Therapeutic efficacy of generic artemether-lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations.

BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP. RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/µL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Synergistic antidepressant-like effect of xylopic acid co-administered with selected antidepressants.

Background: Xylopic acid (XA), a kaurene diterpene from the dried fruits of Xylopia aethiopica, has anxiolytic- and antidepressant-like activity in mice and zebrafish. We aimed to assess the potential synergistic antidepressant-like effects of XA when combined with selected antidepressants in the mouse forced-swim test. Materials and methods: The antidepressant-like effect of xylopic acid (XA) (10, 30, 100 mgkg-1), fluoxetine (Flx) (3, 10, 30 mgkg-1), sertraline (Sert) (3, 10, 30 mgkg-1), imipramine (Imi) (10, 30, 100 mgkg-1) and ketamine (Ket) (0.1, 0.3, 1.0 mgkg-1), was evaluated in forced swim test. The dose (ED50) that achieved a 50% reduction in immobility time was determined from the respective log-dose response curves. XA and the selected antidepressants were co-administered in fixed-dose ratio combinations (1/2:1/2, 1/4:1/4, 1/8:1/8) of the ED50 to identify the experimental ED50 (ED50mix). The theoretical ED50(ED50add), of all combinations was determined using isobolograms and compared with the ED50mix to identify the nature of the interaction. The effect of dose combinations on general locomotor activity was assessed in the open-field test. Results: The interaction index (γ) for the following XA combinations, XA/Flx, XA/Sert, XA/Imi and XA/Ket were 0.42, 0.41, 0.31 and 0.34. An independent sample t-test revealed that the experimental ED50 (ED50mix) was significantly lower than the theoretical ED50 (ED50add) in all combinations of XA, indicative of a synergistic antidepressant-like effect. However, combinations of XA with ketamine significantly reduced general locomotor activity at all dose combinations. Conclusion: The co-administration of xylopic acid and fluoxetine, imipramine, sertraline and ketamine produces a synergistic antidepressant-like effect in mice.

A consideration of CYP2D6 genetic variations in the Ghanaian population as a potential 'culprit' for the tramadol 'abuse crisis'.

BACKGROUND: Cytochrome P450 2D6 is involved in the metabolism of several important medicines including opioids. Variations in CYP2D6 have been implicated in drug response and according to the Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, dosing for CYP2D6 substrates should be based on variants carried by individuals. Although CYP2D6 variations in Ghana had been previously recorded, not all variants have been reported in the Ghanaian population. In this exploratory study we set to investigate certain unreported variations in the Ghanaian population in addition to the previously reported ones and use that to understand the tramadol 'abuse' crisis that is currently being experienced in Ghana. METHODS: This study employed a convenience sampling approach to include 106 unrelated participants who were recruited as part of the PHARMABIOME project. We successfully genotyped 106 samples using Iplex GOLD SNP genotyping protocol after extracting DNA from these individuals. Allele and diplotype frequencies were undertaken by counting from observed genotypes. Comparison of alleles reported from various studies were done. RESULTS: Unreported alleles such as *3, *9 and *41 which are classified as no function and decreased function were observed in our study cohort. In addition, variants such as (*1, *2, *4, *5, *10, *17 and *29 were observed with different frequencies. Our study showed 26% representation of intermediate metabolizers (IM) and 2% poor metabolizers (PM) in the study population. CONCLUSION: The implications for informal sector workers who use tramadol for recreational purposes, is that IMs and PMs will overdose as they may have reduced analgesic effects which will translate into increased risks of unforeseen adverse events. We therefore propose that CYP2D6 should be considered in opioid dosage while making use of these observed variations to implement new approaches to tackle the tramadol 'abuse crisis' in Ghana.

Anxiolytic-like effects of Pseudospondias microcarpa hydroethanolic leaf extract in zebrafish: Possible involvement of GABAergic and serotonergic pathways.

