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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.
... These results are supported by findings in nontransgenic mouse AD models. In a study by Qiang et al., male KM mice, pretreated for 2 weeks by intragastric administration of artemisinin B (20, 40 or 80 mg/kg), were injected via the lateral ventricle with Aβ 25-35 and treated for an additional week postsurgery, resulting in increased levels of anti-inflammatory IL-10 and reduced amounts of pro-inflammatory TNF-α in the cortex and hippocampus, as well suppressing Iba1-positive cell activation in the hippocampal CA1 region [95]. In a more recent study, six-week-old C57 mice, pretreated for one month with intraperitoneal administration of artemisinin at 5 mg/kg/day, were injected with Aβ 1-42 into the hippocampus. ...
... In our own studies, a significant increase in the PSD95 mRNA level was measured in APP/PS1 mice brains upon treatment with 100 mg/kg artesunate compared to the control APP/PS1 mice [77]. The maintenance of synapses after other artemisinins was also reported; in 9-month-old APPswe/PSEN1dE9 mice, DHA (20 mg/kg/day) upregulated the level of synaptophysin in brain homogenates and promoted neurite outgrowth [117], and in mice injected with Aβ 25-35 into the lateral ventricle, artemisinin B inhibited synaptophysin loss in the neurons of the hippocampal CA1 region [95]. ...
... Qiang et al. reported, in 2018, that artemisinin B parallelly reduced neuroinflammation and significantly improved learning and memory abilities of dementia mice in the Morris water maze (MWM) test, including navigation and space exploration experiments, as well as the step-through test, which analyzes the characteristics of mice that prefer dark places and avoid light [95]. In the same study, the open field test, broadly used to evaluate spontaneous activity and exploratory behavior in mice, showed that the drug had no obvious excitatory or inhibitory effects on the mental state and activity of mice. ...
Plant-derived multitarget compounds may represent a promising therapeutic strategy for multifactorial diseases, such as Alzheimer’s disease (AD). Artemisinin and its derivatives were indicated to beneficially modulate various aspects of AD pathology in different AD animal models through the regulation of a wide range of different cellular processes, such as energy homeostasis, apoptosis, proliferation and inflammatory pathways. In this review, we aimed to provide an up-to-date overview of the experimental evidence documenting the neuroprotective activities of artemi-sinins to underscore the potential of these already-approved drugs for treating AD also in humans and propose their consideration for carefully designed clinical trials. In particular, the benefits to the main pathological hallmarks and events in the pathological cascade throughout AD development in different animal models of AD are summarized. Moreover, dose- and context-dependent effects of artemisinins are noted.
... Neuroinflammation in epilepsy is primarily characterized by robust astrogliosis, microglial activation, and the production of cytokines and chemokines [18,20] Several bioactive molecules isolated from Artemisia extract were able to significantly eliminate neuroinflammation in brain tissue and neural cell lines. Artemisinin B isolated from Artemisia annua and DSF-52 isolated from Artemisia argyi were found to exhibit significant anti-neuroinflammatory effects on LPS-activated BV2 cells (microglial cell model) [37], [46]. Both artemisinin B and DSF-52 significantly downregulated LPSinduced increase in NO production, and gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α and upregulated gene expression levels of anti-inflammatory cytokine IL-10 [37,46]. ...
... Artemisinin B isolated from Artemisia annua and DSF-52 isolated from Artemisia argyi were found to exhibit significant anti-neuroinflammatory effects on LPS-activated BV2 cells (microglial cell model) [37], [46]. Both artemisinin B and DSF-52 significantly downregulated LPSinduced increase in NO production, and gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α and upregulated gene expression levels of anti-inflammatory cytokine IL-10 [37,46]. DSF-52 also downregulated pro-inflammatory Prostaglandin E2 (PGE2), iNOS, COX-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokines [37]. ...
... DSF-52 also downregulated pro-inflammatory Prostaglandin E2 (PGE2), iNOS, COX-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokines [37]. 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 [37,46]. DSF-52 also inhibited the phosphorylation of NF-kB, IkB, and Akt, the activation and translocation of NF-kB from the cytoplasm into the nucleus, and NF-kB-DNA binding activity [37]. ...
