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Artemisinin B Improves Learning and Memory Impairment in AD Dementia Mice by Suppressing Neuroinflammation
Abstract
Alzheimer's disease is a chronic neurological ailment that seriously threatens human health and imposes a huge burden on families and the society at large. Emerging evidence suggests that neuroinflammation is an important pathological manifestation of neurodegenerative diseases, and currently considered a new research target. We previously found that artemisinin B from Artemisia annua Linn. has strong anti-inflammatory and immunological activities. In the present study, we assessed the anti-neuroinflammatory effects of artemisinin B in vitro and in vivo, exploring the underlying mechanisms. The results demonstrated that artemisinin B inhibited NO secretion from LPS-induced BV2 cells and significantly reduced the expression levels of the inflammatory cytokines IL-1β, IL-6 and TNF-α. This was accompanied by reduced gene expression levels of MyD88 and NF-κB as well as TLR4 and MyD88 protein levels. These inhibitory effects were further confirmed in AD model mice. This study also showed that artemisinin B improved spatial memory in dementia mice in the water maze and step-through tests, and altered the pathological features and the levels of inflammatory cytokines in the hippocampus and the cortex. These results suggested that artemisinin B might inhibit neuroinflammation and exert neuroprotective effects on cognitive functions by modulating the TLR4-MyD88-NF-κB signaling pathway. This study provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases.
... Several bioactive molecules isolated from Artemisia extract were able to significantly eliminate neuroinflammation in brain tissue and neural cell lines. Artemisinin B isolated from Aretmisia annua and DSF-52 isolated from Artemisia argyi were found to exhibit significant anti-neuroinflammatory effects on LPS-activated BV2 cells (microglial cell model) (Zeng et al., 2014;Qiang et al., 2018). Both artemisinin B and DSF-52 significantly downregulated LPS-induced increase in NO production, and gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and upregulated gene expression levels of the antiinflammatory cytokine IL-10 (Zeng et al., 2014;Qiang et al., 2018). ...
... Artemisinin B isolated from Aretmisia annua and DSF-52 isolated from Artemisia argyi were found to exhibit significant anti-neuroinflammatory effects on LPS-activated BV2 cells (microglial cell model) (Zeng et al., 2014;Qiang et al., 2018). Both artemisinin B and DSF-52 significantly downregulated LPS-induced increase in NO production, and gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and upregulated gene expression levels of the antiinflammatory cytokine IL-10 (Zeng et al., 2014;Qiang et al., 2018). DSF-52 also downregulated pro-inflammatory Prostaglandin E2 (PGE2), iNOS, COX-2 and granulocytemacrophage colony-stimulating factor (GM-CSF) cytokines (Zeng et al., 2014). ...
... DSF-52 also downregulated pro-inflammatory Prostaglandin E2 (PGE2), iNOS, COX-2 and granulocytemacrophage colony-stimulating factor (GM-CSF) cytokines (Zeng et al., 2014). Another important finding of their studies is that both artemisinin B and DSF-52 inhibited major inflammatory transcription factor NF-κB in a dose-dependent manner (Zeng et al., 2014;Qiang et al., 2018). DSF-52 also inhibited the phosphorylation of NF-κB, IkB, and Akt, the activation and translocation of NF-kB from the cytoplasm into the nucleus, and NF-kB-DNA binding activity (Zeng et al., 2014). ...
The Genus Artemisia L. is one of the largest genera in the Asteraceae family growing wild over in Europe, North America, and Central Asia and has been widely used in folk medicine for the treatment of various ailments. Phytochemical and psychopharmacological studies indicated that the genus Artemisia extracts contain various antioxidant and anti-inflammatory compounds and possess antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recently, increasing experimental studies demonstrated that many Artemisia extracts offer a great antiepileptic potential, which was attributed to their bioactive components via various mechanisms of action. However, detailed literature on the antiepileptic properties of the genus Artemisia and its mechanism of action is segregated. In this review, we tried to gather the detailed neuroprotective and antiepileptic properties of the genus Artemisia and its possible underlying mechanisms. In this respect, 63 articles were identified in the PubMed and Google scholars databases, from which 18 studies were examined based on the pharmacological use of the genus Artemisia species in epilepsy. The genus Artemisia extracts have been reported to possess antioxidant, anti-inflammatory, neurotransmitter-modulating, anti-apoptotic, anticonvulsant, and pro-cognitive properties by modulating oxidative stress caused by mitochondrial ROS production and an imbalance of antioxidant enzymes, by protecting mitochondrial membrane potential required for ATP production, by upregulating GABA-A receptor and nACh receptor activities, and by interfering with various anti-inflammatory and anti-apoptotic signaling pathways, such as mitochondrial apoptosis pathway, ERK/CREB/Bcl-2 pathway and Nrf2 pathway. This review provides detailed information about some species of the genus Artemisia as potential antiepileptic agents. Hence, we recommend further investigations on the purification and identification of the most biological effective compounds of Artemisia and the mechanisms of their action to cure epilepsy and other neurological diseases.
... Because of the substantial and unique roles neurotransmitters play in brain function, targeting neurotransmitter metabolism is considered a potent approach to treat neurological and psychiatric disorders (Hyman, 2005). Artemisinin, cannabidiol, geniposide and ginsenoside Rb1 are neuroprotective agents (Supplementary Table S1) (Liu W. et al., 2015;Watt and Karl, 2017;Zhao J. et al., 2018;Qiang et al., 2018). They treat AD and traumatic cerebral injuries and attenuate secondary injuries by inhibiting nitric oxide (NO) release. ...
... Antiinflammatory cytokines prohibit the inflammation process, while pro-inflammatory cytokines promote the inflammation cascade (Boshtam et al., 2017). Artemisinin, cannabidiol, oxymatrine and geniposide treat AD by decreasing the expression of IL-6 (Liu et al., 2015b;Watt and Karl, 2017;Qiang et al., 2018;Chen Y. et al., 2019). Overexpression of proinflammatory cytokines provokes neurodegeneration induced by activated microglia, which are thought to clear the Aβ protein. ...
... Artemisinin, tetrandrine, cannabidiol, oxymatrine, and geniposide directly reduce the expression of proinflammatory cytokines such as IL-6, IL-1β, IL-17A, and TNF-α (Liu et al., 2015b;Watt and Karl, 2017;Qiang et al., 2018;Chen Y. et al., 2019;Ren et al., 2021) to control AD. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which is suppressed by artemisinin, tetrandrine, cannabidiol, and scutellarein (Watt and Karl, 2017;Qiang et al., 2018;Huang et al., 2019;Ren et al., 2021), and cyclooxygenase, which is impeded by geniposide (Liu et al., 2015b), are always involved in the control of proinflammatory cytokines and inflammatory responses to promote AD. ...
