Neuroinflammatory Mechanisms Research Articles

Loss of Fatty Acid Degradation by Astrocytic Mitochondria as a Mechanism of Neuroinflammation and Neurodegeneration

AbstractBackgroundAstrocytes provide key neuronal support, and their phenotypic transformation is strongly implicated in neurodegenerative disorders including Alzheimer’s disease (AD). Metabolically, astrocytes possess modest mitochondrial oxidative phosphorylation (OxPhos) activity, yet the pathological role of astrocytic OxPhos in neurodegeneration remains to be defined.MethodWe generated the TfamAKO mice, in which the transcription factor A mitochondrial (Tfam) is deleted selectively in astrocytes. Behavioral, electrophysiological, immunostaining, transcriptomics, metabolomics, and magnetic resonance imaging analyses were employed to characterize AD‐relevant phenotypes of TfamAKO mice, which were further compared to an AD mouse model (5xFAD). Primary cell cultures and co‐cultures were used to determine the cell autonomous and non‐autonomous mechanisms by which disrupted astrocytic OxPhos induces astrocyte reactivity, neuroinflammation and neurodegeneration.ResultHere we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of AD including reactive astrogliosis, synaptic loss, microgliosis, demyelination, and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl‐CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid‐laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia via IL‐3 signaling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Moreover, the metabolic and transcriptional signatures of the hippocampus of TfamAKO mice highly overlap with that of 5xFAD mice.ConclusionWe reveal a lipid‐centric, AD‐resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.

Immune regulatory roles for Kv1.3 channels in Microglia in Alzheimer’s Disease

AbstractBackgroundIn Alzheimer’s Disease (AD), a sub‐population of disease associated microglia present increased Kv1.3 channel abundance. Pharmacological blockade of Kv1.3 reduces Aβ pathology and dampens pro‐inflammatory function of microglia. To identify Kv1.3‐regulated neuroinflammatory mechanisms in microglia, we examined the interactome of Kv1.3 channels in vitro, and Kv1.3 deletion and inhibition in vivo.MethodsTurboID, a proximity‐dependent biotin ligase, was fused to the N‐term or C‐term of Kv1.3 and transduced in BV2 microglia. Kv1.3 and TurboID presence and activity were confirmed via qPCR, electrophysiology, flow cytometry, and western blot. Mass spectrometry(MS) of biotinylated proteins, under resting and lipopolysaccharide(LPS)‐treated conditions, identified Kv1.3 interactomes. Kcna3(Kv1.3)‐floxed mice were generated and crossed to CMV‐Cre mice for global Kv1.3 deletion. Three and six month old 5xFAD mice were treated with PAP1, a small molecule intracellular blockade of Kv1.3, for three months. At nine months of age behavioral tests were performed. Aβ pathology was evaluated using ELISA and Immunofluorescence. Brain nuclei were isolated for snRNAseq. CSF, plasma, and brain were processed for MS.ResultsProteomics of BV2‐Kv1.3‐TurboID microglia identified distinct N‐term (n = 991) and C‐term Kv1.3 (n = 849) interactors. Kv1.3 N‐term interacts with plasma membrane proteins (e.g. Cars1, Psma2) and mitochondrial trafficking proteins (Timm23). C‐term interactors were modified by LPS‐stimulation (C3, STAT1, Oasl1) (n = 36), and partly dependent on a PDZ‐binding motif (Snx3, ND3, n = 70). Predicted by MS, western blot confirmed mitochondrial Kv1.3 presence. In vivo global Kv1.3 deletion was verified by qPCR. 9month 5xFAD mice with the Kv1.3 blockade show a reduction in Aβ pathology and a rescue of fear conditioning. Brain cell type‐specific and tissue‐level effects of Kv1.3 blockade will be evaluated by snRNAseq and MS.ConclusionsWe identified N and C‐term domain‐specific and context‐dependent interactors of Kv1.3 channels in microglia, including several pro‐inflammatory C‐term interactors. We developed and validated a novel Kv1.3‐floxed line for global, and conditional, Kv1.3 deletion studies in mouse models of AD pathology. Kv1.3 blockers reduce Aβ pathology and correct behavioral deficits in 5xFAD mice. The transcriptomic and proteomic studies of brain and biofluids from this cohort will provide mechanistic insights and identify novel biomarkers of therapeutic efficacy of Kv1.3 blockers.