Pseudospondias microcarpa is used in ethnomedicine to manage central nervous system diseases. The hydroethanolic extract (PME) from the leaves of the plant has shown anxiolytic-like properties in mice anxiety models. However, its effects in chronic anxiety models and possible mechanism(s) of action were not studied. Therefore, the current study evaluated the anxiolytic-like mechanisms of PME in zebrafish models of anxiety. The zebrafish light dark test (LDT) and novel tank test (NTT) were employed to assess the anxiolytic-like effects of PME (0.1, 0.3, 1.0 mg mL-1), fluoxetine (3 × 10-5 mg mL-1) and diazepam (1.5 × 10-7 mg mL-1). The chronic unpredictable stress (CUS) test was used to further evaluate the extract's anxiolytic-like properties. The potential mechanisms of anxiolytic action of the extract was evaluated after pre-treated with flumazenil, granisetron, methysergide, or pizotifen, all at 1 × 10-3 mg mL-1. The extract significantly decreased anxiety behaviours in the NT and LD tests. These observed effects of the extract were however counteracted by flumazenil, granisetron, methysergide and pizotifen pre-treatment. In addition, PME treatment significantly reversed CUS-induced anxiety behaviours in zebrafish. Results show that PME possesses anxiolytic-like effects possibly through interaction with serotonergic and gamma-aminobutyric acid mediated pathways.

Compendium of medically important snakes, venom activity and clinical presentations in Ghana.

BACKGROUND: Snake bite envenoming (SBE) is one neglected tropical disease that has not received the needed attention. The sequelae of burdensome disability and mortality impact the socioeconomic life of communities adversely with little documentation of SBE in health facility records in Ghana. This study details SBE and snake distribution, habits/habitats, type of venom expressed and clinical manifestations. METHODOLOGY: We conducted a structured thematic desk review of peer reviewed papers, books and reports from repositories including PubMed, World Health Organization (WHO) and Women's & Children's Hospital (WCH) Clinical Toxinology Resources using bibliographic software EndNote and search engine Google Scholar with the following key words; snakes, medical importance, snake bites, venom and venom type, envenomation, symptoms and signs, vaccines, venom expenditure, strike behaviour and venom-metering + Ghana, West Africa, Africa, World. We also reviewed data from the District Health Information Management System (DHIMS) of the Ghana Health Service (GHS). Outcome variables were organized as follows: common name (s), species, habitat/habit, species-specific toxin, clinical manifestation, antivenom availability, WHO category. FINDINGS: Snake bites and SBE were grouped by the activity of the expressed venom into neurotoxic, cardiotoxic, haemorrhagic, cytotoxic, myotoxic, nephrotoxic and procoagulants. Neurotoxic snake bites were largely due to elapids. Expressed venoms with cardiotoxic, haemorrhagic, nephrotoxic and procoagulant activities principally belonged to the family Viperidae. Snakes with venoms showing myotoxic activity were largely alien to Ghana and the West African sub-region. Venoms showing cytotoxic activity are expressed by a wide range of snakes though more prevalent among the Viperidae family. Snakes with neurotoxic and haemorrhagic venom activities are prevalent across all the agro-ecological zones in Ghana. CONCLUSION/SIGNIFICANCE: Understanding the characteristics of snakes and their venoms is useful in the management of SBE. The distribution of snakes by their expressed venoms across the agro-ecological zones is also instructive to species identification and diagnosis of SBE.

Modulating Effects of the Hydroethanolic Leaf Extract of Persicaria lanigera R. Br. Soják (Polygonaceae) against Acute Inflammation.

Plant species have been used traditionally to treat numerous inflammatory disorders because of their known medicinal properties. This study aimed to assess the anti-inflammatory effect of aqueous ethanolic leaf extract of Persicaria lanigera using acute inflammatory models. The safety profile of the Persicaria lanigera extract was assessed using an acute toxicity model. The anti-inflammatory effect of the Persicaria lanigera leaf extract (100-600 mg·kg-1, p.o.) was studied in carrageenan-induced paw oedema, zymosan-induced knee joint arthritis, and histamine-induced paw oedema in Sprague-Dawley rats (n = 5). It was observed that the Persicaria lanigera leaf extract administered prophylactically significantly inhibited paw oedema from 99.01 ± 12.59 to 59.10 ± 4.94%, 56.08 ± 3.65%, and 48.62 ± 3.27% at 100 mg·kg-1, 300 mg·kg-1, and 600 mg·kg-1, while the standard drug, aspirin, showed 41.84 ± 9.25% in carrageenan-induced paw oedema, respectively. Furthermore, the extract decreased knee joint inflammation significantly from 62.43 ± 5.73% to 32.07 ± 2.98% and 24.33 ± 8.58% at 300 mg·kg-1 and 600 mg·kg-1 in zymosan-induced knee joint inflammation, respectively. In the histamine-induced paw oedema model, the extract significantly inhibited oedema to 61.53 ± 9.17%, 54.21 ± 9.38%, and 54.22 ± 9.37% at the same doses. Aqueous ethanolic leaf extract of Persicaria lanigera is safe and attenuates inflammation in acute inflammation models.