Currently, many people are afflicted by cerebral diseases that cause dysfunction in the brain and perturb normal daily life of people. Cerebral diseases are greatly affected by cerebral metabolism, including the anabolism and catabolism of neurotransmitters, hormones, neurotrophic molecules and other brain-specific chemicals. Natural medicines (NMs) have the advantages of low cost and low toxicity. NMs are potential treatments for cerebral diseases due to their ability to regulate cerebral metabolism. However, most NMs have low bioavailability due to their low solubility/permeability. The study is to summarize the better bioactivity, cerebral metabolism and pharmacokinetics of NMs and its advanced version. This study sums up research articles on the NMs to treat brain diseases. NMs affect cerebral metabolism and the related mechanisms are revealed. Nanotechnologies are applied to deliver NMs. Appropriate delivery systems (exosomes, nanoparticles, liposomes, lipid polymer hybrid nanoparticles, nanoemulsions, protein conjugation and nanosuspensions, etc.) provide better pharmacological and pharmacokinetic characteristics of NMs. The structure-based metabolic reactions and enzyme-modulated catalytic reactions related to advanced versions of NMs alter the pharmacological activities of NMs.
... However, in non-neuronal cells treatment with artemether led to an elevated gephyrin expression and GABAergic signaling (Li et al. 2017). Moreover, several recent publications reported that artemisinin and its derivatives effectively reduce amyloid plaque load and neuroinflammation in mouse models of AD (Ho et al. 2014;Qiang et al. 2018;Zhao et al. 2020). ...
... Based on the recently reported findings showing a direct link between gephyrin and the potentially neuroprotective artemisinins (Qiang et al. 2018) with both positive (Li et al. 2017) and negative (Kasaragod et al. 2019) modulation of GABAergic signaling in vitro, we treated APP-PS1 mice with artemisinin to test its possible modulatory effects on the inhibitory drive in the AD-brain. Sixweek-old APP-PS1 mice were fed for six weeks with artemisinin-containing diet (10 and 100 mg/kg) and analyzed for the expression of gephyrin at three months of age, when in the hippocampus amyloid plaques are not yet developed (Kiss et al. 2016;Radde et al. 2006). ...
... This finding was supported by an additional study identifying also NF-κB and a Nrf2-dependent mechanisms mediating the antiinflammatory effects of artemether in BV2 microglia (Okorji et al. 2016). More recent studies demonstrated also an improvement of learning and memory in AD mouse models mainly correlating with the suppressed neuroinflammation by artemisinins Qiang et al. 2018;Zhao et al. 2020). Interestingly, in the latter study by Zhao et al., some neuroprotective effects of artemisinin were attributed to the phosphorylation of ERK1/2 and CREB as demonstrated in SH-SY5Y cells (Zhao et al. 2020). ...
Artemisinins, a group of plant-derived sesquiterpene lactones, are efficient antimalarial agents. They also share anti-inflammatory and anti-viral activities and were considered for treatment of neurodegenerative disorders like Alzheimer’s disease (AD). Additionally, artemisinins bind to gephyrin, the multifunctional scaffold of GABAergic synapses, and modulate inhibitory neurotransmission in vitro . We previously reported an increased expression of gephyrin and GABA A receptors in early pre-symptomatic stages of an AD mouse model (APP-PS1) and in parallel enhanced CDK5-dependent phosphorylation of gephyrin at S270. Here, we studied the effects of artemisinin on gephyrin in the brain of young APP-PS1 mice. We detected an additional increase of gephyrin protein level, elevated gephyrin phosphorylation at Ser270, and an increased amount of GABA A R-γ2 subunits after artemisinin-treatment. Interestingly, the CDK5 activator p35 was also upregulated. Moreover, we demonstrate decreased density of postsynaptic gephyrin and GABA A R-γ2 immunoreactivities in cultured hippocampal neurons expressing gephyrin with alanine mutations at two CDK5 phosphorylation sites. In addition, the activity-dependent modulation of synaptic protein density was abolished in neurons expressing gephyrin lacking one or both of these phosphorylation sites. Thus, our results reveal that artemisinin modulates expression as well as phosphorylation of gephyrin at sites that might have important impact on GABAergic synapses in AD.
... ART has already been shown to inhibit TLR4, but these effects have only been seen with in vitro or in vivo models, using a mice sepsis model induced by Escherichia coli (Wang et al. 2006;Qiang et al. 2018). ART may also inhibit microglial activation. ...
... Two-way ANOVA followed by the Bonferroni test (factors: time and treatment). Vec vehicle proinflammatory cytokines IL-1β, IL-6, and TNF-α in BV2 cells pre-stimulated with LPS (Qiang et al. 2018). Signaling via TLR4/MyD88 initiates the activation of nuclear factor-κB and the subsequent expression of proinflammatory genes, which triggers the host's inflammatory response to pain (Qiang et al. 2018). ...
... Vec vehicle proinflammatory cytokines IL-1β, IL-6, and TNF-α in BV2 cells pre-stimulated with LPS (Qiang et al. 2018). Signaling via TLR4/MyD88 initiates the activation of nuclear factor-κB and the subsequent expression of proinflammatory genes, which triggers the host's inflammatory response to pain (Qiang et al. 2018). ...
Artemisinin (ART) was initially described for the control of inflammation and pain. However, the mechanisms involved with its antinociceptive effect are still poorly understood. Thus, this present study aimed to investigate the effect of ART in both free and nanocapsulated form on postoperative pain, as well as the participation of the spinal Toll-like receptor 4 (TLR4) in this process. Postoperative pain was induced using the skin/muscle incision retraction (SMIR) model in male Swiss mice. After 3 and 28 days of SMIR, the animals received an intrathecal injection of free or nanocapsulated ART, and the nociceptive threshold was evaluated by von Frey filament test. To evaluate the involvement of the microglia, astrocytes, and TLR4, minocycline (a microglia inhibitor), fluorocitrate (an astrocyte inhibitor), and Lipopolysaccharide Rhodobacter sphaeroides (LPS-RS), a TLR4 antagonist, were intrathecally injected on the third day of SMIR. The levels of spinal TLR4 protein and proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1β) were quantified by western blot and enzyme-linked immunosorbent assay, respectively. The results showed that free ART reduced postoperative pain (P < 0.001, F5,30 = 7.49, 16.66% for 1000 ng dose; and P < 0.01, F5,30 = 7.49, 14.58% for 500 ng dose) on the 3rd day of SMIR; while the ART nanocapsule had this effect on both the third (P < 0.001; F5,30 = 4.94; 43.75, 39.58 and 72.91% for the 250, 500 and 1000 ng doses, respectively) and 28th (P < 0.05; F5,30 = 7.71; 29.16 and 33.33% for the 500 and 1000 ng doses, respectively) day. The ART nanocapsule had a more potent and longer antinociceptive effect than free ART or morphine. Postoperative pain was also reduced by minocycline and LPS-RS. The ART nanocapsule also reduced the increased levels of TLR4, TNF-α, and IL-1β induced by SMIR. These data suggest that the ART nanocapsule has a potent analgesic effect on postoperative pain at the spinal level, and this response involves the inhibition of TLR4 and the proinflammatory cytokines TNF-α and IL-1β.