Epilepsy is a chronic neuronal disorder characterized by periodic, unpredictable, and recurrent seizures due to either a genetically determined or an acquired brain disorder. Although many anti-epileptics drugs (AEDs) are developed to control epilepsy, 30% of patients still need additional drugs or experience recurrent seizures and psychiatric and behavioral side effects. Thus, the need for medical care for patients with uncontrolled epilepsy remains unmet. The Genus Artemisia L. is one of the largest genera in the Asteraceae family with more than 500 species widely distributed in Europe, Asia, and North America. Many Artemisia species have been used in various treatments since ancient times as folk remedies. They demonstrated strong antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recent studies reveal that some species of Artemisia demonstrated a therapeutic benefit for epilepsy by its anti-oxidant, anti-inflammatory, neuroprotective, and anticonvulsant properties. In this review, we investigate the current state of the literature regarding the neuroprotective and antiepileptic potentials of the genus Artemisia and its possible underlying mechanisms.
... 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.
... 12 Notably, artemisinin B (ART B), a precursor of arteannuin from Artemisia annua L, was first used as antimalarial drugs. 13 Modern pharmacological studies have shown that ART B exhibits strong anti-inflammatory and immunological activities in preliminary screening. 13 It was also reported that ART B could inhibit the proliferation of HT-29, HepG2, SGC-7901, A549, K562, B16-F10, and Du145 cells, while having no obvious toxicity to normal human embryonic liver cells L-02. ...
... 13 Modern pharmacological studies have shown that ART B exhibits strong anti-inflammatory and immunological activities in preliminary screening. 13 It was also reported that ART B could inhibit the proliferation of HT-29, HepG2, SGC-7901, A549, K562, B16-F10, and Du145 cells, while having no obvious toxicity to normal human embryonic liver cells L-02. 14 However, the anti-cancer effect and mechanism of both QBD and ART B on NSCLC are unknown, and the chemical basis of QBD action is also unclear. ...
Purpose
To explore the pharmacological effects and mechanisms of Qinghao Biejia decoction (QBD) against non-small-cell lung cancer (NSCLC) based on network pharmacology and to verify the anticancer effect of artemisinin B (ART B), the active ingredient of QBD, on H1299 cells.
Methods
Ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied to explore the chemoprofile of QBD. A zebrafish xenograft model was used to determine the anti-cancer efficacy of QBD. Cell counting kit-8 assay, terminal deoxyribonucleotide transferase-mediated-dUTP nick-end labeling assay; immunofluorescence, and flow cytometry were used to evaluate the in vitro anti-proliferative and pro-apoptotic effects of QBD and ART B on H1299 cells. Subsequently, the related targets and action mechanisms of both QBD and ART B predicted by network pharmacological analyses were experimentally validated by real-time PCR and Western blot assays on H1299 cells.
Results
UPLC-QTOF-MS/MS identified a total of 69 compounds (such as ART B, mangiferin, and artemisinic acid) in QBD. The in vivo data showed that QBD significantly inhibited the growth of H1299 cells in xenograft larval zebrafish from 125 to 500 μg/mL. The in vitro data showed that QBD induced apoptosis of H1299 cells, accompanied by down-regulating the expression of BCL-2 and up-regulating the expression of BIM, PUMA, BAX, c-PARP, γ-H2A.X, c-CASP3, and c-CASP8. Alike QBD, ART B exerted similar anti-proliferative and pro-apoptotic effects on H1299 cells. Moreover, ART B inhibited expressions of BCL2L1, AKT1, AKT2, MMP-2, and EGFR, and up-regulated ALB expression. Mechanistically, ART B promoted apoptosis of H1299 cells by inhibiting PI3K/Akt signaling pathway.
Conclusion
This study revealed the anti-NSCLC efficacy of QBD. ART B, the effective component of QBD, plays an anti-NSCLC role by down-regulating the PI3K-Akt signaling pathway. It suggests that QBD and ART B are promising drug candidates for NSCLC treatment.
... 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 can exert anti-inflammatory effects by inhibiting the TLR/MyD88/NF-κB signal pathway, resulting in aberrant expression of TLR4, reducing B cell activation and plasma cell formation. Additionally, β-aminoartemisinin maleate (SM934), a watersoluble artemisinin derivative, can inhibit the expression of IL-6, TNF-α, and IL-1β, promote the secretion of IL-10 by macrophages and impede T-cell activation and proliferation, thus producing anti-inflammatory effects [49][50][51][52]. Yang et al. [53] developed models of dry eye with insufficient tears and hyperevaporative dry eye through subcutaneous injection of scopolamine hydrobromide and benzamide chloride. ...