Apolipoprotein E genetic variation, atherogenic index and cardiovascular disease risk assessment in an African population: An analysis of HIV and malaria patients in Ghana.

BACKGROUND: Apolipoprotein E is involved in lipid transport and clearance of lipoprotein through low-density lipoprotein receptors (LDLR). ApoE variation has been linked to cardiovascular disease (CVD) risk. There are 3 isoforms of ApoE which originate from two non-synonymous single nucleotide polymorphisms denoted as ε2, ε3 and ε4. The ε2 isoform is implicated in higher levels of atherogenic lipoprotein with the ε4 isoform causing LDLR downregulation. This leads to variable effects and differential CVD risk. Malaria and HIV are life-threatening diseases affecting several countries globally especially in sub-Saharan Africa. Parasite and viral activities have been implicated in lipid dysregulation leading to dyslipidaemia. This study examined ApoE variation and CVD risk assessment in malaria and HIV patients. METHODS: We compared 76 malaria-only, 33 malaria-HIV coinfected, 21-HIV-only and 31 controls from a tertiary health facility in Ghana. Fasting venous blood samples were taken for ApoE genotyping and lipid measurements. Clinical and laboratory data were collected with ApoE genotyping performed using Iplex Gold microarray and PCR-RFLP. Cardiovascular disease risk was calculated using the Framingham BMI and cholesterol risk and Qrisk3 tools. RESULTS: The frequency of C/C genotype for rs429358 was 9.32%, whiles T/T genotype for rs7412 was found in 2.48% of all participants. ε3/ε3 was the most distributed ApoE genotype accounting for 51.55% of the total participants whiles ε2/ε2 was found in 2.48% of participants, with 1 in malaria-only and 3 in HIV-only patients. There was a significant association between ε4+ and high TG (OR = 0.20, CI; 0.05-0.73; p = 0.015), whiles ε2+ was significantly associated with higher BMI (OR; 0.24, CI; 0.06-0.87; p = 0.030) and higher Castelli Risk Index II in females (OR = 11.26, CI; 1.37-92.30; p = 0.024). A higher proportion of malaria-only participants had a moderate to high 10-year CVD risk. CONCLUSION: Overall malaria patients seem to have a higher CVD risk though the means through which this occurs may be poorly understood. ε2/ε2 genotypes was observed in our population at a lower frequency. Further studies are vital to determine CVD risk in malaria and how this occurs.

Fast-onset effects of Pseudospondias microcarpa (A. Rich) Engl. (Anacardiaceae) hydroethanolic leaf extract on behavioral alterations induced by chronic mild stress in mice.