... Compared with traditional arteannuin derivatives, it has no peroxy bridge structure, as Compared with traditional arteannuin derivatives, it has no peroxy bridge structure, as shown in Figure 1. Modern pharmacological researches have shown that AB has no antimalarial activity [3], but it exhibits strong anti-inflammatory and immunological activities in preliminary screening [4]. With the deepening of research, people gradually discovered some new pharmacological activities of AB. ...
... With the deepening of research, people gradually discovered some new pharmacological activities of AB. For example, Qiang et al. [4] found that AB demonstrates significant immunosuppressive activity and also has a certain role in antineuroinflammation and treatment of neurodegenerative diseases. Our preliminary experiments found that AB exhibited a good therapeutic effect on mouse lung cancer metastasis models. ...
Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (D50). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the IC50 of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate T/C of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications.
... The Y maze test also demonstrated that artemisinin could improve spatial cognition in sepsis models. It has been reported that artemisinin B, one of the compounds isolated from Artemisia annua L., improved spatial memory in the water maze test in a mouse model of dementia [33]. This study provides preliminary evidence for the neuroprotective effect of artemisinins against neurodegenerative diseases. ...
... Excessive microglial activation has been demonstrated to be one of the main pathogenic mechanisms of neurocognitive deficits associated with sepsis [6,35]. Activated microglia release multiple inflammatory factors, resulting in hippocampal neuronal damage, which ultimately leads to cognitive dysfunction [33]. Therefore, suppressing microglial activation has therapeutic potential in the treatment of sepsis-induced neurocognitive deficits [36,37]. ...
Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 μg · kg−1 · d−1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg−1 · d−1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 μΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.
... Artemisinin preconditioned mice exhibited better spatial learning-memory than the LPS-challenged group. It has been reported that artemisinin B, one of the compounds isolated from Artemisia annuaL., improves spatial memory in the water maze test in a mouse model of dementia [25]. This study provides preliminary evidence for the neuroprotective effect of artemisinins against neurodegenerative diseases. ...
... Excessive activation of microglia has been demonstrated as one of the main mechanisms of pathogenesis in neurocognitive de cits associated with sepsis [5,27]. Activation of microglia releases multiple in ammatory factors resulting in hippocampal neuronal damage which ultimately leads to cognitive dysfunction [25]. Therefore, suppression of microglial activation has therapeutic potential in the treatment of neurocognitive de cits associated with sepsis [28,29]. ...
Background and purpose: Artemisinin has been in use as an anti-malarial drug for almost half a century in the world. There is growing evidence that artemisinin also possesses potent anti-inflammatory and immunoregulatory properties. However, the efficacy of artemisinin treatment in neurocognitive deficits associated with sepsis remains unknown. Here, we evaluate the possible protective effects and explore the underlying mechanism of artemisinin on cognitive impairment resulting from sepsis.
Methods: Male C57BL/6 mice were pretreated with either vehicle or artemisinin, and then injected with LPS to establish an animal model of sepsis. The cognitive function was then assessed using the Morris water maze. Neuronal damage and neuroinflammation in the hippocampus were evaluated by immunohistochemical and ELISA analysis. Additionally, the protective mechanism of artemisinin was determined in vitro.
Results: The results showed that artemisinin preconditioning attenuated LPS-induced cognitive impairment, neural damage, and microglial activation in the mouse brain. The in vitro experiment revealed that artemisinin could reduce the production of pro-inflammatory cytokines and suppress the microglial migration in the BV2 microglia cells. Meanwhile, western blot demonstrated that artemisinin suppressed nuclear translocation of nuclear factor kappa-B and the expression of pro-inflammatory cytokines (i.e. tumor necrosis factor alpha, interleukin-6) by activating adenosine monophosphate-activated protein kinaseα1 (AMPKα1) pathway. Furthermore, knock-down of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin.
Conclusion: Artemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect was probably mediated by the activation of AMPKα1 signalling pathway in microglia.
... Artemisinins have been demonstrated to suppress inflammatory responses through the suppression of many pro-inflammatory cytokines (Lin et al., 2016;Feng et al., 2017;Lu et al., 2018;Qiang et al., 2018;Sun et al., 2018). ...
... Therefore, inhibiting NF-κB might treat neurodegenerative disorders Subedi et al., 2017;Zhang and Xu, 2018). Another recent study showed that artemisinin B, an artemisinin derivative without a dioxygen bridge, could alleviate learning and memory impairment in AD through inhibiting neuro-inflammatory responses (Qiang et al., 2018). Both the in vivo and in vitro studies have demonstrated that artemisinin B might play its anti-neuroinflammatory role through regulating the toll-like receptor 4-myeloid differentiation factor 88/NF-κB pathway. ...
Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer’s disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aβ). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.
... Artemisinin B (63) inhibited the expression of MyD88 and NF-κB in the abnormally activated microglia, reduced inflammation and amyloid production by regulating toll-like receptor (TLR)4-NF-κB signaling pathway (Qiang et al. 2018a). ...
In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.
... Artemether also attenuated Aβ 25-35 -induced cognitive impairments by down-regulating Aβ, BACE1, and tau proteins in a rat model [64]. These findings, combined with the fact that Artemisinins can easily cross the BBB, highlight their potential as therapeutic candidates for the treatment of neurodegenerative disorders such as AD [65]. However, the assessment of the therapeutic potential of Artemisinin and its analogs towards ageassociated neurodegenerative diseases is still in an early stage [66]. ...
