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Short-term aversive memory impairment without locomotor and exploratory changes following Plasmodium berghei ANKA infection. Aversive memory, locomotor and exploratory activities measurement of P. berghei-infected mice on day 5 and 6 post-infection (pi) and of control group in the step-down inhibitory avoidance test (a-c) and in the open field (d-e). (a) Latency in seconds during training session (5 pi) in the step-down inhibitory avoidance test; (b) Short-term memory analysed 1.5 hours after training session in the step-down inhibitory avoidance test; (c) Long-term memory analysed 24 hours (6 pi) after training session in the step-down inhibitory avoidance test; (d) number of crossings and (e) number of rearing episodes analysed on day 5 post-infection in the open field. Results are expressed as mean ± SEM and are representative of two independent experiments. Asterisk(s) indicate statistical differences, *p < 0.05.
Source publication
Cerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most...
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... berghei-infected mice exhibited short-term aversive memory impairment Figure 1 shows the effect of P. berghei infection in the step- down inhibitory avoidance test and open field test. No difference in the step-down latency between P. berghei- infected mice and controls was found in the training session (Figure 1a). ...
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... berghei-infected mice exhibited short-term aversive memory impairment Figure 1 shows the effect of P. berghei infection in the step- down inhibitory avoidance test and open field test. No difference in the step-down latency between P. berghei- infected mice and controls was found in the training session (Figure 1a). In the test session performed 1.5 hours after the training to evaluate the short-term aversive mem- ory, infected mice presented a significant decrease in the step-down latency (Figure 1b; p = 0.03). ...
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... difference in the step-down latency between P. berghei- infected mice and controls was found in the training session (Figure 1a). In the test session performed 1.5 hours after the training to evaluate the short-term aversive mem- ory, infected mice presented a significant decrease in the step-down latency (Figure 1b; p = 0.03). No difference was found in the long-term aversive memory analysed 24 hours (day 6 pi) after training session (Figure 1c; p = 0.99). ...
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... the test session performed 1.5 hours after the training to evaluate the short-term aversive mem- ory, infected mice presented a significant decrease in the step-down latency (Figure 1b; p = 0.03). No difference was found in the long-term aversive memory analysed 24 hours (day 6 pi) after training session (Figure 1c; p = 0.99). ...
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... the open field test, there were no significant differ- ences in the number of crossings (Figure 1d; p = 0.89) and rearings (Figure 1e; p = 0.91) in the P. berghei- infected group compared to the controls on day 5 pi, indicating no difference in motor and exploratory activ- ities, respectively. However, on day 6 pi, the period when the long-term memory was assessed, P. berghei-infected Figure 2 Frontal cortex and hippocampus mRNA expression of pro-inflammatory cytokines following Plasmodium berghei ANKA infection. ...
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... the open field test, there were no significant differ- ences in the number of crossings (Figure 1d; p = 0.89) and rearings (Figure 1e; p = 0.91) in the P. berghei- infected group compared to the controls on day 5 pi, indicating no difference in motor and exploratory activ- ities, respectively. However, on day 6 pi, the period when the long-term memory was assessed, P. berghei-infected Figure 2 Frontal cortex and hippocampus mRNA expression of pro-inflammatory cytokines following Plasmodium berghei ANKA infection. ...
Citations
... Therefore, our results strongly demonstrate that mVDR exists on the cell membrane of PMs, which has not been reported in previous studies. AS is an antimalarial recommended by the World Health Organization (WHO) that possess many important effects, such as anti-inflammation and anti-tumor effects [18,[38][39][40]. Recently, AS was observed to play an immune-regulating effect in CLP-induced immunesuppression mice in our lab, which is tightly related to its inhibition of both VDR expression and VDR binding to NFκB p65. ...
It is unclear whether membrane vitamin D receptor (mVDR) exists on the macrophage membrane or whether mVDR is associated with lipopolysaccharide (LPS) tolerance. Herein, we report that interfering with caveolae and caveolae-dependent lipid rafts inhibited the formation of LPS tolerance. VDR was detected as co-localized with membrane molecular markers. VDR was detected on the cell membrane and its level was higher in LPS-tolerant cells than that in only LPS treatment cells. Anti-VDR antibodies could abolish the effect of artesunate (AS) to reverse LPS tolerance, and the wild-type peptides (H397 and H305) of VDR, but not the mutant peptide (H397D and H305A), led to the loss of AS’s effect. AS decreased the mVDR level in LPS-tolerant cells. In vivo, AS significantly reduced VDR level in the lung tissue of LPS-tolerant mice. In summary, mVDR exists on the cell membrane of macrophages and is closely associated with the formation of LPS tolerance and the effects of AS.