INTRODUCTION: Pseudospondias microcarpa (Anacardiaceae) is a plant widely used traditionally for treating various central nervous system disorders. A previous study in our laboratory confirmed that the hydroethanolic leaf extract (PME) of the plant produces an antidepressant-like effect in rodent models of behavioral despair. However, its effect on depressive-like behavior induced by chronic mild stress (CMS) and its time course of action are still unknown. In this context, the long-term effects of PME on cognitive function and depressive- and anxiety-like behavior caused by CMS were assessed. METHODS: Male ICR mice were exposed to CMS for nine weeks and anhedonia was evaluated by monitoring sucrose intake (SIT) weekly. PME (30, 100, or 300 mg kg-1) or fluoxetine (FLX) (3, 10, or 30 mg kg-1) was administered to the mice during the last six weeks of CMS. Behavioral tests-coat state, splash test, forced swimming test (FST), tail suspension test (TST), elevated plus maze (EPM), open field test (OFT), novelty suppressed feeding (NSF), EPM transfer latency, and Morris water maze (MWM)-were performed after the nine-week CMS period. RESULTS: When the mice were exposed to CMS, their SIT and grooming behavior reduced (splash test), their coat status was poor, they became more immobile (FST and TST), more anxious (OFT, EPM, and NSF), and their cognitive function was compromised (EPM transfer latency and MWM tests). Chronic PME treatment, however, was able to counteract these effects. Additionally, following two (2) weeks of treatment, PME significantly boosted SIT in stressed mice (30 mg kg-1, P<0.05; 100 mg kg-1, P<0.05; and 300 mg kg-1, P<0.001), as compared to four (4) weeks of treatment with FLX. CONCLUSION: The present findings demonstrate that PME produces a rapid and sustained antidepressant-like action and reverses behavioral changes induced by chronic exposure to mild stressors.

Antibacterial, Resistance Modulation, Anti-Biofilm Formation, and Efflux Pump Inhibition Properties of Loeseneriella africana (Willd.) N. Halle (Celastraceae) Stem Extract and Its Constituents.

This study investigated the antibacterial, resistance modulation, biofilm inhibition, and efflux pump inhibition potentials of Loeseneriella africana stem extract and its constituents. The antimicrobial activity was investigated by the high-throughput spot culture growth inhibition (HT-SPOTi) and broth microdilution assays. The resistance modulation activity was investigated using the anti-biofilm formation and efflux pump inhibition assays. Purification of the extract was carried out by chromatographic methods, and the isolated compounds were characterized based on nuclear magnetic resonance, Fourier transform infrared and mass spectrometry spectral data and comparison with published literature. The whole extract, methanol, ethyl acetate, and pet-ether fractions of L. africana all showed antibacterial activity against the test bacteria with MICs ranging from 62.5 to 500.0 µg/mL The whole extract demonstrated resistance modulation effect through strong biofilm inhibition and efflux pump inhibition activities against S. aureus ATCC 25923, E. coli ATCC 25922 and P. aeruginosa ATCC 27853. Chromatographic fractionation of the ethyl acetate fraction resulted in the isolation of a triterpenoid (4S,4αS,6αR,6ßS,8αS,12αS,12ßR,14αS,14ßR)-4,4α,6ß,8α,11,11,12ß,14α-Octamethyloctadecahydropicene-1,3(2H,4H)-dione) and a phytosterol (ß-sitosterol). These compounds showed antibacterial activity against susceptible bacteria at a MIC range of 31-125 µg/mL and potentiated the antibacterial activity of amoxicillin (at » MIC of compounds) against E. coli and P. aeruginosa with modulation factors of 32 and 10, respectively. These compounds also demonstrated good anti-biofilm formation effect at a concentration range of 3-100 µg/mL, and bacterial efflux pump inhibition activity at ½ MIC and » MIC against E. coli and P. aeruginosa. Loeseneriella africana stem bark extracts and constituents elicit considerable antibacterial, resistance modulation, and biofilm and efflux pump inhibition activities. The results justify the indigenous uses of L. africana for managing microbial infections.

Evaluation of the anti-inflammatory and antioxidant potential of the stem bark extract and some constituents of Aidia genipiflora (DC.) dandy (rubiaceae).

