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Brain and Behavior Feb 2023Neuropathic pain (NP) caused by the injury or dysfunction of the nervous system is a chronic pain state accompanied by hyperalgesia, and the available clinical treatment... (Review)
Review
BACKGROUND
Neuropathic pain (NP) caused by the injury or dysfunction of the nervous system is a chronic pain state accompanied by hyperalgesia, and the available clinical treatment is relatively scarce. Hyperalgesia mediated by pro-inflammatory factors and chemokines plays an important role in the occurrence and maintenance of NP.
DATA TREATMENT
Therefore, we conducted a systematic literature review of experimental NP (PubMed Medline), in order to find the mechanism of inducing central sensitization and explore the intervention methods of hyperalgesia caused by real or simulated injury.
RESULT
In this review, we sorted out the activation pathways of microglia, astrocytes and neurons, and the process of crosstalk among them. It was found that in NP, the microglia P2X4 receptor is the key target, which can activate the mitogen-activated protein kinase pathway inward and then activate astrocytes and outwardly activate neuronal tropomyosin receptor kinase B receptor to activate neurons. At the same time, activated neurons continue to maintain the activation of astrocytes and microglia through chemokines on CXCL13/CXCR5 and CX3CL1/CX3CR1. This crosstalk process is the key to maintaining NP.
CONCLUSION
We summarize the further research on crosstalk among neurons, microglia, and astrocytes in the central nervous system, elaborate the ways and connections of relevant crosstalk, and find potential crosstalk targets, which provides a reference for drug development and preclinical research.
Topics: Humans; Hyperalgesia; Neuroglia; Neuralgia; Neurons; Spinal Cord; Microglia; Astrocytes
PubMed: 36602945
DOI: 10.1002/brb3.2868 -
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 Immunology 2023Neuropathic pain is caused by a neurological injury or disease and can have a significant impact on people's daily lives. Studies have shown that neuropathic pain is...
BACKGROUND
Neuropathic pain is caused by a neurological injury or disease and can have a significant impact on people's daily lives. Studies have shown that neuropathic pain is commonly associated with neurodegenerative diseases. In recent years, there has been a lot of literature on the relationship between neuropathic pain and neurodegenerative diseases. However, bibliometrics is rarely used in analyzing the general aspects of studies on neuropathic pain in neurodegenerative diseases.
METHODS
The bibliometric analysis software CiteSpace and VOSviewer were used to analyze the knowledge graph of 387 studies in the Science Citation Index Expanded of the Web of Science Core Collection Database.
RESULTS
We obtained 2,036 documents through the search, leaving 387 documents after culling. 387 documents were used for the data analysis. The data analysis showed that 330 papers related to neuropathic pain in neurodegenerative diseases were published from 2007-2022, accounting for 85.27% of all published literature. In terms of contributions to the scientific study of neuropathic pain, the United States is in the top tier, with the highest number of publications, citations, and H-indexes.
CONCLUSION
The findings in our study may provide researchers with useful information about research trends, frontiers, and cooperative institutions. Multiple sclerosis, Parkinson's disease, and Alzheimer's disease are the three most studied neurodegenerative diseases. Among the pathological basis of neurodegenerative diseases, microglia-regulated neuroinflammation is a hot research topic. Deep brain stimulation and gamma knife radiosurgery are two popular treatments.
Topics: Humans; Neurodegenerative Diseases; Neuralgia; Alzheimer Disease; Parkinson Disease; Bibliometrics
PubMed: 37503342
DOI: 10.3389/fimmu.2023.1182411 -
Journal of Neuroinflammation Mar 2023Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of... (Review)
Review
Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia-metabolism interface.
Topics: Humans; Microglia; Diabetes Mellitus; Hyperglycemia; Central Nervous System; Dementia
PubMed: 36869375
DOI: 10.1186/s12974-023-02740-x -
Brain and Neuroscience Advances 2020Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and... (Review)
Review
Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.
PubMed: 33447663
DOI: 10.1177/2398212820978049 -
Journal of Alzheimer's Disease Reports Apr 2020Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is... (Review)
Review
Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. sildenafil protected neural mitochondria from Aβ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ levels reported significant improvements except the two that used the highest dosage, consistent with the dose-limiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1α signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.
PubMed: 32467879
DOI: 10.3233/ADR-200166 -
Frontiers in Molecular Neuroscience 2023The pathomechanisms underlying migraine are intricate and remain largely unclear. Initially regarded as a neuronal disorder, migraine research primarily concentrated on...
BACKGROUND
The pathomechanisms underlying migraine are intricate and remain largely unclear. Initially regarded as a neuronal disorder, migraine research primarily concentrated on understanding the pathophysiological changes within neurons. However, recent advances have revealed the significant involvement of neuroinflammation and the neuro-glio-vascular interplay in migraine pathogenesis.
METHODS
A systematic search was conducted in PubMed, Scopus, and Web of Science databases from their inception until November 2022. The retrieved results underwent a screening process based on title and abstract, and the full texts of the remaining papers were thoroughly assessed for eligibility. Only studies that met the predetermined inclusion criteria were included in the review.
RESULTS
Fifty-nine studies, consisting of 6 human studies and 53 animal studies, met the inclusion criteria. Among the 6 human studies, 2 focused on genetic analyses, while the remaining studies employed functional imaging, serum analyses and clinical trials. Regarding the 53 animal studies investigating glial cells in migraine, 19 of them explored the role of satellite glial cells and/or Schwann cells in the trigeminal ganglion and/or trigeminal nerve. Additionally, 17 studies highlighted the significance of microglia and/or astrocytes in the trigeminal nucleus caudalis, particularly in relation to central sensitization during migraine chronification. Furthermore, 17 studies examined the involvement of astrocytes and/or microglia in the cortex.
CONCLUSION
Glial cells, including astrocytes, microglia, satellite glial cells and Schwann cells in the central and peripheral nervous system, participate both in the development as well as chronic progression of migraine in disease-associated regions such as the trigeminovascular system, trigeminal nucleus caudalis and cortex, among other brain regions.
PubMed: 37456527
DOI: 10.3389/fnmol.2023.1219574 -
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 -
Brain, Behavior, and Immunity Oct 2023The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS)...
INTRODUCTION
The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity.
METHODS
We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05.
RESULTS
156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, P < 0.001, I = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, P < 0.001, I = 64%) and other neurodegenerative disorders (SMD = 0.929, P < 0.001, I = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all P < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; V-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance).
CONCLUSION
This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to V-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.
PubMed: 37543251
DOI: 10.1016/j.bbi.2023.07.023 -
Orphanet Journal of Rare Diseases Jun 2023CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain... (Review)
Review
CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.
Topics: Humans; Neuroglia; Leukoencephalopathies; Brain; Mutation; Nervous System Malformations; Atrophy
PubMed: 37349768
DOI: 10.1186/s13023-023-02772-9