Artemisinin is a sesquiterpene lactone extracted from the chrysanthemum plant, Artemisia annua. It is known for its curative effects in the treatment of pulmonary hypertension, leukemia, diabetes, malaria, and other diseases, owing to its abundant biological activity. In recent years, with the development of plant secondary metabolite research, other potential pharmacological effects of artemisinin-based drugs have received increasing attention; in particular, reports of their application for the potential treatment of ophthalmology-related diseases have gradually increased. Recently, studies confirmed that artemisinin plays therapeutic roles in eye diseases through regulation of signaling pathways, such asNrf2/HO-1/Keap1, TLR/MyD88/NF-κb, PI3K/AKT/mTOR, and FASN/Kmal-mTOR/SREBP1, and biological factors, such as protein kinase B, AMP-activated protein kinase, tumor necrosis factor alpha, nod-like receptor protein 3, vascular endothelial growth factor, malonyl-coenzyme A and cytochrome C. However, since ocular diseases are often caused by various factors, how artemisinin can play a good disease prevention role by modulating these factors needs to be further verified, and most of the current studies focus on in vitro and animal experiments, lacking sufficient information on clinical trial studies. To better explore and perfect the mechanism of action of artemisinin in ophthalmic diseases, and to better promote the clinical application of artemisinin, this study reviews the latest progress of artemisinin treatment for uveitis, uveal melanoma, age-related macular degeneration, diabetic retinopathy, ocular neovascularization, and dry eye, and it will provide theoretical support for the large-scale application of artemisinin in ophthalmic diseases in the future.
... Due to their unique ability to suppress the inflammatory response, flavonoids have demonstrated promise in slowing the course of AD (Kim and Park 2021). Terpenoids such as artemisinin, parthenolide, and carnosol have been shown in studies using animal models of AD to inhibit the p38 MAPK and NF-κB pathways (Wang, J.a,, et al. 2020;Qiang et al. 2018;Abulfadl et al. 2018), Ginsenoside Rg1, a substance isolated from ginseng plant roots, has been shown to significantly lower Aβ peptide levels in AD mice (Fang, et al. 2012). It has been shown that natural plant compounds such as crocin, α-cyperone, chrysophanol, and aloe-emodin possess characteristics that hinder the creation of tau protein and slow down the advancement of AD (Karakani et al. 2015;Azimi et al. 2016;Gong et al. 2014). ...
Alzheimer’s disease is a devastating neurodegenerative disorder that affects millions of people worldwide. One of the key pathological features of Alzheimer’s disease is oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species and the body’s ability to neutralize them with antioxidants. In recent years, there has been growing interest in the potential role of antioxidant supplementation in mitigating oxidative stress markers in Alzheimer’s disease. This review paper aims to provide a comprehensive overview of the current research on antioxidant supplementation in Alzheimer’s disease and its effects on oxidative stress markers. The paper will examine the underlying mechanisms of oxidative stress in Alzheimer’s disease, the potential benefits of antioxidant supplementation, and the challenges and limitations of using antioxidants as a therapeutic strategy.
... MyD88 is a transduction protein that regulates the intracellular inflammatory signaling cascade, which involves TLR4 in the activation of microglia. Hence, this finding concludes that artemisinin attenuated neuroinflammation through TLR4/MyD88/NF-kB pathway (Qiang et al., 2018). (Table 28.2). ...
... Neuroinflammation is an important pathological factor of neurodegenerative diseases. ART was found to decrease the release of NO, as well as inflammatory cytokines, like IL-1β, IL-6 and TNF-α, reducing neuroinflammation while improving cognitive memory impairment in AD mice (Qiang et al., 2018). The inhibitory effect of ART on inflammation is generally related to phosphorylation, exerting anti-inflammatory effects by inhibiting the expression and phosphorylation of AKT, PI3K, ERK, NF-κB, retinoic-acid-receptorrelated orphan nuclear receptor γ (ROR-γt), and other signal transduction proteins. ...
Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-[Formula: see text]B, p38 MAPK, I[Formula: see text]B[Formula: see text]. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress [Formula: see text]-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.
... Artemisinin was given an hour before 3-NPA treatment. Doses of the drugs used in this study were chosen from previous studies [12,[31][32][33]. The experimental procedure is schematically shown in Fig. 1. ...