... Malaria also plays a deleterious role in the immune system. In an experimental model conducted on female C57Bl/6 mice infected with P. berghei, artesunate (hemisuccinate derivative of ART) administered i.p. at a dose of 32 mg/kg on the 4th day of the post infection led to a marked improvement in expression of pro-inflammatory cytokines as well as neurological symptoms in the hippocampus and frontal cortex of the mice [93]. In the same study, it was concluded that ART derivatives could most likely lead to a reduction in brain inflammatory response as a consequence of quicker parasitaemia clearance related to an inherent anti-inflammatory feature. ...
... Nevertheless, the levels of interferon and TNF-α as well as IL 4 and IL 10 in the artemisone treated group were reversed, indicating the preventive effect of the compound. Artesunate was investigated in P. berghei strain ANKA model of cerebral malaria [93]. Flow cytometry was employed to determine parasitemia induced in female C57BL/6 mice, while mRNA expression of pro-inflammatory cytokines; e.g. ...
Artemisinin (ART) is a bioactive compound isolated from the plant Artemisia annua and has been traditionally used to treat conditions such as malaria, cancer, viral infections, bacterial infections, and some cardiovascular diseases, especially in Asia, North America, Europe and other parts of the world. This comprehensive review aims to update the biomedical potential of ART and its derivatives for treating human diseases highlighting its pharmacokinetic and pharmacological properties based on the results of experimental pharmacological studies in vitro and in vivo. Cellular and molecular mechanisms of action, tested doses and toxic effects of artemisinin were also described. The analysis of data based on an up-to-date literature search showed that ART and its derivatives display anticancer effects along with a wide range of pharmacological activities such as antibacterial, antiviral, antimalarial, antioxidant and cardioprotective effects. These compounds have great potential for discovering new drugs used as adjunctive therapies in cancer and various other diseases. Detailed translational and experimental studies are however needed to fully understand the pharmacological effects of these compounds.
... Therefore, to avoid these side effects, researchers are being attracted by anti-inflammatory compounds from natural sources. A larger number of natural products particularly plants have been exhibiting excellent anti-inflammatory potentials both in vivo and in vitro (Miranda et al. 2013). ...
People of Pakistan have undisturbed customs for the employment of medicinal plants for healthcare requisites. Chloroform extract of F. hygrometrica (CE FH) was examined for its ability to reduce inflammation and to produce analgesia. Carrageenan and formalin-induced paw edema model for inflammatory activity, hot-plate and tail-flick methods to assess analgesic activity were executed. Phytochemical analysis was done by UHPLC–MS and GC–mass spectrometer. The results demonstrated that in carrageenan-induced paw edema, maximum reduction in inflammation was observed at 5th hour at the dose 100 mg/kg; while at doses 250 and 500 mg/kg, maximum response was observed at 5th and 6th hours. Analgesic activity results indicated that maximum analgesia was observed up to 120 min at 100 mg/kg, while up to 90 min in case of 250 and 500 mg/kg doses. The formalin-induced rat paw edema showed significant (p < 0.05) anti-inflammatory activity after 5 days treatment. After, testing period of 10 days, the biochemical parameters such as CBC, CRP, serum enzymes like CAT, SOD, GSH and inflammatory mediators like TNF-α, IL-6, IL-4 and IL-10 were estimated. The administration of formalin resulted in an increase in the level of leucocytes, total WBC, CRP, serum enzymes and in the diameters of paw thickness, while pre-treatment with CE FH at dose levels of 100, 250 and 500 mg/kg exhibited a diminution in the levels of SOD, GSH, CAT, total RBC and HB. Acute inflammatory mediators such as TNFα, IL -6 and IL-4 were reduced, and IL-10 was upregulated in the treated group as compared to the control. Many phytoconstituents, i.e., chitobiose, chlorovulone III, γ-tocotrienol, emmotin, cassine, hexacosanedioic acid, neophytadiene, fumaric acid, neophytadiene, hexadecanoic acid, phytol and stigmasterol were detected during UHPLC–MS and GC–MS analysis seems to be responsible for the said activity in correlation with the already reported data about these compounds. The results concluded that CE FH possess noteworthy anti-inflammatory and central analgesic action at different doses (100, 250 and 500 mg/kg).