Aging is associated with the occurrence of diverse degenerative changes in various tissues and organs and with an increased incidence of neurological disorders, especially neurodegenerative diseases such as Alzheimer’s disease (AD). In recent years, the search for effective components derived from medicinal plants in delaying aging and preventing and treating neurodegenerative diseases has been increasing and the number of related publications shows a rising trend. Here, we present a concise, updated review on the preclinical and clinical research progress in the assessment of the therapeutic potential of different traditional Chinese medicines and derived active ingredients and their effect on the signaling pathways involved in AD neuroprotection. Recognized by their multitargeting ability, these natural compounds hold great potential in developing novel drugs for AD.
... These detailed data point to the possibility that spinal CCL21 over-expression facilitates TREM2 and DAP12 accumulation to further cause nociception phenotypes and that inhibiting this may provide a novel therapeutic target for pain conditions. Artemisinin and its derivatives perform a potent antineuroinflammatory protection on Alzheimer's disease (Qiang et al., 2018), traumatic brain injuries (Zhou et al., 2020), and lipopolysaccharide (LPS)-induced cognitive dysfunction (Lin et al., 2021). Recent investigation has highlighted that artesunate therapy downregulates the severity of bacterial infection, the release of inflammatory mediators, nociception-like phenomena, and septic death (Bang et al., 2021). ...
Chronic pain after bone fracture and orthopedic surgery is often refractory to most analgesics currently in use, thus emphasizing the urgent need for improved therapeutic medications. Chemokine-dependent neuroinflammation is critical for excitatory synaptic plasticity and central nociception sensitization. Recent studies have focused on the inhibition of inflammatory responses by artesunate, the first anti-malaria drug extracted from artemisinin. The present study investigated the analgesic effects and potential targets of artesunate in a mouse model of chronic pain induced by tibial fracture and orthopedic surgery. Three injections of artesunate were intrathecally administered on a daily basis from days 4 to 6 after fracture. We reported that repetitive exposure to artesunate (10 and 100 μg but not 1 μg) dose-dependently prevented fracture-induced mechanical and cold allodynia. Moreover, single intrathecal injection of artesunate (100 μg) alleviated the established chronic pain on day 14 after fracture surgery. Intraperitoneal artesunate (10 and 50 mg kg ⁻¹ ) therapy was effective against chronic fracture pain. Intriguingly, artesunate inhibited the upregulation of spinal chemokine CCL21, triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12) expressions and microglia activation in fracture mice. Furthermore, spinal CCL21 neutralization attenuated the severity of fracture-associated post-surgical pain. Exogenous CCL21-induced acute inflammatory pain was impaired by artesunate therapy. Additionally, the pharmacological blockage of TREM2 reduced recombinant CCL21-elicited behavioral hypernociception. The present findings demonstrate that artesunate therapy reduces the initiation and maintenance of fracture-associated chronic postoperative pain by inhibiting CCL21-dependent TREM2/DAP12 inflammatory signaling and microglia activation, thus suggesting that artesunate could emerge as a therapeutic strategy for fracture pain management.
... Although, the mechanisms underlying the brain-blood connection relative to MYD88 is not known, this adaptor protein might represent a valuable therapeutic target [24,[30][31][32], albeit being hypothetically beneficial in AD, raises concerns due to its critical role in anti-infectious defence. In this context, we have investigated if the ADspecific treatment with Rivastigmine, an acetylcholinesterase inhibitor, having also anti-inflammatory properties [33], is impacting on MYD88 transcript levels in the blood of the investigated AT mice. ...
Background
Neuroinflammation plays a prominent role in Alzheimer’s disease (AD), both in pathogenesis and disease progression. It has been shown that TLR/MYD88 signaling is involved in the chronic low-grade sterile inflammation associated with AD. Several studies have evidenced high levels of MYD88 in the brain of patients and animal models of AD, but no study has assessed so far its levels in blood.
Methods
In this study we evaluated the blood mRNA levels of MYD88 in a mouse model of AD, and also the putative effect of Rivastigmine treatment on MYD88 expression. Twenty-eight transgenic APP/TAU mice (AT) and twenty-two control C57/BL6j mice (WT) were included in this study, out of which five transgenic AT and five WT mice were treated with Rivastigmine.
Results
Increased MYD88 transcript in the whole blood from AT mice as compared to WT controls was found, which seems to increase in time due to disease progression and not to aging. This finding suggests that blood leukocytes are primed to develop TLR/MYD-mediated inflammatory processes. Moreover, results indicate that MYD88 blood levels were not modulated by the diseases-specific treatment with Rivastigmine.
Conclusions
Our results suggest that MYD88 might be a promising blood biomarker to monitor AD progression.
... Flavonoids, owing to their characteristic property of inhibiting inflammatory response, have shown potential for working against AD progression [180]. Studies in animal models of AD have reported terpenoids, such as artemisinin, parthenolide, and carnosol can inhibit NF-κB and p38 MAPK pathways [181][182][183]. Ginsenoside Rg1, a compound obtained from the roots of the Ginseng plant, has been reported to cause a significant drop in levels of Aβ peptide levels in AD mice [184]. ...
Alzheimer’s disease (AD) rate is accelerating with the increasing aging of the world’s population. The World Health Organization (WHO) stated AD as a global health priority. According to the WHO report, around 82 million people in 2030 and 152 million in 2050 will develop dementia (AD contributes 60% to 70% of cases), considering the current scenario. AD is the most common neurodegenerative disease, intensifying impairments in cognition, behavior, and memory. Histopathological AD variations include extracellular senile plaques’ formation, tangling of intracellular neurofibrils, and synaptic and neuronal loss in the brain. Multiple evidence directly indicates that oxidative stress participates in an early phase of AD before cytopathology. Moreover, oxidative stress is induced by almost all misfolded protein lumps like α-synuclein, amyloid-β, and others. Oxidative stress plays a crucial role in activating and causing various cell signaling pathways that result in lesion formations of toxic substances, which foster the development of the disease. Antioxidants are widely preferred to combat oxidative stress, and those derived from natural sources, which are often incorporated into dietary habits, can play an important role in delaying the onset as well as reducing the progression of AD. However, this approach has not been extensively explored yet. Moreover, there has been growing evidence that a combination of antioxidants in conjugation with a nutrient-rich diet might be more effective in tackling AD pathogenesis. Thus, considering the above-stated fact, this comprehensive review aims to elaborate on the basics of AD and antioxidants, including the vitality of antioxidants in AD. Moreover, this review may help researchers to develop effectively and potentially improved antioxidant therapeutic strategies for this disease as it also deals with the clinical trials in the stated field.