Aidia genipiflora (DC.) Dandy (Rubiaceae) is used to treat various microbial and inflammatory conditions by traditional healers in West African countries. However, there is no information on anti-inflammatory potential of A. genipiflora. This work therefore provides information on the anti-inflammatory and the antioxidant activities of the stem bark extracts and some bioactive constituents of Aidia genipiflora. Method: The anti-inflammatory activities of the extracts and compounds from A. genipiflora were investigated using the carrageenan-induced footpad oedema assay and the egg albumin denaturation assay. The antioxidant activities of the extract and compounds were investigated using the DPPH radical scavenging assay and the phosphomolybdenum total antioxidant capacity assay. The whole extract of A. genipiflora was also investigated for its acute oral toxicity using the fixed-dose procedure described by the Organization for Economic Cooperation Development guidelines. Result: The whole extract showed no acute toxicity effect and the LD50 was estimated to be greater than 3000 mg/kg body weight. The whole extract, methanol, and ethyl acetate fractions (30, 100, and 300 mg/kg) showed in vivo anti-inflammatory activity with respective percentage inhibition of oedema of 45.11 ± 3.41, 31.12 ± 3.42 and 29.28 ± 3.58 (p < 0.001) at the highest dose of 300 mg/kg. Diclofenac, used as a reference drug, gave a % inhibition of 48.94 ± 3.58. The compounds isolated from A. genipiflora demonstrated in-vitro anti-inflammatory activity at the IC50 range (16-96 µg/mL) compared to diclofenac (IC50 of 74.48 µg/mL). Oleanonic acid (AG1) and D-mannitol (AG4) further demonstrated in vivo anti-inflammatory activity (ED50 = 20.61 ± 1.29; 23.51 ± 1.26 mg/kg respectively) which was less potent compared to diclofenac (ED50 = 12.50 ± 1.41 mg/kg) in the carrageenan-induced oedema assay. The whole extract, pet. ether, ethyl acetate, and methanol fractions of A. genipiflora exhibited DPPH scavenging activities with respective IC50 of 222.2, 169.7, 121.5, and 40.7 µg/mL. The whole extract of A. genipiflora exhibited considerable total antioxidant capacity with respective values of 248.5 mg/g of ascorbic acid equivalent. All the compounds exhibited low DPPH scavenging activity with IC50 (64-86 µg/mL), compared to ascorbic acid (IC50 of 3.13 ± 1.20 µg/mL). These results highlight the anti-inflammatory and antioxidant activities of Aidia genipiflora stem bark extract and its constituents as evidence to support its traditional uses.

Depression in Sub-Saharan Africa.

Mood disorders can be considered among the most common and debilitating mental disorders. Major depression, as an example of mood disorders, is known to severely reduce the quality of life as well as psychosocial functioning of those affected. Its impact on the burden of disease worldwide has been enormous, with the World Health Organisation projecting depression to be the leading cause of mental illness by 2030. Despite several studies on the subject, little has been done to contextualise the condition in Africa, coupled with the fact that there is still much to be understood on the subject. This review attempts to shed more light on the prevalence of depression in Sub-Saharan Africa (SSA), its pathophysiology, risk factors, diagnosis and the experimental models available to study depression within the sub-region. It also evaluates the contribution of the sub-region to the global research output of depression as well as bottlenecks associated with full exploitation of the sub region's resources to manage the disorder.

Extract of Xylopia aethiopica and its kaurene diterpene, xylopic acid, improve learning and memory in mice.

Background: Cognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimer's disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Xylopia aethiopica and its kaurene derivative, xylopic acid, have previously demonstrated neuroprotective effects in animal models. The aim of the present study was to investigate the effect of an extract of Xylopia aethiopica fruit and xylopic acid, on learning and memory using murine models. Materials and methods: Unripe Xylopia aethiopica fruits were collected, dried, and extracted using 70% v/v ethanol. Xylopic acid was isolated from the fruits using petroleum ether, concentrated with ethyl acetate and then recrystallized with petroleum ether before purifying with ethanol (96%v/v). Institute of Cancer Research (ICR) mice received oral doses of the extract of Xylopia aethiopica (XAE; 30, 100 and 300 mg/kg), xylopic acid (XA; 30, 100 and mg/kg), citicoline (300 mg/kg), piracetam (300 mg/kg) or ketamine (30 mg/kg) and saline (vehicle). The animals were then taken through the Morris water maze test (MWM), spontaneous alternation Y-maze test (Y-maze), and novel object recognition test (NOR), to assess learning and memory. Results: In the NOR test, XAE (30, 100 and 300 mg/kg) and XA (30, 100 and 300 mg/kg) increased the percentage exploration and recognition index (p = 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs. Conclusion: The ethanolic extract of Xylopia aethiopica fruit and xylopic acid improved exploratory learning and recognition memory, spatial working, recognition, and reference memories in the behavioral tests.