Chronic interleukin-6 mediated neuroinflammation decreases anxiety, and impaires spatial memory in aged female mice

IntroductionNeuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level.MethodsThis study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory.ResultsFemale GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs.ConclusionIn conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM.

Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay

Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1β signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1β converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.

Advances in the Study of the Pathology and Treatment of Alzheimer's Disease and Its Association with Periodontitis.

Alzheimer's disease (AD) has become one of the leading causes of health problems in the elderly, and studying its causes and treatments remains a serious challenge for researchers worldwide. The two main pathological features of Alzheimer's disease are the extracellular deposition of β-amyloid (Aβ) to form senile plaques and the intracellular aggregation of hyperphosphorylated Tau protein to form neurofibrillary tangles (NFTs). Researchers have proposed several hypotheses to elucidate the pathogenesis of AD, but due to the complexity of the pathophysiologic factors involved in the development of AD, no effective drugs have been found to stop the progression of the disease. Currently, the mainstay drugs used to treat AD can only alleviate the patient's symptoms and do not have a therapeutic effect. As researchers explore interactions among diseases, much evidence suggests that there is a close link between periodontitis and AD, and that periodontal pathogenic bacteria can exacerbate Aβ deposition and Tau protein hyperphosphorylation through neuroinflammatory mechanisms, thereby advancing the pathogenesis of AD. This article reviews recent advances in the pathogenesis of AD, available therapeutic agents, the relevance of periodontitis to AD, and mechanisms of action.

In vitro model for human astrocytes identifies potential neuroinflammatory mechanisms underlying major depressive disorder in people with HIV

In vitro model for human astrocytes identifies potential neuroinflammatory mechanisms underlying major depressive disorder in people with HIV

Emerging trends and hotspots of the itch research: A bibliometric and visualized analysis.

Itch, a common uncomfortable sensory experience, occurs frequently in inflammatory or allergic disorders. In recent years, with the discovery of itch-specific pathways in the peripheral and central nervous system, the association between immunology and neural pathways has gradually emerged as the main mechanism of itch. Although many studies have been conducted on itch, no bibliometric analysis study focusing on this topic has been conducted. This study aimed to explore the research hotspots and trends in the itch field from a bibliometric perspective. Publications relevant to itch, published from 2003 to 2022, were retrieved from the Science Citation Index-Expanded of Web of Science Core Collection. Publications were critically reviewed and analyzed with CiteSpace software, Vosviewer, and the bibliometric online analysis platform. Visual maps were conducted in terms of annual production, collaborating countries or institutions, productive authors, core journals, co-cited references, and keyword bursts. 2395 articles on itch that met our criteria were identified and the quantity of publications has been increasing rapidly since 2012. The USA was the most influential country. University Hospital Münster was the institution with the most publications. Gil Yosipovitch was the most prolific author. Atopic dermatitis (AD), intradermal serotonin, chronic pruritus, mechanical itch, gastrin-releasing peptide, substance p, interleukin-31 receptor, histamine-induced itch, bile acid, scratching behavior, and h-4 receptor were the top 11 clusters in co-citation cluster analysis. Keyword burst analysis suggested that treatment, inflammation, and AD are current research hotspots. Global publications on itch research have increased steadily and rapidly over the past 20 years. Inflammation and AD are current research hotspots. The neuroimmunological and neuroinflammatory mechanisms of itch, as well as clinical assessment methods and therapeutic targets, will be novel research directions in the future. This study provides guidance for further itch research.

The role of cellular immunity and systemic inflammation indices in the pathogenetic mechanisms of mental disorders

To date, inflammatory mechanisms are known to be involved in neuronal damage and increased risk of associated mental disorders, but most previous work has focused primarily on cytokines and other inflammatory markers that are difficult to replicate and not economically feasible for use in routine clinical practice. Other extremely important indicators of the systemic inflammatory process are circulating blood cells and changes in their number, composition, and ratio. Hematologic indices of systemic inflammation (HISI) are already used in somatic specialties: neutrophil-lymphocyte (NLR), monocyte-lymphocyte (MLR) and platelet-lymphocyte (PLR) ratios, as well as the Systemic Immune Inflammation Index (SII) and the System Inflammation Response Index (SIRI). In the context of psychopathology, the HISI require additional investigation, which makes it necessary to pay more attention to the possible mechanisms underlying their changes. The article provides data on the contribution of each cellular element to the mechanism of neuroinflammation and neurodegeneration and on their role in the development of psychopathological processes.