Neurodegenerative disorders like Huntington’s disease (HD) are a major threat to human health, with severe gait abnormalities and pathological changes (oxidative stress, neuroinflammation, and apoptosis) playing important roles in their development. The effects of artemisinin (ART) alone and in combination with the ERK antagonist PD98059 against 3-nitropropionic acid (3-NPA)-induced cell death and oxidative stress in SH-SY5Y cells were determined using the MTT and DCFH-DA assays, as well as RT-qPCR assays. In vivo, possible neuroprotective effects of ART (10, 20, and 40 mg/kg i.p.) against the neurotoxicity generated by 21-day 3-NPA (10 mg/kg i.p.) treatment was evaluated in rats by assessing behavioral parameters on days 1, 14, and 21. Further, various biochemical, inflammatory, apoptotic markers, histopathological changes, and protein expression were assessed using brain striatal samples. ART significantly mitigated the neurotoxic effect of 3-NPA in SH-SY5Y cells by regulating the mRNA expression of ERK, Bax, Bcl2, and cytochrome C. However, ART’s neuroprotective activity was reduced in the presence of PD98059. Also, ART treatment for 21 days substantially alleviated the behavioral impairments associated with 3-NPA toxicity. It reduced the oxidative stress induced by 3-NPA, as evidenced by the lower levels of MDA, nitrite, and improved catalase, SOD activity, and GSH levels. ART treatment restored 3-NPA-induced histopathological alterations in the striatal area. ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression. ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.
... Artemisinin has been recently shown to exert anti-inflammatory effects in various disease models [21,22]. In addition, it has been demonstrated that artemisinin can control the inflammatory response by inhibiting various pro-inflammatory factors, such as CXCR3/CXCL10 [23], IL-1β [24][25][26], NF-κB [27], Nrf2, and ROS-dependent p38 MARK [28]. Moreover, our experiments confirmed that artemisinin reduced the retinal levels of CXCR3, CXCL10, and IL-1β expression. ...
Introduction
Traumatic optic neuropathy is known to be a critical condition that can cause blindness; however, the specific mechanism underlying optic nerve injury is unclear. Recent studies have reported that artemisinin, considered vital in malaria treatment, can also be used to treat neurodegenerative diseases; however, its precise role and mechanism of action remain unknown. Therefore, in this study, we aimed to investigate the impact and probable mechanism of action of artemisinin in retinal ganglion cells (RGCs) in a mouse model of traumatic optic neuropathy induced by optic nerve crush (ONC).
Methods
ONC was induced in the left eye of mice by short-term clamping of the optic nerve; oral artemisinin was administered daily. The neuroprotective effect of the drug was assessed using Tuj-1 staining in RGCs. In addition, the inflammatory response and the expression levels of phosphorylated tau protein and tau oligomers were observed using RT-qPCR, TUNEL assay, and fluorescence staining to investigate the underlying mechanisms.
Results
Artemisinin increased the survival rate of RGCs 14 days after ONC. Artemisinin significantly reduced the levels of inflammatory factors such as CXCL10, CXCR3, and IL-1β in the retina and decreased the apoptosis of RGCs. Moreover, downregulation of the phosphorylation of tau proteins and the expression of tau oligomers were observed after artemisinin treatment.
Conclusion
Our results suggest that artemisinin can increase the survival rate of RGCs after ONC and reduce their apoptosis. This effect may be achieved by inhibiting the inflammatory response it triggers and downregulating tau protein phosphorylation and tau oligomer expression. These findings suggest the potential application of artemisinin as a therapeutic agent for neuropathy.
... The selected dosage of Art was based on previous studies (Lin et al. 2021;Qiang et al. 2018). After the Y-maze test (YMT) Morris water maze test (MWMT), hippocampal tissues were harvested for hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM) analysis, and measurement of the iron, ROS, MDA and GSH concentrations by kits. ...
Background
Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region.
Methods
STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe ²⁺ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively.
Results
Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe ²⁺ , and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin.
Conclusion
Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.
Graphical Abstract
... This was recovered only in the 30 days exposure group. Our study results coincide with previous reports where Syp decreased in an amyloid beta induced model of Alzheimer's disease (Kincheski et al. 2017;Qiang et al. 2018;Sanchez-Ramos et al. 2009) ultimately leading to cognitive impairment. Syp is a vesicle protein, an important index of synaptic integrity, and is largely associated with spatial memory (Xu et al. 2019). ...
Aluminum is a potent neurotoxin, responsible for memory impairment and cognitive dysfunction. The neurotoxic effect of aluminum on cognitive impairment is well documented, however, exposure to aluminum in a time-dependent manner and post-exposure self-recovery still needs to be elaborated. This research aimed to (1) study the time-dependent effect of aluminum exposure by administering a total dose of 5850 mg/kg of Al over two different time periods: 30 and 45 days (130 and 195 mg/kg of AlCl3 respectively), and (2) study 20 days post-exposure self-recovery effect in both aluminum-exposed groups by giving distilled water. Cognitive abilities were investigated through Morris water maze test and hole board test and compared in both exposure and recovery groups. Oxidative stress markers and neurotransmitter levels were measured for both exposure and recovery groups. To understand the mechanism of aluminum exposure and recovery, immunohistochemical analysis of synaptophysin (Syp) and glial fibrillary acidic protein (GFAP) was performed. Results showed cognitive dysfunction, oxidative stress-induced damage, reduced neurotransmitter levels, decreased immunoreactivity of Syp, and increased GFAP. However, these parameters showed a larger improvement in the recovery group where rats were given aluminum for 30 days period in comparison to recovery group followed by 45 days of aluminum exposure. These results suggest that restoration of cognitive ability is affected by the duration of aluminum exposure. The study findings provide us with insight into the adverse effects of aluminum exposure and can be utilized to guide future preventive and therapeutic strategies against aluminum neurotoxicity.