... Several medicinal herb extracts and their products were screened as the source of natural compounds for antiviral activities against Severe Acute Respiratory Syndrome associated coronavirus (SARS-CoV), which recommended some promising compounds such as kaempferol glycosides, alkaloids and terpenoids 2,9,10 . The compounds, which were isolated from A. annua, L. radiata, and L. aggregata have been identified to show antiviral activity against SARS-CoV, along with anti-neurological inflammation and as a candidate anti-Alzheimer's disease drugs [11][12][13][14] . Senecio genus is one of the most important and complex genera of the Asteraceae family, which is composed of approximately 1500 species distributed around the world 15 . ...
The composition of the essential oil obtained from the dried aerial parts of Senecio massaicus was analyzed by GC/MS. Twenty-two components have been identified and represented 97.41 % of the total oil composition. The major constituents of the essential oil were m-cymene (30.58 %), n-hexadecanoic acid (14.88 %) and docosane-11-decyl (10.43 %). Four methods were used to determine the antioxidant activity: DPPH, ABTS, CUPRAC and reducing power assay. The results indicate that the essential oil extract has moderate to low activity compared to the reference antioxidant compounds. In vitro anticholinesterase activity of the essential oil has also been studied. It exhibited higher inhibitory activity against butyrylcholinesterase (BChE) than against acetylcholinesterase (AChE). Docking studies conducted for Alzheimer's disease-related enzymes have displayed that compounds docosane-11-decyl and octaethyleneglycol monododecyl ether have strong potency, and compounds 15,15’Bi1,4,7,10,13-pentaoxacyclohexadecane and n-Hexadecanoic acid have moderate inhibitory potential. In addition, these three compounds (Docosane-11-decyl, octaethyleneglycol monododecyl ether and 15,15’Bi1,4,7,10,13-pentaoxacyclohexadecane) of the essential oil displayed strong interaction against SARS-CoV-2 main protease and Nsp15 endoribonuclease. Therefore, it could be useful to provide anticholinesterase agent and anti-coronavirus candidate drugs.
... Moreover, proinflammatory cytokines (IL-1β, IL-6, TNF-α) and the TLR4/MyD-88/NF-κB signaling pathway was suppressed (Table 3). [87][88][89] Myasthenia gravis is a neuromuscular autoimmune disease affecting muscles of the eyes, face, and swallowing. ...
The sesquiterpene lactone artemisinin from Artemisia annua L. is well established for malaria therapy, but its bioactivity spectrum is much broader. In this review, we give a comprehensive and timely overview of the literature regarding the immunosuppressive activity of artemisinin‐type compounds toward inflammatory and autoimmune diseases. Numerous receptor‐coupled signaling pathways are inhibited by artemisinins, including the receptors for interleukin‐1 (IL‐1), tumor necrosis factor‐α (TNF‐α), β3‐integrin, or RANKL, toll‐like receptors and growth factor receptors. Among the receptor‐coupled signal transducers are extracellular signal‐regulated protein kinase (ERK), c‐Jun N‐terminal kinase (JNK), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K), AKT serine/threonine kinase (AKT), mitogen‐activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) kinase (MEK), phospholipase C γ1 (PLCγ), and others. All these receptors and signal transduction molecules are known to contribute to the inhibition of the transcription factor nuclear factor κ B (NF‐κB). Artemisinins may inhibit NF‐κB by silencing these upstream pathways and/or by direct binding to NF‐κB. Numerous NF‐κB‐regulated downstream genes are downregulated by artemisinin and its derivatives, for example, cytokines, chemokines, and immune receptors, which regulate immune cell differentiation, apoptosis genes, proliferation‐regulating genes, signal transducers, and genes involved in antioxidant stress response. In addition to the prominent role of NF‐κB, other transcription factors are also inhibited by artemisinins (mammalian target of rapamycin [mTOR], activating protein 1 [AP1]/FBJ murine osteosarcoma viral oncogene homologue [FOS]/JUN oncogenic transcription factor [JUN]), hypoxia‐induced factor 1α (HIF‐1α), nuclear factor of activated T cells c1 (NF‐ATC1), Signal transducers and activators of transcription (STAT), NF E2‐related factor‐2 (NRF‐2), retinoic‐acid‐receptor‐related orphan nuclear receptor γ (ROR‐γt), and forkhead box P‐3 (FOXP‐3). Many in vivo experiments in disease‐relevant animal models demonstrate therapeutic efficacy of artemisinin‐type drugs against rheumatic diseases (rheumatoid arthritis, osteoarthritis, lupus erythematosus, arthrosis, and gout), lung diseases (asthma, acute lung injury, and pulmonary fibrosis), neurological diseases (autoimmune encephalitis, Alzheimer's disease, and myasthenia gravis), skin diseases (dermatitis, rosacea, and psoriasis), inflammatory bowel disease, and other inflammatory and autoimmune diseases. Randomized clinical trials should be conducted in the future to translate the plethora of preclinical results into clinical practice.
... Terpenoids, having two or more isoprene units in their structures, have also been widely reported on for their anti-neuroinflammation properties in vitro and in animal models. Parthenolide, which is a sesquiterpene lactone present in Tanacetum parthenium [96], artemisinin, that is another sesquiterpene lactone found Artemisia annua [97], thymoquinone, which is the bioactive constituent of Nigella sativa, carnosic acid and carnosol, that are natural diterpenes found in Rosmarinus officinalis [98], and Ginkgo biloba extract, that is rich in polyphenolic compounds and terpene lactones [99], have all been demonstrated to inhibit neuroinflammation by reducing levels of pro-inflammatory mediators and regulating Nrf2, NF-κB and p38 MAPK pathways. Although a spice, Crocus sativus (Saffron) is famous for its wide variety of therapeutic applications, including AD [100]. ...
Alzheimer’s disease (AD) is the number one neurovegetative disease, but its treatment options are relatively few and ineffective. In efforts to discover new strategies for AD therapy, natural products have aroused interest in the research community and in the pharmaceutical industry for their neuroprotective activity, targeting different pathological mechanisms associated with AD. A wide variety of natural products from different origins have been evaluated preclinically and clinically for their neuroprotective mechanisms in preventing and attenuating the multifactorial pathologies of AD. This review mainly focuses on the possible neuroprotective mechanisms from natural products that may be beneficial in AD treatment and the natural product mixtures or extracts from different sources that have demonstrated neuroprotective activity in preclinical and/or clinical studies. It is believed that natural product mixtures or extracts containing multiple bioactive compounds that can work additively or synergistically to exhibit multiple neuroprotective mechanisms might be an effective approach in AD drug discovery.