Aging-related genes revealed Neuroinflammatory mechanisms in ischemic stroke by bioinformatics

Ischemic stroke (IS) is a leading cause of disability, morbidity, and mortality globally. Aging affects immune function and contributes to poor outcomes of IS in elderly individuals. However, little is known about how aging-related genes (ARGs) are involved in IS. In this study, the relationship between ARGs and IS immune microenvironment biomarkers was explored by bioinformatics. Two IS microarray datasets (GSE22255, GSE16561) from human blood samples were analyzed and 502 ARGs were identified, from which 29 differentially expressed ARGs were selected. Functional analysis revealed that 7 of these ARGs (IL1B, FOS, JUN, CXCL5, PTGS2, TNFAIP3 and TLR4) were involved in five top enriched pathways (IL-17 signaling pathway, TNF signaling pathway, Rheumatoid arthritis, NF-kappa B signaling pathway and Pertussis) related to immune responses and inflammation. Five hub DE-ARGs (IL2RB, FOS, IL7R, ALDH2 and BIRC2) were identified using machine learning algorithms, and their association with immune-related characteristics was confirmed by additional tests. Single-cell sequencing dataset GSE129788 was retrieved to analyze aging molecular-related features, which was in accordance with microarray datasets. Clustering analysis revealed two subtypes of IS, which were distinguished by their differential expression of genes related to the NF-kappa B signaling pathway. These findings highlight the importance of ARGs in regulating immune responses in IS and suggest potential prevention and treatment strategies as well as guidelines for future research.

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

Melatonin Improves Mitochondrial Dysfunction and Attenuates Neuropathic Pain by Regulating SIRT1 in Dorsal Root Ganglions

Neuropathic pain is a debilitating chronic pain condition and is refractory to the currently available treatments. Emerging evidence suggests that melatonin exerts analgesic effects in rodent models of neuropathic pain. Nevertheless, the exact underlying mechanisms of the analgesic effects of melatonin on neuropathic pain are largely unknown. Here, we observed that spinal nerve ligation (SNL) in rats L5 and L6 induced an obvious decrease in the 50% paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), indicating the induction of mechanical allodynia and the hyperalgesia, and melatonin prevented the genesis and maintenance of mechanical allodynia and the hyperalgesia. Notably, the inhibitory action of melatonin on SNL-induced mechanical allodynia and heat hypersensitivity was inhibited by a SIRT1 inhibitor (EX527). Melatonin treatment increased the expression of neuronal sirtuin1 (SIRT1) in DRGs following nerve injury. Furthermore, melatonin treatment restored the injury-dependent decrease in mitochondrial membrane potential and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and reduced the injury-dependent increase in hydrogen peroxide and 8-hydroxy-2-deoxyguanosine (8-OHdG), which was inhibited by EX527. In addition, we found that EX527 impeded the inhibitory effects of melatonin on the SNL-induced increased expression of cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). In conclusion, the above data demonstrated that melatonin alleviated mechanical allodynia and hyperalgesia induced by peripheral nerve injury via SIRT1 activation. Melatonin resolved mitochondrial dysfunction—oxidative stress-dependent and neuroinflammation mechanisms that were driven by SIRT1 after nerve injury.

Microglia in the pathogenesis of depression, insomnia and their comorbidity

Microglia have been shown to regulate sleep homeostasis and depressive behavior. However, the mechanism of how microglia are involved in the pathogenesis of depression and insomnia is not well understood. Given the complex and interdependent relationship between sleep and depression, it is important and worthy to clarify the role of microglia in this comorbidity. This review summarizes the current understandings of microglia in insomnia and depression, as well as suggesting their shared mechanisms in neuroinflammation, synaptic plasticity and purinergic signaling, which may promote the precise treatment of comorbid insomnia and depression and facilitate early intervention of insomnia to prevent the onset of depression.