Graphic abstract
... We found that the mRNA expressions of pro-inflammatory factors including IL-1β, IL-6, and TNF-α remained unchanged after ART treatment while IL-10 expression was remarkably and ulcerative colitis. [15][16][17][18][19][20] However, the underlying mechanisms of its immunomodulatory effects remain unclarified. It is well-recognized that microglia play an important role in maintaining immune homeostasis, which can be polarized into M1 phenotype to release pro-inflammatory factors including TNF-α, IL-1β, IL-6, and M2 phenotype to up-regulate anti-inflammatory factors such as IL-10, Arg-1, if disturbed. ...
Background
Artesunate (ART), a member of the artemisinin family, possesses multi-properties, including anti-inflammation, anti-oxidation, and anti-tumor. ART was recently reported to show anti-neovascularization effect on the cornea, iris, and retina. Compared to the expensive anti-VEGF treatment, this versatile, economical treatment option is attractive in the ophthalmic field. The safety and toxicity profile of ART intravitreal application are in utmost need.
Methods
In this study, immortalized microglial (IMG) cells were treated with ART to determine the safe concentrations without inducing overt inflammatory reactions. Reverse transcription-polymerase chain reaction analysis was used to detect the cytokine expressions in IMG cells in response to ART stimulation. Various doses of ART were intravitreally injected into the right eyes of C57BL/6 mice. Retinal function was tested by electroretinogram, and retinal ganglion cell (RGC) survival was evaluated by counting Brn3a stained cells in flat-mounted retinas at 7 days after ART injection.
Results
ART below 5μM was safe for IMG cells in vitro. Both 2.5 and 5μM ART treatment increased IL-10 gene expression in IMG cells while not changing IL-1β, IL-6, TNF-α, and Arg-1. In the in vivo study, intravitreal injection of ART below 100μM did not cause deterioration in the retinal function and RGC survival of the mouse eyes, while 1mM ART treatment significantly attenuated both the scotopic and photopic b-wave amplitudes and impaired RGC survival. In addition, treatment with ART of 25, 50, and 100μM significantly decreased TNF-α gene expression while ART of 100μM significantly increased IL-10 in the mouse retina.
Conclusion
Intravitreal injection of 100μM ART could downregulate TNF-α while upregulate IL-10 in the mouse retina without causing retinal functional deterioration and RGC loss. ART might be used as anti-inflammatory agent for retinal disorders.
... Artesunate is a more stable derivative of artemisinin that is obtained from the Chinese plant Artemisia annua that has been used in traditional Chinese medicine to treat severe malaria (Rosenthal, 2008;Woodrow et al., 2005). Artesunate has been shown to exhibit anti-inflammatory properties in cerebral malaria (Clemmer et al., 2011;Miranda et al., 2013), stroke, and neurodegenerative diseases with the ability to reach and sustain a high concentration in the brain without any side effects Zuo et al., 2016). Artesunate administration in a mouse CCI model alleviated the TBI-induced inflammatory response by significantly reducing NLRP3 inflammasome, astrocyte, and microglial activation which was associated with a decrease in TNF-α, NF-kB, IL-1β, and iNOS expression 24 h post-TBI (Gugliandolo et al., 2018). ...
Given the ambiguity surrounding TBI pathophysiology and the lack of any Food and Drug Administration (FDA)-approved neurotherapeutic drugs, there is an increasing need to better understand the mechanisms of traumatic brain injury (TBI). Recently, the roles of inflammasomes have been highlighted as both potential therapeutic targets and diagnostic markers in different neurodegenerative disorders. Indeed, inflammasome activation plays a pivotal function in the central nervous system (CNS) response to many neurological conditions, as well as to several neurodegenerative disorders, specifically, TBI. This comprehensive review summarizes and critically discusses the mechanisms that govern the activation and assembly of inflammasome complexes and the major methods used to study inflammasome activation in TBI and its implication for other neurodegenerative disorders. Also, we will review how inflammasome activation is critical in CNS homeostasis and pathogenesis, and how it can impact chronic TBI sequalae and increase the risk of developing neurodegenerative diseases. Additionally, we discuss the recent updates on inflammasome-related biomarkers and the potential to utilize inflammasomes as putative therapeutic targets that hold the potential to better diagnose and treat subjects with TBI.