... Furthermore, Artemisia protects neurons against mitochondrial potential loss, attenuates reactive oxygen species and protects neurons against H 2 O 2 -induced death by upregulating the Nrf2 pathway [66]. ARTs improve learning and memory in mouse models of Alzheimer's disease mice by blocking Aβ25-35-induced increase in the levels of inflammatory cytokines IL-1β, IL-6 and TNF-α and by restoring the autophagic flux and promoting the clearance of Aβ fibrils [67,68]. ...
Background and Objectives: Artemisia is one of the most widely distributed genera of the family Astraceae with more than 500 diverse species growing mainly in the temperate zones of Europe, Asia and North America. The plant is used in Chinese and Ayurvedic systems of medicine for its antiviral, antifungal, antimicrobial, insecticidal, hepatoprotective and neuroprotective properties. Research based studies point to Artemisia's role in addressing an entire gamut of physiological imbalances through a unique combination of pharmacological actions. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes are some of the major phytochemicals of the genus. Notable among the phytochemicals is artemisinin and its derivatives (ARTs) that represent a new class of recommended drugs due to the emergence of bacteria and parasites that are resistant to quinoline drugs. This manuscript aims to systematically review recent studies that have investigated artemisinin and its derivatives not only for their potent antiviral actions but also their utility against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Materials andMethods: PubMed Central, Scopus and Google scholar databases of published articles were collected and abstracts were reviewed for relevance to the subject matter. Conclusions: The unprecedented impact that artemisinin had on public health and drug discovery research led the Nobel Committee to award the Nobel Prize in Physiology or Medicine in 2015 to the discoverers of artemisinin. Thus, it is clear that Artemisia's importance in indigenous medicinal systems and drug discovery systems holds great potential for further investigation into its biological activities, especially its role in viral infection and inflammation.
... Shi et al. (2018) suggested that artemisinins are capable to treat neuroinflammation-related central nerve system (CNS) diseases in both direct and indirect manners. Qiang et al. (2018) provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases. Wu et al. (2016) described the novel artemisinin derivatives in the treatment of autoimmune diseases. ...
Artemisia annua L. (Chinese wormwood herb, Asteraceae) synthesizes artemisinin, which is known as qinghaosu, considers as a unique sesquiterpene endoperoxide lactone. In traditional Chinese medicine, it has been used for the treatment of fevers and haemorrhoides. More researches on Artemisia annua L. and its derivatives, especially artemisinin and other metabolites will help to increase the knowledge and value of A. annua and its constituents. Phenolics from Artemisia annua consists of coumarins, flavones, flavonols, phenolic acids, and miscellaneous. Artemisinin has attracted much attention from scientists due to its potent antimalarial properties as secondary metabolites. Moreover, more attentions are focusing on the roles of artemisinin and its derivatives in treating obesity and metabolic diseases. They also have anti-bacterial, anti-inflammatory, anti-tumor, anti-protozoa, anti-helminthic, anti-fungal, anti-angiogenic and antiproliferation properties. The most important derivatives of Artemisia annua L. are arteether, artemether, artemiside, artemisinin, artemisone, artesunate, and dihydroartemisinin. Artemisinin also use against some cancers such as liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer. This important gift from ancient Chinese traditional medicine can guarantee health of people all around the world. Further researches should be done on the new advances and development of artemisinin and its derivatives as potential natural medicine in the global fight against so many diseases, malaria included.
... Shi et al. (2018) suggested that artemisinins are capable to treat neuroinflammation-related central nerve system (CNS) diseases in both direct and indirect manners. Qiang et al. (2018) provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases. Wu et al. (2016) described the novel artemisinin derivatives in the treatment of autoimmune diseases. ...
Artemisia annua L. (Chinese wormwood herb, Asteraceae) synthesizes artemisinin, which is known as qinghaosu, considers as a unique sesquiterpene endoperoxide lactone. In traditional Chinese medicine, it has been used for the treatment of fevers and haemorrhoides. More researches on Artemisia annua L. and its derivatives, especially artemisinin and other metabolites will help to increase the knowledge and value of A. annua and its constituents. Phenolics from Artemisia annua consists of coumarins, flavones, flavonols, phenolic acids, and miscellaneous.Artemisinin has attracted much attention from scientists due to its potent antimalarial properties as secondary metabolites. Moreover, more attentions are focusing on the roles of artemisinin and its derivatives in treating obesity and metabolic diseases. They also have anti-bacterial, anti-inflammatory, anti-tumor, anti-protozoa, anti-helminthic, anti-fungal, anti-angiogenic and antiproliferation properties. The most important derivatives of Artemisia annua L. are arteether, artemether, artemiside, artemisinin, artemisone, artesunate, and dihydroartemisinin. Artemisinin also use against some cancers such as liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer. This important gift from ancient Chinese traditional medicine can guarantee health of people all around the world. Further researches should be done on the new advances and development of artemisinin and its derivatives as potential natural medicine in the global fight against so many diseases, Malaria included.
... These authors further suggest that the observed inhibition of neuroinflammation by artemisinin was related to its modulatory effects on the NF-κB signalling pathway in the microglia. Subsequent studies showed that this compound was neuroprotective in a mouse model of AD through reduction in the levels of IL-1β, IL-6 and TNF-α in the hippocampus and the cortex (Qiang et al. 2018). Similarly, we have reported that artemisinin analogues, artesunate and artemether inhibited neuroinflammation by targeting NF-κB signalling in BV-2 microglia Okorji et al. 2016). ...
Alzheimer's disease (AD) is the most common form of dementia and affects 44 million people worldwide. New emerging evidence from pre-clinical and clinical investigations shows that neuroinflammation is a major pathological component of AD suggesting that anti-inflammatory strategies are important in delaying the onset or slowing the progression of the disease. However, efforts to employ current anti-inflammatory agents in AD clinical trials have produced limited success. Consequently, there is a need to explore anti-inflammatory natural products, which target neuroinflammatory pathways relevant to AD pathogenesis. This review summarises important druggable molecular targets of neuroinflammation and presents classes of anti-neuroinflammatory natural products with potentials for preventing and reducing symptoms of AD.
... Toll-like receptor 4 (TLR4) is a type of pattern recognition receptor, and is involved in innate and adaptive immunity by producing pro-inflammation cytokines, chemokines and apoptosis [9] . Studies have reported that TLR4 in the central nervous system (CNS) involved in memory, learning impairment [10] and cognitive decline [11]. Recently, TLR4 was also identified as a modulator of neurogenesis in the brain during injuries, cerebral ischemia, and cognitive decline [12], and it is recognized to contribute to neuroplasticity [13]. ...