Correlations of inflammatory processes caused by cerebral stroke with the outcome of the disease

Introduction. Inflammation plays a central role in the pathogenesis of stroke, so understanding inflammatory processes can greatly improve stroke treatment options. In this analysis, we review the positive and negative role of neuroinflammatory mechanisms in stroke.Negative influence of inflammatory cells and mediators in brain injury patients. All neuroinflammatory reactions and mediators play a negative role in initiating the pathological response to stroke and thus promote the development of inflammatory processes.Nosocomial infection. Elevated inflammatory markers and other prognostic factors are directly associated with higher rates of in-hospital complications such as pneumonia, urinary tract infection, and unfavorable stroke outcomes. New treatment directions can significantly improve clinical outcomes by reducing the incidence of hospital-acquired infections, which are one of the main complications after stroke.Vascular dementia. Stroke is a causative factor in vascular dementia, but certain neuroinflammatory processes in the brain are also involved. These processes may have detrimental effects on cognitive function after stroke. Therapeutic approaches that enhance pro-inflammatory cytokines and the immune system may be useful in preventing cognitive dysfunction, particularly after stroke.Physical disability. A stroke associated with ischemic, hemorrhagic, and neuroinflammatory processes in the course of the disease can cause a reduction or increase in physical disability and neurological deficit, which are very important for daily activities and quality of life.Positive influence of inflammatory cells and mediators in brain injury patients. All inflammatory cells and mediators play a positive role in complicating the pathological response to stroke and also in maintaining brain cell homeostasis.Discussion. Since the situation in this matter is quite controversial, a debatable question arises whether inflammatory processes have a positive or negative effect on the course and outcome of the disease in patients with stroke.Conclusions. After reviewing the latest scientific articles on this topic, we can say that the inflammatory process plays an ambiguous role in the pathogenesis of stroke and that its influence on the course and outcome of the disease can be both positive and negative. Therefore, today it is necessary to carry out more detailed scientific research in order to gain a deeper understanding of this issue and to achieve a better cure for the disease.

Development and characterisation of mgTHP-1, a novel in vitro model for neural macrophages with microglial characteristics

ABSTRACTNeuroinflammation is primarily characterised by activation of the brain’s resident macrophages – the microglia. However, other central nervous system (CNS) cells also contribute to this response, including the astrocytes and endothelial cells. In addition, there is infiltration into the CNS of peripherally derived immune cells. Together these cells mediate inflammation by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers, and enacting of the appropriate response to those signals. However, deciphering the specific contributions of each cell type has been challenging. Studying CNS cell biology is often challenging, as the isolation of primary cells is not always feasible, and differentiation towards microglia-like cells is complex. Here, we demonstrate a novel method whereby THP-1 monocytic cells are differentiated into neural macrophage cells with microglia-like cell characteristics. The cells, designated mgTHP-1, show typical morphological and gene expression patterns of resident CNS macrophages and functionally respond to inflammatory stimuli by producing inflammatory cytokines. Furthermore, with the addition of Vicenin-2 (an anti-inflammatory flavonoid) such responses can be reversed. This novel cell model will allow further investigations, and hence insights, into the neuroinflammatory mechanisms associated with CNS diseases.

NLRP3 neuroinflammatory intervention of Mahuang-Lianqiao-Chixiaodou decoction for mental disorders in atopic dermatitis mice