... Different from 1,8-cineole treatment, in the presence of artesunate, parasitemia was 100% controlled culminating in the absence of brain edema. These observations agree with studies showing that treatment of infected mice with artesunate (starting right at infection or starting after increased parasitemia), via different administration routes, promote rapid depletion of parasites and effectively attenuate brain inflammation by decreasing leukocytes recruitment [46][47][48]. If a combination between 1,8-cineole and artesunate could positively cooperate to rescue brain tissue and cognitive function, further experiments will clarify this issue. ...
1,8-Cineole is a naturally occurring compound found in essential oils of different plants and has well-known anti-inflammatory and antimicrobial activities. In the present work, we aimed to investigate its potential antimalarial effect, using the following experimental models: (1) the erythrocytic cycle of Plasmodium falciparum ; (2) an adhesion assay using brain microvascular endothelial cells; and (3) an experimental cerebral malaria animal model induced by Plasmodium berghei ANKA infection in susceptible mice. Using the erythrocytic cycle of Plasmodium falciparum , we characterized the schizonticidal effect of 1,8-cineole. This compound decreased parasitemia in a dose-dependent manner with a half maximal inhibitory concentration of 1045.53 ± 63.30 μM. The inhibitory effect of 972 μM 1,8-cineole was irreversible and independent of parasitemia. Moreover, 1,8-cineole reduced the progression of intracellular development of the parasite over 2 cycles, inducing important morphological changes. Ultrastructure analysis revealed a massive loss of integrity of endomembranes and hemozoin crystals in infected erythrocytes treated with 1,8-cineole. The monoterpene reduced the adhesion index of infected erythrocytes to brain microvascular endothelial cells by 60%. Using the experimental cerebral malaria model, treatment of infected mice for 6 consecutive days with 100 mg/kg/day 1,8-cineole reduced cerebral edema with a 50% reduction in parasitemia. Our data suggest a potential antimalarial effect of 1,8-cineole with an impact on the parasite erythrocytic cycle and severe disease.
... However, the doses used in these studies were high, and findings of neurotoxicity have not been substantiated in humans. In contrast, newer studies have assessed the anti-inflammatory properties of artesunate in mouse models of traumatic brain injury [36] and experimental cerebral malaria [37] and found it to be neuroprotective in these conditions. Consistent with these animal studies, we found artemisinin derivatives to be associated with fewer neurologic deficits at discharge than quinine in children with CM (41.9% of children treated with quinine had neurologic deficits compared to 24.0% of children treated with artemisinin derivatives, p=0.008) and with improved internalizing and externalizing behaviors and better executive function over 2 years of followup in children with CM or SMA. ...
... In murine studies, artesunate treatment of CM decreased pro-inflammatory cytokine production in the hippocampus [37], reduced astrocyte and microglia activation, down-regulated multiple inflammasome pathways, and modulated neurotropic factors that affect neuronal survival in a model of traumatic brain injury [36], including brain-derived neurotropic factor, which has been implicated in CM severity [38]. We also observed significantly lower levels of CRP at 1-month follow-up in surviving children treated with artemisinin derivatives. ...
Background:
In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.
Methods:
From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.
Results:
346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07-0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.
Conclusions:
Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.
... In recent years, a great quantity of natural products, especially form plants, have been reported to exhibit obvious antiinflammatory effects both in vitro and in vivo [95]. In the light of molecular structure type, natural products form plants with antiinflammation effects mainly include monoterpene, diterpene, titerpene, phenylpropanoid, lignanoid, coumarin, flavonoid, anthraquinone, alkaloid and polyphenol. ...