... A microinjection needle was connected to a microcontinuous injection pump and injected at a flow rate of 1 μL/min. 19 The injection time was 3 min, and the needle was kept for 10 min to ensure the diffusion of the drug into the brain. ...
Background
Jiaohong pills (JHP) consist of Pericarpium Zanthoxyli (PZ) and Radix Rehmanniae, two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment. However, the precise mechanisms underlying the beneficial effects remain elusive. Here, research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease.
Methods
BV‐2 cell inflammation was induced by lipopolysaccharide. AD mice were administered amyloid‐β (Aβ). Behavioral experiments were used to evaluate learning and memory ability. The levels of nitric oxide (NO), tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐10 (IL‐10) were detected using enzyme‐linked immunosorbent assay (ELISA). The protein expressions of inducible nitric oxide synthase (iNOS) and the phosphorylation level of mitogen‐activated protein kinase (MAPK) and nuclear factor kappa‐B (NF‐κB) were detected using Western blot. Nissl staining was used to detect neuronal degeneration.
Results
The results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO, IL‐1β, TNF‐α, and iNOS; increased the expression level of IL‐10; and significantly decreased the phosphorylation levels of MAPK and NF‐κB. These inhibitory effects were further confirmed in the AD mouse model. Meanwhile, JHP improved learning and memory function in AD mice, reduced neuronal damage, and enriched the Nissl bodies in the hippocampus. Moreover, IL‐1β and TNF‐α in the cortex were significantly downregulated after JHP administration, whereas IL‐10 showed increased expression.
Conclusions
It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF‐κB signaling pathway.
... For instance, some studies reported the efficacy of artemisinins in treating neuro inflammation-related central nerve system (CNS) diseases [37]. Another study reports strong evidence for the potential use of artemisinin B in treating neuroinflammatory diseases [38]. Finally, one study also reported the liver protective effect of artemisinin, noting the enhanced stability and reduced damage to the liver cell membrane and cells. ...
... For instance, some studies reported the efficacy of artemisinins in treating neuro inflammation-related central nerve system (CNS) diseases [37]. Another study reports strong evidence for the potential use of artemisinin B in treating neuroinflammatory diseases [38]. Finally, one study also reported the liver protective effect of artemisinin, noting the enhanced stability and reduced damage to the liver cell membrane and cells. ...
... For instance, some studies reported the efficacy of artemisinins in treating neuro inflammation-related central nerve system (CNS) diseases [37]. Another study reports strong evidence for the potential use of artemisinin B in treating neuroinflammatory diseases [38]. Finally, one study also reported the liver protective effect of artemisinin, noting the enhanced stability and reduced damage to the liver cell membrane and cells. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the reason behind the third zoonotic outbreak from the Coronaviridae family during the 21 st century. COVID-19 was declared a pandemic by the WHO on 11 March 2020, and it has been posing a challenge for the health care system all around the world. Research groups worldwide are trying to find potential leads for drugs against SARS-CoV-2. Investigating natural products and extracts from known medicinal plants has been one area of focus in searching for potential inhibitors of SARS-CoV-2. This review aims to highlight the importance of including natural plants and plants derived compounds in this investigation. We particularly focused on compounds from Artemisia species (artemisinin and its derivatives), as this plant is highly valuable and has various pharmacological profiles. Rezumat SARS-CoV-2 (Coronaviridae) este agentul etiologic al pamdemiei COVID-19, o provocare pentru sistemul de sănătate din întreaga lume. Investigarea produselor naturale și a extractelor din plante medicinale cunoscute este un domeniu de interes în iderntificarea potențialilor inhibitori SARS-CoV-2. Acest review analizează compușii din speciile Artemisia (artemisinina și derivații săi), datorită diversității profilurilor fitochimic și farmacologic.