Low incidence of COVID-19 case severity and mortality in Africa; Could malaria co-infection provide the missing link?

BACKGROUND: Despite reports of malaria and coronavirus diseases 2019 (COVID-19) co-infection, malaria-endemic regions have so far recorded fewer cases of COVID-19 and deaths from COVID-19, indicating a probable protection from the poor outcome of COVID-19 by malaria. On the contrary, other evidence suggests that malaria might contribute to the death caused by COVID-19. Hence, this paper reviewed existing evidence hypothesizing poor outcome or protection of COVID-19 patients when co-infected with malaria. METHODS: PRISMA guidelines for systematic review were employed in this study. Published articles from December 2019 to May 2021on COVID-19 and malaria co-infection and outcome were systematically searched in relevant and accessible databases following a pre-defined strategy. Studies involving human, in vivo animal studies, and in vitro studies were included. RESULTS: Twenty three (23) studies were included in the review out of the 3866 records identified in the selected scientific databases. Nine (9) papers reported on co-infection of COVID-19 and malaria. Five (5) papers provided information about synergism of malaria and COVID-19 poor prognosis, 2 papers reported on syndemic of COVID-19 and malaria intervention, and 7 studies indicated that malaria protects individuals from COVID-19. CONCLUSIONS: Low incidence of COVID-19 in malaria-endemic regions supports the hypothesis that COVID-19 poor prognosis is prevented by malaria. Although further studies are required to ascertain this hypothesis, cross-immunity and common immunodominant isotopes provide strong evidence to support this hypothesis. Also, increase in co-inhibitory receptors and atypical memory B cells indicate synergy between COVID-19 and malaria outcome, though, more studies are required to make a definite conclusion.

Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring.

In pregnancy, there is a significant risk for developing embryos to be adversely affected by everyday chemicals such as food additives and environmental toxins. In recent times, several studies have documented the detrimental effect of exposure to such chemicals on the behaviour and neurodevelopment of the offspring. This study evaluated the influence of the food additive, monosodium glutamate (MSG), on behaviour and development in mice. Pregnant dams were exposed to MSG 2 or 4 g/kg or distilled water from gestation day 10-20. On delivery, postnatal day 1 (PN 1), 3 pups were sacrificed and whole brain samples assayed for KCC2 expression by western blot. The remaining pups were housed until PN 43 before commencing behavioural assessment. Their weights were measured at birth and at 3 days intervals until PN 42. The impact of prenatal exposure to MSG on baseline exploratory, anxiety and depression behaviours as well as spatial and working memory was assessed. In utero exposure to 4 g/kg MSG significantly reduced exploratory drive and increased depression-like behaviours but did not exert any significant impact on anxiety-like behaviours (p < 0.01). Additionally, there was a two-fold increase in KCC2 expression in both 2 and 4 g/kg MSG-exposed offspring. CONCLUSION: This study indicates that, in utero exposure to MSG increases the expression of KCC2 and causes significant effect on locomotion and depression-like behaviours but only marginally affects memory function.

Antidepressant and Anxiolytic Effects and Subacute Toxicity of the Aerial Parts of Psychotria ankasensis J.B.Hall (Rubiaceae) in Murine Models.

BACKGROUND: The present study aimed at validating the traditional use and toxicity profile of a methanolic extract of the aerial parts of Psychotria ankasensis in alleviating depression and anxiety disorders. METHOD: The antidepressant effect of methanolic extract of Psychotria ankasensis (PAE 30, 100, and 300 mg/kg, p.o.) was assessed in mice using the forced swim test (FST) and the tail suspension test (TST). The plant's anxiolytic potential was also evaluated in mice using the elevated plus-maze (EPM) and the open field tests (OFT). The subacute toxicity was assessed via oral administration of PAE at doses of 100, 300, and 1000 mg/kg in rats for 28 days. RESULTS: PAE 100 and 300 mg/kg showed antidepressant-like properties by significantly (at least p < 0.05) decreasing the frequency and duration of immobility in FST and TST. PAE (100 and 300 mg/kg) also showed a significant (at least p < 0.05) anxiolytic effect in both EPM and OFT. In the EPM test, E max for PAE and diazepam were 92.52 ± 40.11% and 85.95 ± 45.92%, respectively, whereas E max was approximately 100% for both test drugs in the OFT. Subacute administration of PAE did not reveal any toxic effects with respect to organ weight index, haematological, serum biochemical, and histopathological parameters. CONCLUSIONS: Methanolic extract of P. ankasensis exhibited antidepressant-like and anxiolytic-like effects devoid of significant toxicity at the doses tested in murine models.