Historically, natural products (NP’s) have played a significant role in drug discovery, not only in cancer and infectious diseases, but also in other therapeutic areas including cardiovascular diseases and multiple sclerosis. Profit and loss, Partnerships and averages, natural products also present certain challenges for drug discovery, such as technical obstacles to screening, isolation, characterization and optimization, which added to decline in their search by the pharmaceutical industry from the 1990s onwards. In recent days the applications of molecular biological techniques have increased the availability of novel compounds that can be conveniently produced in bacteria or yeast or plant sources. In addition to this, combinational chemistry approaches are being based on natural product scaffolds to create screening libraries that closely resemble drug-like compounds. Employing these technologies gives us a chance to execute research in screening new molecules by means of a software and data base to ascertain natural products as a major source for drug discovery. It lastly directs to lead structure discovery. This review discusses plant based natural product drug discovery and how innovative technologies play a role in next generation drug discovery and highlights from the published literature on plants as sources of antiinflammatory agents. GRAPHICAL ABSTRACT
... Artemether, artesunate and dihydroartemisinin etc. are its derivatives. Artesunate and its active congener dihydroartemisinin are used for the treatment and management of drug-resistant Plasmodium falciparum malaria [30,31,32]. ...
... Recent study showed that single dose of artesunate administered in cerebral malaria not only restricted the systemic parasitesbut also regulated inflammatory mediated responses in the brain by reducing the production of local proinflammatory cytokines and other mediators which are involved in cognitive impairment. It also caused different pattern of cytokine expression in a key area related to learning and memory such as frontal cortex and hippocampus (31). Another study has proved the antiepileptic activity of artesunate in Wistar rats by using MES and PTZ model, where it has been shown to have activity against MES-induced seizures. ...
Background: Alzheimer's disease (AD) is a geriatric neurodegenerative disorder, a common cause of dementia among older adults. Artemisinin and its derivatives (artesunate) have been proved to affect neuroinflammation at different concentrations. This study was aimed to investigate the effect of artesunate in aluminium chloride (AlCl3) induced AD. Objectives: To evaluate the effect of artesunate on learning and memory in experimentally induced AD in albino Wistar rats. Materials and Method: AD was induced in the rats by administration of 100 mg/kg bw. of aluminium chloride orally. Thirty albino Wistar rats were divided in to five groups (n=6), the groups I and II received distilled water (negative control) and AlCl3 (positive control) respectively for 60 days, groups III, IV and V were treated with AlCl3 for30 days followed by30 days of artesunate (28mg/kg bw), rivastigmine (1mg/kg bw), and memantine (20mg/kg bw) respectively along with AlCl3. Passive avoidance test (PAT) was used to test learning and memory on day 60 which was followed by histopathological examination of the hippocampus by Haematoxylin and Eosin staining (H and E). Results: The artesunate, rivastigmine, and memantine showed a protective effect in behavioural observations when compared to control and diseasegroups. These results were consistent with histopathological findings in the brain tissue. Conclusion: Artesunate has shown to have a promising effect in the aluminium chloride induced dementia model of AD comparable to the standard drugs.
... We do not exclude a direct role of the artesunate, considering its described antioxidant/ anti-inflammatory effect. 27,28 For this purpose, in the future, it will be interesting to compare GI symptoms responses in children receiving intravenous treatment versus ACT. ...
The role of Plasmodium in the etiology of acute diarrhea in developing countries remains controversial, and gastrointestinal (GI) symptoms are inconsistently reported in malaria. In this observational case-control study, we investigated the prevalence and risk factors for GI symptoms in hospitalized malarious children aged 1 month to 5 years in northern Uganda. Children with a diagnosis of Plasmodium falciparum malaria were enrolled as cases, and feverish children in whom malaria was excluded were enrolled as controls. Among 451 malarious children, 46.1% had GI symptoms at admission. Compared with controls, the frequency of diarrhea (24.8% versus 11.2%, P < 0.001) and vomiting (35.5% versus 17.5%, P < 0.001) was significantly higher in children with malaria, who had a higher chance of showing either vomiting (odds ratio [OR]: 3.22; 95% CI: 2.14-4.91) or diarrhea (OR: 3.14; 95% CI: 1.99-5.07) at hospital admission. A subgroup analysis performed in children with severe malaria, severe anemia, or high-grade fever confirmed these results. Diarrhea was more frequent in infants and children younger than 3 years than in older children. The analysis of 71 malarious children with diarrhea who received intravenous artesunate showed that the symptom resolved within the first 24 hours since the beginning of the treatment in 85.9% of cases. The 3-fold higher prevalence of diarrhea and vomiting in malarious children compared with febrile controls may provide rationale for incorporating malaria testing in the symptom-guided diagnostic approach of the young child with diarrhea and vomiting in malaria-endemic settings.