... Proposed mechanisms of actions include the modulation of oxidative stress caused by mitochondrial ROS production and imbalance of antioxidant enzymes, protection of the mitochondrial membrane potential required for ATP production, and interference with various anti-inflammatory and anti-apoptotic signaling pathways, such as NF-kappaB and PI3 kinase/Akt, and ERK/CREB/Bcl-2 and Nrf2 [38,45,46]. Recently, it was also shown that artemisinins improve cognitive capacities in AD-models reducing Aβ levels, inflammation and amyloid plaque load, and were recommended as potential candidates for the treatment of Alzheimer's disease in humans [45][46][47][48][49]. In agreement with these data, our recent study analyzing the effects of artemisinin and artesunate in APP/PS1 mice confirmed their potent anti-amyloidogenic properties, and identified for artesunate the limitation of APP-processing as one effective mechanism for mediating these effects, especially when used in a lower dose [33]. ...
Alzheimer’s disease (AD) is characterized by synaptic failure and neuronal loss. Recently, we demonstrated that artemisinins restored the levels of key proteins of inhibitory GABAergic synapses in the hippocampus of APP/PS1 mice, a model of cerebral amyloidosis. In the present study, we analyzed the protein levels and subcellular localization of α2 and α3 subunits of GlyRs, indicated as the most abundant receptor subtypes in the mature hippocampus, in early and late stages of AD pathogenesis, and upon treatment with two different doses of artesunate (ARS). Immunofluorescence microscopy and Western blot analysis demonstrated that the protein levels of both α2 and α3 GlyRs are considerably reduced in the CA1 and the dentate gyrus of 12-month-old APP/PS1 mice when compared to WT mice. Notably, treatment with low-dose ARS affected GlyR expression in a subunit-specific way; the protein levels of α3 GlyR subunits were rescued to about WT levels, whereas that of α2 GlyRs were not affected significantly. Moreover, double labeling with a presynaptic marker indicated that the changes in GlyR α3 expression levels primarily involve extracellular GlyRs. Correspondingly, low concentrations of artesunate (≤1 µM) also increased the extrasynaptic GlyR cluster density in hAPPswe-transfected primary hippocampal neurons, whereas the number of GlyR clusters overlapping presynaptic VIAAT immunoreactivities remained unchanged. Thus, here we provide evidence that the protein levels and subcellular localization of α2 and α3 subunits of GlyRs show regional and temporal alterations in the hippocampus of APP/PS1 mice that can be modulated by the application of artesunate.
... Likewise, Yan collaborators reported that TLR4 attenuate GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn [43], and Noelker and collaborators reported that TLR4 regulates dopamine levels in the striatum [34]. Additionally, studies have reported that TLR4 in the central nervous system is involved in memory, learning impairment [57], and cognitive decline [58], as a modulator of neurogenesis in the brain during injuries, cerebral ischemia, and cognitive decline [59], and it is recognized to contribute to neuroplasticity [60]. On the other hand, expression of mHtt has been related to neuroinflammation and neuronal damage [61]. ...
Toll-like receptors (TLRs) are central players in innate immunity responses. They are expressed in glial cells and neurons, and their overactivation leads to the production of proinflammatory molecules, neuroinflammation, and neural damage associated with many neurodegenerative pathologies, such as Huntington’s disease (HD). HD is an inherited disorder caused by a mutation in the gene coding for the protein Huntingtin (Htt). Expression of mutated Htt (mHtt) causes progressive neuronal degeneration characterized by striatal loss of GABAergic neurons, oxidative damage, neuroinflammatory processes, and impaired motor behavior. The main animal models to study HD are the intrastriatal injection of quinolinic acid (QA) and the transgenic B6CBA-Tg (HDexon1)61Gpb/1 J mice (R6/1). Those models mimic neuronal damage and systemic manifestations of HD. The objective of this work was to study the participation of TLR4 in the manifestations of neuronal damage and HD symptoms in the two mentioned models. For this purpose, C57BL6/J and TLR4-KO mice were administered with QA, and after that motor activity, and neuronal and oxidative damages were measured. R6/1 and TLR4-KO were mated to study the effect of low expression of TLR4 on the phenotype manifestation in R6/1 mice. We found that TLR4 is involved in motor activity, and neurological and oxidative damage induced by intrastriatal injection of QA, and the low expression of TLR4 causes a delay in the onset of phenotypic manifestations by the mHtt expression in R6/1 mice. Our results show that TLR4 is involved in both models of HD and focuses then as a therapeutic target for some deleterious reactions in HD.
... 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.
... For instance, some studies reported the efficacy of artemisinins in treating neuro inflammation-related central nerve system (CNS) diseases [37]. Another study reports strong evidence for the potential use of artemisinin B in treating neuroinflammatory diseases [38]. Finally, one study also reported the liver protective effect of artemisinin, noting the enhanced stability and reduced damage to the liver cell membrane and cells. ...