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways.

The diversity offered by natural products has timelessly positioned them as a good source for novel therapeutics for the management of diverse medical conditions, including pain. This study evaluated hydro-ethanolic root bark extract of Ziziphus abyssinica (ZAE) as well as ß-amyrin and polpunonic acid isolated from the plant for analgesic property. The study also investigated the mechanism responsible for this action in the extract. The antinociceptive potential of ZAE (30, 100, and 300 mg/kg, p. o.) was assessed using the tail-immersion test (TIT), acetic acid-induced writhing test (AAT), and formalin test (FT). The extract's effect on acute and chronic musculoskeletal pain was also assessed by administering carrageenan unilaterally into the rat gastrocnemius muscles and measuring pain at 12 h and 10 days for acute and chronic pain respectively. The involvement of pro-inflammatory mediators (prostaglandin E2, bradykinin, TNF-α, and IL-1ß) was assessed. The possible pathways mediating the observed analgesic effect of ZAE were further assessed using the antagonists: naloxone, glibenclamide, NG-L-nitro-arginine methyl ester (L-NAME), atropine, nifedipine, and yohimbine in the FT. Also the analgesic effect of two triterpenoid compounds, ß-amyrin and polpunonic acid, previously isolated from the plant was assessed using the TIT. The anti-nociceptive activity of ZAE was demonstrated in the TIT by the significant (p < 0.05) increase in tail withdrawal threshold in ZAE-treated mice. ZAE also markedly reduced writhing and paw licking responses in both AAT and FT and significantly (p < 0.05) attenuated both acute and chronic musculoskeletal pain. ZAE also significantly reversed hyperalgesia induced by intraplantar injection of PGE2, bradykinin, TNF-α, and IL-1ß. Furthermore, data revealed the involvement of opioidergic, ATP-sensitive K+ channels and NO-cGMP pathways in the analgesic effect of ZAE. Both ß-amyrin and polpunonic acid exhibited analgesic activity in the tail suspension test. Our study demonstrates ZAE as an important source of new therapeutic agents for pain management.

Celecoxib exhibits therapeutic potential in experimental model of hyperlipidaemia.

Hyperlipidaemia is a major risk factor for cardiovascular diseases, the leading cause of death globally. Celecoxib attenuated hypercholesterolaemia associated with CCl4-induced hepatic injury in rats without improving liver function in our previous study. This present study investigated the lipid lowering potential of celecoxib in normal rats fed with coconut oil subjected to five deep-frying episodes. Male Sprague Dawley rats were randomly assigned to groups (n = 6 rats/group) which received physiological saline (10 mL/kg), unheated coconut oil (UO, 10 mL/kg) or heated coconut oil (HO, 10 ml/kg) for 60 days. Groups that received HO were subsequently treated with either physiological saline, atorvastatin (25 mg/kg), celecoxib (5 mg/kg) or celecoxib (10 mg/kg) in the last fifteen days of the experiment. Rats were sacrificed 24 hours after last treatment and blood and tissue samples collected for analysis. HO consumption produced significant hyperlipidaemia and elevation in marker enzymes of hepatic function. Celecoxib ameliorated the hyperlipidaemia as shown by the significantly (P<0.05) lower total cholesterol, triglycerides, low and very low density lipoprotein in the celecoxib-treated rats when compared with HO-fed rats that received saline. Celecoxib also reduced (P<0.05) alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and liver weight of hyperlipidaemic rats. Similarly, hepatocellular damage with the hyperlipidaemia was significantly reversed by celecoxib. However, serum TNF-α and IL-6 did not change significantly between the various groups. Taken together, data from this study suggest that celecoxib may exert therapeutic benefit in hyperlipidaemia and its attendant consequences.