Ethnopharmacological relevanceMahuang-Lianqiao-Chixiaodou decoction (MLCD) is a traditional Chinese medicinal (TCM) formula recorded in the Treatise on Febrile Diseases. It is commonly used for clinical treatment of atopic dermatitis (AD). However, the potential mechanisms of MLCD intervention in AD combined with mental disorders behaviors such as anxiety and depression remain elusive and deserves further investigation. Aim of the studyThe study aims to observe the effect of MLCD on anxiety- and depression-like behaviors in AD mice and explore the possible neuroinflammatory mechanism of NOD-like receptor 3 (NLRP3) inflammasome. Materials and methodsThe chemical components of MLCD extracts were identified using UHPLC-MS. The AD mice were induced by 2,4-dinitrofluorobenzene and treated with MLCD or mometasone furoate (MF, as a positive control) for 7 days. The pathological changes in their skin tissue and brain hippocampus were observed by hematoxylin-eosin staining. Elevated plus-maze test (EPM), open field test (OFT), and the suspended tail (TST) were used to measure the anxiety- and depressive-like behaviors in AD mice. Expression of NLRP3 inflammasome-related proteins in brain hippocampus were measured by the quantitative real-time polymerase chain reaction (qPCR) and western blotting (WB). ResultsWe found that MLCD contain many active ingredients, including ephedrine, Forsythoside A, phillyrin, glycyrrhizic acid, etc. Both MLCD and MF alleviated skin lesions and promoted positive histopathological changes in the hippocampus of AD mince to varying degrees. MLCD however, could further increase their proportion of open arm entry times (Oentries%) in EPM, residence time in the central area (Ctime) and the proportion of the number of times in the central area (Centries%) in OFT significantly. MLCD also reduces their immobility time in TST considerably. Mechanistically, MLCD downregulated the relative mRNA expression and protein level of NLRP3, Caspase-1, IL-1β, and IL-18 in hippocampal tissue compared to the model group. ConclusionsMLCD can alleviate anxiety-like and depression-like behaviors in AD mice by intervening in the gene and protein expression of NLRP3 inflammasome-related factors, thus treating AD.

Attention-deficit/hyperactivity disorder and inflammation: natural product-derived treatments-a review of the last ten years.

Attention-deficit hyperactivity disorder (ADHD) is a psychiatric disorder characterized by symptoms of inattention, hyperactivity, and impulsivity. Stimulant medication is the main pharmacological treatment for ADHD. However, the traditional pharmacological treatments may have significant side effects; therefore, non-pharmacological approaches are needed. Thus, there has been growing interest in alternative herbal treatments. The aim of this review was to comprehensively assess the current evidence for plant-based treatment of ADHD in human and animal models, as well as their ability to modulate the inflammatory process. This study was an integrative review of the current evidence for the plant-based treatment of ADHD. The research involved using literature available on PubMed and Scopus databases. Spontaneously hypersensitive rats treated with baicalin exhibited significant reductions in locomotion, increased spatial learning skills, and increased levels of dopamine in the striatum. Supplementation with Sansonite improved memory and attention capacity. In human studies, Ginkgo biloba significantly improved the symptoms of inattention and reduced memory impairment. In studies conducted using Korean Red ginseng, Klamath, and Crocus sativus L., the patients showed significant improvements in symptoms of inattention and hyperactivity/impulsivity. Furthermore, we demonstrated that the identified plants modulate the inflammatory process through pro-inflammatory and anti-inflammatory cytokines, nitric oxide, Th cells, Toll-like receptor 4, and mitogen-activated protein kinases. All the studies included in this review focused on plants with demonstrated potential against inflammatory processes, positioning them as promising candidates for ADHD treatment, due to their potential to attenuate or even prevent neuroinflammatory mechanisms.

Ilexchinene, a new seco-ursane triterpenoid from the leaves of Ilex chinensis with therapeutic effect on neuroinflammation by attenuating the MAPK/NF-κB signaling pathway

BackgroundNeuroinflammation is a vital factor participating in the whole pathogenetic process of diverse neurodegenerative disorders, but accessible clinical drugs are still insufficient due to their inefficacy and side effects. Triterpenoids are reported to possess potential anti-neuroinflammatory activities, and the leaves of Ilex chinensis are a commonly used herbal medicine containing many ursane-type and oleanane-type triterpenoids. However, the novel triterpenoids from I. chinensis and their underlying mechanisms are still elusive. PurposeTo isolate novel seco-ursane triterpenoids with anti-neuroinflammatory effects from the leaves of I. chinensis and reveal their underlying mechanisms. Study design and methodsThe novel compound was purified by column chromatography and identified by comprehensive spectroscopic experiments. The LPS-induced BV-2 cell model and LPS-induced acute murine brain inflammation model were used to assess the anti-neuroinflammatory effect of the structure and further understand its underlying mechanisms by cell viability, ELISA, Western blot analysis, qRT‒PCR analysis, behavior analysis, H&E staining, and immunofluorescence staining experiments. ResultsIlexchinene is a novel ursane-type triterpenoid with a rare 18,19-seco-ring skeleton that was first isolated and identified from I. chinensis. Ilexchinene evidently reduced the overexpression of inflammatory substances in vitro. A mechanistic study suggested that ilexchinene could decrease NF-κB activation to prevent the formation of the NLRP3 inflammasome in the early neuroinflammatory response; in addition, it could prevent the phosphorylation of ERK and JNK. In vivo, ilexchinene remarkably improved LPS-induced mouse behavioral deficits and diminished the number of overactivated microglial cells. Furthermore, ilexchinene evidently diminished the overexpression of inflammatory substances in mouse brains. A mechanistic study confirmed that ilexchinene markedly suppressed the MAPK/NF-κB pathway to relieve the neuroinflammatory response. ConclusionWe identified a novel 18,19-seco-ursane triterpenoid from the leaves of I. chinensis and revealed its underlying mechanism of neuroinflammation for the first time. These findings suggest that ilexchinene might possess promising therapeutic effects in neuroinflammation.