... 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]. ...
Simple Summary
Alzheimer’s disease (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. Oxidative stress plays a crucial role in activating and causing various cell signaling pathways that result in lesion formations of toxic substances, which advances 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, 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 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.
Abstract
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 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.
Neurodegenerative disease (ND) incidence has recently increased due to improved life expectancy. Alzheimer's (AD) or Parkinson's disease (PD) are the most prevalent NDs. Both diseases are poly genetic, multifactorial and heterogenous. Preventive medicine, a healthy diet, exercise, and controlling comorbidities may delay the onset. After the diseases are diagnosed, therapy is needed to slow progression. Recent studies show that local, peripheral and age-related inflammation accelerates NDs' onset and progression. Patients with autoimmune disorders like inflammatory bowel disease (IBD) could be at higher risk of developing AD or PD. However, no increase in ND incidence has been reported if the patients are adequately diagnosed and treated. Autoantibodies against abnormal tau, β amyloid and α- synuclein have been encountered in AD and PD and may be protective. This discovery led to the proposal of immune-based therapies for AD and PD involving monoclonal antibodies, immunization/vaccines, pro-inflammatory cytokine inhibition and anti-inflammatory cytokine addition. All the different approaches have been analysed here. Future perspectives on new therapeutic strategies for both disorders are concisely examined.
Currently, artemisinin (ART) and many of its semisynthetic derivatives are considered as potential neuroprotectors. The effect of ART in an animal model of Alzheimer’s disease (AD) induced by aggregated amyloidogenic peptide Aβ1–42 was studied by electrophysiology and morphology analysis to detect changes in brain memory caused by activation of the entorhinal cortex as synaptic potentiation and depression as well as identifying a correlation with in silico studies of the direct interaction of ART with amyloidogenic peptides 5Aβ17–42 and 18Aβ9–40.
We have shown the preventive effect of ART in an animal model of AD. Electrophysiological studies showed that in the pre-injection of ART, there is an obvious and significant decrease in excitotoxicity, which precedes both depressor and excitatory post-stimulus effects, approaching normal, indicating its powerful protective effect. Protection was more effective in relation to the depressor sequence. Histo-morphological analysis showed that the preliminary injection of ART acts as a neuroprotective agent that prevents or slows down damage to brain tissue and also promotes the restoration of neurons and their environment.
The conducted in silico studies indicate the direct interaction of ART with amyloidogenic peptides 5Aβ17–42 and 18Aβ9–40 with high binding energies. At the same time, ART can stop the formation and growth of the 18Aβ9–40 fibril, as well as destabilize the already formed amyloid, which correlates with in vivo studies.
Ethnopharmacological relevance:
Artemisia annua L. belongs to the Asteraceae family and has a long history of clinical application in China. It has been widely used for centuries to treat fever, malaria, jaundice and some skin diseases (such as scabies and sores). Modern pharmacological studies have shown that it has anti-inflammatory, immunomodulatory, antimalarial and antibacterial effects.
Aim of study:
This study aimed to investigate the anti-eczema effect of A. annua aqueous extract (AAE), profile its potential bioactive components and try to explore its possible underlying mechanisms.
Materials and methods:
The MTT assay was employed to assess the cytotoxicity of AAE. The anti-eczema effect of AAE was evaluated using both an in vitro 3D epidermal inflammation model and an in vivo guinea pig itching model. The bioactive components of AAE were characterized by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry coupled with the UNIFI platform.
Results:
In this study, we found that AAE is safe for primary human skin keratinocytes at concentrations ranging from 31.3 μg/mL to 250 μg/mL. Further investigations indicate that AAE can increase the itching threshold, inhibit the expression of the inflammatory cytokine TSLP, and promote the expression of FLG mRNA. Additionally, the utilization of UPLC-QTOF/MS and UNIFI platform enabled us to identify 61 potential bioactive components of AAE, with sesquiterpenes and phenolic acids being the most abundant components.
Conclusions:
In this study, the anti-inflammatory and anti-itch effects of the A. annua extract were revealed, along with sesquiterpenes and phenolic acids were identified as potential bioactive components according to literature. The AAE extract holds potential for utilization in the treatment of eczema.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased learning ability and memory deficits. Our previous findings suggested that benzene, 1,2,4-trimethoxy-5-(2-methyl-1-propen-1-yl) (BTY) can ameliorate the dysfunction of GABAergic inhibitory neurons associated with neurological diseases. On this basis, we investigated the neuroprotective effect of BTY on AD and explored the underlying mechanism. This study included in vitro and in vivo experiments. BTY could maintain cell morphology, improve cell survival rate, reduce cell damage, and inhibit cell apoptosis in vitro experiments. Further, BTY has good pharmacological activity in vivo experiments, of which behavioral experiments showed that BTY could improve AD-like mice's learning and memory abilities. Besides, histopathological experiments indicated that BTY could maintain the morphology and function of neurons, reduce amyloid β-protein 42 (Aβ42) and phosphorylated tau (p-tau) accumulation, and decrease the levels of inflammatory cytokines. Finally, western blot experiments showed that BTY could inhibit the expression of apoptosis-related proteins and promote the expression of memory-related proteins. In conclusion, this study indicated that BTY may be a promising drug candidate for AD.
Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the occurrence of cognitive deficits. With no effective treatments available, the search for new effective therapies has become a major focus of interest. In the present study, we describe the potential therapeutic effect of Artemisia annua (A. annua) extract on AD. Nine-month-old female 3xTg AD mice were treated with A. annua extract for three months via oral administration. Animals assigned to WT and model groups were administrated with an equal volume of water for the same period. Treated AD mice significantly improved the cognitive deficits and exhibited reduced Aβ accumulation, hyper-phosphorylation of tau, inflammatory factor release and apoptosis when compared with untreated AD mice. Moreover, A. annua extract promoted the survival and proliferation of neural progenitor cells (NPS) and increased the expression of synaptic proteins. Further assessment of the implicated mechanisms revealed that A. annua extract regulates the YAP signaling pathway in 3xTg AD mice. Further studies comprised the incubation of PC12 cells with Aβ1–42 at a concentration of 8 μM with or without different concentrations of A. annua extract for 24 h. Obtained ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis and assessment of the signaling pathways involved was performed using western blot and immunofluorescence staining. The obtained results showed that A. annua extract significantly reversed the Aβ1–42-induced increase in ROS levels, caspase-3 activity and neuronal cell apoptosis in vitro. Moreover, either inhibition of the YAP signaling pathway, using a specific inhibitor or CRISPR cas9 knockout of YAP gene, reduced the neuroprotective effect of the A. annua extract. These findings suggest that A. annua extract may be a new multi-target anti-AD drug with potential use in the prevention and treatment of AD.
Neuroinflammation is one of the important mechanisms of trimethyltin chloride (TMT) central neurotoxicity. Artemisinin (ARS) is a well-known antimalarial drug that also has significant anti-inflammatory effects. Prokineticin 2 (PK2) is a small molecule secreted protein that is widely expressed in the nervous system and plays a key role in the development of neuroinflammation. However, it remains unclear whether ARS can ameliorate neuroinflammation caused by TMT and whether PK2/PKRs signaling pathway plays a part in it. In this research, male Balb/c mice were administered TMT (2.8mg/kg, i.p.) followed by immunohistochemistry to assess the expression of PK2, PKR1, and PKR2 proteins in the hippocampus. Network pharmacology was used to predict the intersection targets of ARS, central nervous system(CNS) injury and TMT. The neurobehavior of mice was evaluated by behavioral scores. Histopathological damage of the hippocampus was evaluated by HE, Nissl and Electron microscopy. Western blotting was used to identify the expression of synapse-related proteins (PSD95, SYN1, Synaptophysin), PK system-related proteins (PK2, PKR1, PKR2), and inflammation-related proteins (TNF-α, NF-κB p65).Immunohistochemistry showed that TMT resulted in elevated PK2 and PKR2 protein expression in the CA2 and CA3 regions of the hippocampus in mice, while PKR1 protein was not significantly altered. Network pharmacology showed that PK2 could interact with the intersectional targets of ARS, CNS injury, and TMT. ARS remarkably attenuated TMT-induced seizures and hippocampal histological damage. Further studies demonstrated that ARS treatment attenuated TMT-induced hippocampal ultrastructural damage, possibly by increasing the number of rough endoplasmic reticulum and mitochondria as well as upregulating the levels of synapse-associated proteins (PSD95, SYN1, Synaptophysin). Western blotting results revealed that ARS downregulated TMT-induced TNF-α and NF-κB p65 protein levels. In addition, ARS also decreased TMT-induced protein expression of PK2 and PKR2 in the mouse hippocampus, but had no significant effect on PKR1 protein expression. Our results suggested that ARS ameliorated TMT-induced abnormal neural behavior and hippocampal injury, which may be achieved by regulating PK2/PKRs inflammatory pathway and ameliorating synaptic injury. Therefore, we suggest that PK2/PKRs pathway may be involved in TMT neurotoxicity and ARS may be a promising drug that can relieve TMT neurotoxicity.
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.
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.