Abstract Toll-like receptor 4 (TLR4) is a crucial receptor in neuroinflammation and apoptotic neuronal death, and increasing evidences indicated that β2-microglobulin (B2M) is thought to be a major contributor to age-related cognitive decline. In present study, we designed to investigate the effects of TLR4 on B2M-induced age-related cognitive decline. Wild-type (WT) C57BL/6, TLR4 knockout (TLR4 -KO) mice and hippocampal neurons from the two type mice were respectively divided into two groups: (1) Veh group; (2) B2M-treated group. The behavioral responses of mice were measured using Morris Water Maze. Hippocampal neurogenesis and neuronal damage, inflammatory response, apoptosis, synaptic proteins and neurotrophic factors, and TLR4/MyD88/NF-κB signaling pathway proteins were examined using molecular biological or histopathological methods. The results showed that WT mice received B2M in the DG exhibited age-related cognitive declines, increased TLR4 mRNA expression and high levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and apoptotic neuronal death in the hippocampus, which were partially attenuated in TLR4-KO mice. Moreover, in absence of TLR4, B2M treatment improved hippocampus neurogenesis and increased synaptic related proteins. Our cell experiments further demonstrated that deletion of TLR4 could significantly increase synaptic related protein, decrease neuroinflammatory fators, inhibited apoptotic neuronal death, and regulated MyD88/NF-κB signal pathway after B2M treatment. In summary, our results support the TLR4 contributes to B2M-induced age-related cognitive decline due to neuroinflammation and apoptosis through TLR4/MyD88/NF-κB signaling pathway via a modulation of hippocampal neurogenesis and synaptic function. This may provide an important neuroprotective mechanism for improving age-related cognitive decline.
Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by a progressive loss of memory and cognitive functions, language disorders, functional and behavioral alterations. The neurotoxicity is associated with the aggregation of β-amyloid (Aβ) plaques and the downstream pathologies events such as Tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysregulation play critical roles in the development of AD. With no effective treatment available for the prevention and treatment of AD, the search for new therapies has become the focus of many researchers.
Methods: Artemisia annua extracts were extracted and a water-soluble artemisia annua extract (Ex1) was used in treatment for 3xTg AD mice via oral administration. Cognitive functional recovery, Aβ accumulation, hyper-tau-phosphorylation, and the release of inflammatory factors and apoptosis were assessed three months after the treatment. In vitro, PC12 cells were incubated with 8 μM Aβ1-42 with or without Ex1 at different concentrations for 24h. ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis, inflammation, and the phosphorylation of Tau, as well as involvement in the signaling pathway, were assessed by using biological technology.
Results: Oral administration of Ex1 to AD 3xTg mice significantly improved the cognitive deficits, reduced Aβ accumulation, hyper-tau-phosphorylation, and the release of inflammatory factors and apoptosis. Ex1 promoted the survival and proliferation of neural progenitor cells (NPS), increased the expression of synaptic proteins and neuronal cell survival. Similarly, Ex1 significantly reversed the Aβ1-42-induced increase of ROS levels, caspase-3 activity, neuronal cell apoptosis, inflammation, and the phosphorylation of tau in vitro.
Conclusions: These findings suggest that a water-soluble artemisia annua extract (Ex1) may be a new multi-target anti-AD drug with potential use in the prevention and treatment of Alzheimer’s disease.
Experimental studies on the pathogenetic process of paclitaxel-induced neuropathic pain (PINP) have been initially carried out, but PINP still has no effective therapy. Recently reported studies have highlighted the involvement of glutamate receptors and neuroinflammation in peripheral and central nociceptive transmission in PINP. Artesunate is a first-line antimalarial drug with established efficacy in alleviating pain in a variety of pathologies. The current work assessed whether artesunate inhibits PINP by modulating metabotropic glutamate receptor 5 (mGluR5) and neuroinflammation in mice. The anti-hyperalgesic effect of artesunate was verified by assessing mechanical frequency and thermal latency in the paw withdrawal test as well as spontaneous pain. The expression levels of mGluR5, pain-related receptors and neuroinflammatory markers in dorsal root ganglion (DRG) were examined. In addition, treatment with CHPG and 2-methyl-6-(phenyl ethynyl) pyridine (MPEP) (mGluR5 agonist and antagonist, respectively) was performed to determine mGluR5’s role in the anti-hyperalgesic properties of artesunate. We demonstrated artesunate prevented PINP in a dose-dependent manner, while exerting a clear anti-hyperalgesic effect on already existing PINP. Artesunate normalized paclitaxel-related expression changes in DRG mGluR5, NR1, and GluA2, as well as six paclitaxel related neuroinflammation markers. Intrathecal application of MPEP treated PINP by reversing NR1 and GluA2 expression changes but had no effects on chemokines and inflammatory factors. Furthermore, artesunate treatment reversed acute pain following CHPG application. In conclusion, this study revealed that artesunate alleviates paclitaxel-induced hyperalgesia and spontaneous pain by decreasing DRG mGluR5 expression and neuroinflammation in the mouse model of PINP.
Effectiveness of enzyme therapy is limited by enzyme drawbacks such as short half-life, low bioavailability and high immunogenicity. We loaded asparaginase (Aase) into hydroxypropyl- or sulfonbutylether-beta cyclodextrin to form supramolecular amphiphilic molecules by self-assembly followed by entrapment inside the cores of two biomimetic lipidic nanovectors (AS-XLNs). Supramolecular structure was simulated by molecular docking. AS-XLNs maintained superior activity through isolating Aase from external environment due to docking with cyclodextrin and coating with biomimetic membrane. Fluorescent probes and computational simulations were used to reveal possible interactions between serum albumin/trypsin and Aase/nanovector membrane components which were partly responsible for enhanced bioavailability and bioactivity of AS-XLNs compared to Aase. AS-XLNs significantly increased cytotoxicity against pulmonary tumor cells, due to synergistic effects of Aase and nanovector membrane components (killing tumor cells through apoptosis induced by asparagine depletion and autophagy inhibition or via targets such as vascular endothelial growth factor A, alpha-amylase, p-selectin or androgen receptor).