The Anticonvulsant Effect of Hydroethanolic Leaf Extract of Calotropis procera (Ait) R. Br. (Apocynaceae).

A number of currently used drugs have been obtained from medicinal plants which are a major source of drugs. These drugs are either used in their pure form or modified to a semisynthetic drug. Drug discovery through natural product research has been fruitful over the years. Traditionally, Calotropis procera is used extensively in the management of epilepsy. This study is conducted to explore the anticonvulsant effect of a hydroethanolic leaf extract of Calotropis procera (CPE) in murine models. This effect was evaluated using picrotoxin-induced convulsions, strychnine-induced convulsions, and isoniazid- and pilocarpine-induced status epilepticus in mice of both sexes. The results showed that CPE (100-300 mg/kg) exhibited an anticonvulsant effect against strychnine-induced clonic seizures by significantly reducing the duration (p = 0.0068) and frequency (p = 0.0016) of convulsions. The extract (100-300 mg/kg) caused a profound dose-dependent delay in the onset of clonic convulsions induced by picrotoxin (p < 0.0001) and tonic convulsions (p < 0.0001) in mice. The duration of convulsions was reduced significantly also for both clonic and tonic (p < 0.0001) seizures as well. CPE (100-300 mg/kg), showed a profound anticonvulsant effect and reduced mortality in the pilocarpine-induced convulsions. ED50 (~0.1007) determined demonstrated that the extract was less potent than diazepam in reducing the duration and onset of convulsions but had comparable efficacies. Flumazenil-a GABAA receptor antagonist-did not reverse the onset or duration of convulsions produced by the extract in the picrotoxin-induced seizure model. In isoniazid-induced seizure, CPE (300 mg kg1, p.o.) significantly (p < 0.001) delayed the onset of seizure in mice and prolonged latency to death in animals. Overall, the hydroethanolic leaf extract of Calotropis procera possesses anticonvulsant properties.

Neuropharmacological Assessment of the Hydroethanolic Leaf Extract of Calotropis procera (Ait). R. Br. (Apocynaceae) in Mice.

BACKGROUND: Calotropis procera has been widely used traditionally for its analgesic and anti-inflammatory effects. It is also reportedly used in ethnomedicine for mental health disorders including epilepsy even in the absence of supporting scientific data. Thus, the potential of the plant to affect neurological functions was evaluated. METHODS: Irwin's test was performed to determine the effect of the oral administration of the extract (30-3000 mg kg-1) on gross behaviour and physiological function. The activity meter, rotarod, pentylenetetrazol- (PTZ-) induced convulsion, pentobarbitone-induced sleep test, and the tail immersion tests were used to evaluate the spontaneous activity, neuromuscular function, convulsive threshold, sedation, and analgesic effects of the Calotropis procera extract (30-1000 mg/kg), respectively, in mice. RESULTS: Calotropis procera extract (CPE) exhibited significant (p < 0.0001) anticonvulsant and analgesic effects. There was a significant increase in withdrawal latency of the CPE-treated animals in the tail immersion test for analgesia (p < 0.0001), while latency and duration of PTZ-induced convulsions were positively modulated. Calotropis procera extract showed significant (p < 0.0001) central nervous system depressant effects in pentobarbitone-induced hypnosis at 100-1000 mg/kg and spontaneous activity test (30-1000 mg/kg). The extract also depicted impaired motor coordination at 100-1000 mg/kg dose levels. LD50 was estimated to be above 1000 mg kg-1. CONCLUSIONS: Calotropis procera extract has significant central nervous system depressant and analgesic effects in mice.

Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms.

BACKGROUND: Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models. METHODS: The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA's antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA's effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA's influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1-10 µM) in zebrafish and (10, 30, 100 mg kg-1) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST. RESULTS: The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by D-cycloserine and Nω-Nitro-L-arginine methyl ester (L-NAME) but not by D-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes. CONCLUSION: Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.