Natural products for the treatment of neurodegenerative diseases

BackgroundNeurodegenerative diseases are among the most common diseases in older adults worldwide. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases, and are accompanied by cerebral cortical atrophy, neuronal loss, protein accumulation, and excessive accumulation of metal ions. Natural products exhibit outstanding performance in improving cerebral circulatory disorders, promoting cerebral haematoma absorption, repairing damaged nerve tissue, and improving damaged nerve function. In recent years, studies have shown that neuroinflammatory mechanisms and signalling pathways closely related to the occurrence and development of neurological diseases include microglial activation, nuclear factor-κB (NF-κB) pathway, mitogen activated protein kinases (MAPK) pathway, reactive oxygen pathway, nucleotide binding oligomerisation domain-like receptor protein3 (NLRP3) inflammasomes, toll-like receptor4 (TLR4) pathway, nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) pathway, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, and intestinal flora. Therefore, this study considered the mechanism of neurological diseases as the starting point to review the mechanism of action of natural products in the prevention and treatment of AD and PD in recent years to provide a theoretical basis for clinical prevention and treatment. AimNatural products are a promising source of novel lead structures that have long been used to treat various nervous system diseases. MethodologyThis review collected literature on neurological diseases and natural products from 2012 to 2022, which were mainly searched through databases such as ScienceDirect, Springer, PubMed, SciFinder, China National Knowledge Infrastructure (CNKI), Wanfang, Google Scholar, and Baidu Academic. The following keywords were searched: neurological disorders, natural products, signalling pathway, mechanism of action. ResultsThis review summarises the pathogenesis of degenerative neurological diseases, recent findings on natural products used in neurodegenerative diseases, and the molecular mechanisms underlying these effects.

SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study.

SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease. SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival. SerpinA1serum was significantly decreased in ALS (median: 1032 μg/mL) compared with controls (1343 μg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 μg/mL) compared with slow (4.43 μg/mL, p = 0.01) and intermediate (4.42 μg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival. Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.

Parkinson's and Alzheimer's disease as system-wide neurodegenerative disorders

Parkinson's and Alzheimer's disease (PD/AD) are characterized by cellular pathological changes that precede clinical manifestation and symptom onset by decades (prodromal period) as well as by aheterogeneity of clinical symptoms. Both diseases are recognized as system-wide diseases with organ-transgressing dysregulation and involvement of immunological and neuroinflammatory mechanisms facilitating pathological protein aggregation and neurodegeneration. Overview of natural course, phenotypes and classification of PD/AD with afocus on underlying (system-wide) immunological and neuroinflammatory mechanisms. Literature research and consideration of expert opinions. The accumulation of misfolded proteins such as amyloid‑β and synuclein in the course of neurodegenerative processes forms the basis of the current biological classifications, understanding of course and subtypes. Protein aggregation in PD/AD induces an innate immune response by activating microglia and the release of inflammatory mediators such as cytokines and chemokines and leading to further spread of neurodegeneration and accumulation of intracellular neurofibrillary tangles (NFTs). There is also growing evidence that adaptive immune responses involving auto-antibodies or auto-antigen-specific T‑/B-cell reactions involving tau, amyloid‑β or synuclein might be involved in the disease progression or subtypes of PD/AD. Both innate and adaptive immune responses seem to be substantially involved in the pathological cascade leading to neurodegeneration in PD/AD and may contribute to disease progression and clinical subtypes. Thus, future targeted interventions should not only focus on protein aggregation but also on neuroinflammatory and immunological mechanisms.