Inflammation plays a key role in the development of age-related diseases. In Alzheimer's Disease, neuronal cell death is attributed to Amyloid beta oligomers that trigger microglia activation. Stem cells have shown promise as therapies for inflammatory diseases, due to their paracrine activity combined with their ability to respond to the inflammatory environment. However, the mechanisms underlying stem cell-promoted neurological recovery are poorly understood. To elucidate these mechanisms, we primed stem cells with the secretome of Lipopolysaccharides- or Amyloid beta-activated microglia and compared the extracellular vesicles (EVs) of primed and non-primed stem cells for their immunomodulatory effects. Our results demonstrate that EVs from primed cells are more effective in inhibiting microglia and astrocyte activation, amyloid deposition, demyelination as well as memory loss, motor and anxiety-like behavioral dysfunction, compared to EVs from non-primed cells. MicroRNA(miRNA) profiling revealed the upregulation of at least 19 miRNAs on primed-stem cell EVs. The targeted genes of the upregulated miRNAs were identified and KEGG pathway analysis showed that the overexpressed miRNAs target key genes on the TLR4 signaling pathway. Overall, our results demonstrate that priming of MSCs with the secretome of activated-microglia results in the release of miRNAs from EVs with enhanced immune regulatory potential able to fight neuroinflammation.
Background
Borna disease virus (BoDV-1) can infect the hippocampus and limbic lobes of newborn rodents, causing cognitive deficits and abnormal behavior. Studies have found that neuroinflammation caused by viral infection in early life can affect brain development and impair learning and memory function, revealing the important role of neuroinflammation in cognitive impairment caused by viral infection. However, there is no research to explore the pathogenic mechanism of BoDV-1 in cognition from the direction of neuroinflammation.
Methods
We established a BoDV-1 infection model in rats, and tested the learning and memory impairment by Morris water maze (MWM) experiment. RNAseq was introduced to detect changes of the gene expression profile of BoDV-1 infection, focusing on inflammation factors and related signalling pathways.
Results
BoDV-1 infection impairs learning and memory of SD rats in the MWM test and increases the expression of inflammatory cytokines in the hippocampus. RNAseq analysis found 986 differentially expressed genes (DEGs), of which 845 genes were upregulated and 141 genes were downregulated, and 28 genes were found to be enriched in the Toll-like receptor (TLR) pathway. The expression of TLR4, MyD88, and IRF5 in the hippocampus were significantly changed in the BoDV-1 group.
Conclusion
Our results indicate that BoDV-1 infection stimulates TLR4/MyD88/IRF5 pathway activation, causing the release of downstream inflammatory factors, which leads to neuroinflammation in rats. Neuroinflammation may play a significant role in learning and memory impairment caused by BoDV-1 infection.
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Alzheimer's disease (AD) is the most frequent form of dementia, characterized histopathologically by the formation of amyloid plaques and neurofibrillary tangles in the brain. Amyloid β-peptide (Aβ) is a major component of amyloid plaques and is released together with carboxy-terminal fragments (CTFs) from the amyloid precursor protein (APP) through proteolytic cleavage, thought to contribute to synapse dysfunction and loss along the progression of AD. Artemisinins, primarily antimalarial drugs, reduce neuroinflammation and improve cognitive capabilities in mouse models of AD. Furthermore, artemisinins were demonstrated to target gephyrin, the main scaffold protein of inhibitory synapses and modulate GABAergic neurotransmission in vitro. Previously, we reported a robust decrease of inhibitory synapse proteins in the hippocampus of 12-month-old double transgenic APP-PS1 mice which overexpress in addition to the Swedish mutated form of the human APP a mutated presenilin 1 (PS1) gene and are characterized by a high plaque load at this age. Here, we provide in vivo evidence that treating these mice with artemisinin or its semisynthetic derivative artesunate in two different doses (10 mg/kg and 100 mg/kg), these compounds affect differently inhibitory synapse components, amyloid plaque load and APP-processing. Immunofluorescence microscopy demonstrated the rescue of gephyrin and γ2-GABAA-receptor protein levels in the brain of treated mice with both, artemisinin and artesunate, most efficiently with a low dose of artesunate. Remarkably, artemisinin reduced only in low dose the amyloid plaque load correlating with lower levels of mutated human APP (hAPPswe) whereas artesunate treatment in both doses resulted in significantly lower plaque numbers. Correspondingly, the level of APP-cleavage products, specifically the amount of CTFs in hippocampus homogenates were reduced significantly only by artesunate, in line with the findings in hAPPswe expressing cultured hippocampal neurons evidencing a concentration-dependent inhibition of CTF-release by artesunate already in the nanomolar range. Thus, our data support artemisinins as neuroprotective multi-target drugs, exhibiting a potent anti-amyloidogenic activity and reinforcing key proteins of inhibitory synapses.
Artemisinin and its derivatives have been the frontline drugs for treating malaria. In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS). However, the precise mechanisms underlying their anti‐neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)‐NMR showed the direct binding of artemisinin to TLR4 co‐receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS‐induced TLR4 dimerization and endocytosis in microglial BV‐2 cells. Therefore, artemisinin was found to inhibit the TLR4‐JNK signaling axis and block LPS‐induced pro‐inflammatory factors nitric oxide, IL‐1β and TNF‐α in BV‐2 cells. Furthermore, artemisinin restored LPS‐induced decrease of junction proteins ZO‐1, Occludin and Claudin‐5 in primary brain microvessel endothelial cells, and attenuated LPS‐induced blood brain barrier disruption in mice as assessed by Evans blue. In all, this study unambiguously adds MD2 as a direct binding target of artemisinin in its anti‐neuroinflammatory function. The results also suggest that artemisinin could be repurposed as a potential therapeutic intervention for inflammatory CNS diseases.
Objective
Alzheimer’s disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aβ clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro.
Methods
The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax.
Results
In parallel, the expression of the antiapoptotic protein Bcl-2 increased after oral DHA treatment. Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis.
To evaluate the quality of Artemisia annua L., an accurate HPLC-DAD method has been developed, validated and applied to the simultaneous quantification of five flavonoids, two coumarins and four sesquiterpenes. An LC-ESI-QTOF-MS/MS confirmation method has been utilized to avoid false-positive results. Principal component analysis and hierarchical cluster analysis results indicated that their contents had obvious regional characteristics. Samples with high contents of artemisinin (8.24 ± 2.92 mg/g) and isorhamnetin (0.28 ± 0.25 mg/g) are mainly distributed south of the Yangtze River, and samples with high contents of scopolin (0.46 ± 0.22 mg/g), scopoletin (1.05 ± 0.17 mg/g), chrysosplenol D (0.64 ± 0.14 mg/g), casticin (1.07 ± 0.23 mg/g), arteannuin B (0.69 ± 0.18 mg/g) and artemisinic acid (3.02 ± 1.00 mg/g) are mainly distributed in eastern and northern China. Geographic content differences of the components in A. annua indicate the potential differences in the health-promoting effects of its clinical application.
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
Three things are needed to turn the tide on the costliest crisis in health care.