Meta-Analysis)
Meta-Analysis Review
Clinical features of COVID-19 range from mild respiratory symptoms to fatal outcomes. Autopsy findings are important for understanding COVID-19-related pathophysiology and clinical manifestations. This systematic study aims to evaluate autopsy findings in paediatric cases. We searched PubMed, EMBASE, and Cochrane Database Reviews. We included studies that reported autopsy findings in children with COVID-19. A total of 11 studies (24 subjects) were included. The mean age of patients was 5.9 ± 5.7 years. Grossly, there was pericardial and pleural effusion, hepatosplenomegaly, cardiomegaly, heavy soft lung, enlarged kidney, and enlarged brain. The autopsy findings of the lungs were diffuse alveolar damage (78.3%), fibrin thrombi (43.5%), haemorrhage (30.4%), pneumonia (26%), congestion and oedema (26%), angiomatoid pattern (17.4%), and alveolar megakaryocytes (17.4%). The heart showed interstitial oedema (80%), myocardial foci of band necrosis (60%), fibrin microthrombi (60%), interstitial and perivascular inflammation (40%), and pancarditis (30%). The liver showed centrilobular congestion (60%), micro/macrovesicular steatosis (30%), and arterial/venous thrombi (20%). The kidney showed acute tubular necrosis (75%), congestion (62.5%), fibrin thrombi in glomerular capillaries (37.5%), and nephrocalcinosis, mesangial cell hyperplasia, tubular hyaline/granular casts (25% each). The spleen showed splenitis (71.4%), haemorrhage (71.4%), lymphoid hypoplasia (57.1%), and haemophagocytosis (28.6%). The brain revealed oedema (87.5%), congestion (75%), reactive microglia (62.5%), neuronal ischaemic necrosis (62.5%), meningoencephalitis (37.5%), and fibrin thrombi (25%). SARS-CoV-2 and CD68 were positive by immunohistochemistry in 85.7% and 33.3% cases, respectively. Autopsy findings of COVID-19 in children are variable in all important organs. It may help in better understanding the pathogenesis of SARS-CoV-2.
Topics: Humans; Child; Infant; Child, Preschool; COVID-19; SARS-CoV-2; Autopsy; Lung; Thrombosis; Fibrin; Necrosis
PubMed: 36048325
DOI: 10.1007/s12024-022-00502-4 -
Neuro-oncology Advances 2022Checkpoint inhibitor immunotherapy has not proven clinically effective in glioblastoma. This lack of effectiveness may be partially attributable to the frequent...
BACKGROUND
Checkpoint inhibitor immunotherapy has not proven clinically effective in glioblastoma. This lack of effectiveness may be partially attributable to the frequent administration of dexamethasone in glioblastoma patients. In this systematic review, we assess whether dexamethasone (1) affects the glioblastoma microenvironment and (2) interferes with checkpoint inhibitor immunotherapy efficacy in the treatment of glioblastoma.
METHODS
PubMed and Embase were systematically searched for eligible articles published up to September 15, 2021. Both in vitro and in vivo preclinical studies, as well as clinical studies were selected. The following information was extracted from each study: tumor model, corticosteroid treatment, and effects on individual immune components or checkpoint inhibitor immunotherapy.
RESULTS
Twenty-one preclinical studies in cellular glioma models ( = 10), animal glioma models ( = 6), and glioblastoma patient samples ( = 7), and 3 clinical studies were included. Preclinical studies show that dexamethasone decreases the presence of microglia and other macrophages as well as the number of T lymphocytes in both tumor tissue and periphery. Dexamethasone abrogates the antitumor effects of checkpoint inhibitors on T lymphocytes in preclinical studies. Although randomized studies directly addressing our research question are lacking, clinical studies suggest a negative association between corticosteroids and survival outcomes in glioblastoma patients receiving checkpoint inhibitors after adjustment for relevant prognostic factors.
CONCLUSIONS
Preclinical research shows that dexamethasone inhibits the antitumor immune response in glioma, thereby promoting a protumorigenic microenvironment. The efficacy of checkpoint inhibitor immunotherapy in glioblastoma patients may therefore be negatively affected by the use of dexamethasone. Future research could investigate the potential of edema-reducing alternatives to dexamethasone.
PubMed: 35990704
DOI: 10.1093/noajnl/vdac087 -
Molecular Neurobiology Oct 2022Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between... (Review)
Review
Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review.
Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the "quantal" elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.
Topics: Antipsychotic Agents; Dopamine; Glutamic Acid; Humans; Inflammation; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 35963926
DOI: 10.1007/s12035-022-02976-3 -
Frontiers in Aging Neuroscience 2022Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of...
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra of the brain. In this review, we summarize evidence obtained by animal studies demonstrating neuroinflammation as one of the central pathogenetic mechanisms of PD. We also focus on the protein factors that initiate the development of PD and other neurodegenerative diseases. Our targeted literature search identified 40 pre-clinical and studies written in English. Nuclear factor B (NF-kB) pathway is demonstrated as a common mechanism engaged by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6hydroxydopamine (6-OHDA), as well as the bacterial lipopolysaccharide (LPS). The α-synuclein protein, which plays a prominent role in PD neuropathology, may also contribute to neuroinflammation by activating mast cells. Meanwhile, 6-OHDA models of PD identify microsomal prostaglandin E synthase-1 (mPGES-1) as one of the contributors to neuroinflammatory processes in this model. Immune responses are used by the central nervous system to fight and remove pathogens; however, hyperactivated and prolonged immune responses can lead to a harmful neuroinflammatory state, which is one of the key mechanisms in the pathogenesis of PD.
PubMed: 35912090
DOI: 10.3389/fnagi.2022.855776 -
Medical Research Archives Aug 2022Opioid use disorder (OUD) is an epidemic in the United States. In the past 12 months alone, there have been 75,000+ deaths attributed to opioid overdose: more than any...
Opioid use disorder (OUD) is an epidemic in the United States. In the past 12 months alone, there have been 75,000+ deaths attributed to opioid overdose: more than any other year in American history. Current pharmacotherapies for the treatment of OUD effectively suppress opioid withdrawal symptoms, but long-term relapse rates remain unacceptably high. Novel treatments for OUD are desperately needed to curb this epidemic. One target that has received considerable recent interest is the neuroimmune system. The neuroimmune system is anchored by glial cells, i.e., microglia and astrocytes, but neuroimmune signaling is known to influence neurons, including altering neurotransmission, synapse formation, and ultimately, brain function. Preclinical studies have shown that experimental attenuation of pro-inflammatory neuroimmune signaling modulates opioid addiction processes, including opioid reward, tolerance, and withdrawal symptoms, which suggests potential therapeutic benefit in patients. Whereas the peripheral immune system in OUD patients has been studied for decades and is well-understood, little is known about the immune system in OUD patients or its viability as a treatment target. Herein, we review the literature describing relationships between opioid administration and the neuroimmune system, the influence of neuroimmune signaling on opioid addiction processes, and the therapeutic potential for targeting the neuroimmune system in OUD subjects using glial modulator medications.
PubMed: 37744743
DOI: 10.18103/mra.v10i8.2955