Dissecting the antidepressant effect of troxerutin: modulation of neuroinflammatory and oxidative stress biomarkers in lipopolysaccharide-treated mice.

The role of neuroinflammation in the pathogenesis of depression has prompted the search for new antidepressants. Troxerutin, a bioflavonoid with anti-inflammatory and antioxidant properties, has shown promise, but its impact on neurobehavioral functions remains poorly understood. This study aimed to investigate the antidepressant potential of troxerutin and its effect on the neuroinflammatory response. Here, we exposed male Swiss mice (n = 5/group) to various treatments, including naive and negative controls receiving distilled water, troxerutin-treated groups administered at different doses (10, 20, 40 mg/kg, i.p.), and an imipramine-treated group (25 mg/kg, i.p.). After seven days of treatment, with the exception of the naive group, mice were administered a single dose of lipopolysaccharide (LPS, 0.83 mg/kg). Behavioral evaluations, consisting of the novelty-suppressed feeding (NSF) test, forced swim test (FST), and open field test (OFT), were conducted. Additionally, brain samples were collected for biochemical and immunohistochemical analyses. Troxerutin significantly reduced immobility time in the FST and mitigated behavioral deficits in the NSF test. Additionally, troxerutin increased glutathione (GSH) and superoxide dismutase (SOD) levels while reducing nitrite, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) levels compared to the negative control. Immunohistochemistry analysis revealed decreased expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) in troxerutin-treated mice. Overall, these findings suggest that troxerutin exerts significant antidepressive-like effects, likely mediated by its anti-inflammatory and antioxidant mechanisms. The reduction in neuroinflammatory and oxidative stress biomarkers, along with the improvement in behavioral outcomes, underscores troxerutin's potential as a therapeutic agent for depression.

Ganoderma lucidum ethanol extract promotes weight loss and improves depressive-like behaviors in male and female Swiss mice.

Metabolic and mood-related disturbances can increase the risks of developing adverse mental health problems. The medicinal mushroom, Ganoderma lucidum, is utilized in indigenous medicine to improve quality of life, promote health, and boost vitality. This study investigated the effects of Ganoderma lucidum ethanol extract (EEGL) on feeding behavioral parameters, depressive-like symptoms, and motor activity in Swiss mice. We hypothesized that EEGL would have beneficial effect on metabolic and behavioral outcomes in a dose-related manner. The mushroom was identified and authenticated via techniques of molecular biology. Forty Swiss mice (n = 10/group) of either sex were given distilled water (10 mL/kg) and graded doses of EEGL (100, 200, and 400 mg/kg) orally for 30 days, during which feed and water intake, body weight, neurobehavioral, and safety data were documented. The animals experienced a significant decrease in body weight gain and feed intake while water intake increased in a dose-dependent manner. Furthermore, EEGL significantly diminished immobility time in forced swim test (FST) and tail suspension test (TST). At the 100 and 200 mg/kg, EEGL did not cause significant alteration in motor activity in the open field test (OFT). Meanwhile, an increase in motor activity in male mice without remarkable difference in female mice was observed at the highest dose (400 mg/kg). Eighty percent of mice treated with 400 mg/kg survived till day 30. These findings suggest that EEGL at 100 and 200 mg/kg reduces the amount of weight gained and elicits antidepressant-like effects. Thus, EEGL might be useful for the management of obesity and depressive-like symptoms.

Quercetin Exerts Anticonvulsant Effect through Mitigation of Neuroinflammatory Response in Pentylenetetrazole-induced Seizure in Mice.

Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-É£ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain.

Mechanisms underpinning Carpolobia lutea G. Don ethanol extract's neurorestorative and antipsychotic-like activities in an NMDA receptor antagonist model of schizophrenia.

ETHNOPHARMACOLOGICAL RELEVANCE: Persistent ketamine insults to the central nervous system block NMDA receptors and disrupt putative neurotransmission, oxido-nitrosative, and inflammatory pathways, resulting in schizophrenia-like symptoms in animals. Previously, the ethnomedicinal benefits of Carpolobia lutea against insomnia, migraine headache, and insanity has been documented, but the mechanisms of action remain incomplete. AIM OF THE STUDY: Presently, we explored the neuro-therapeutic role of Carpolobia lutea ethanol extract (C. lutea) in ketamine-induced schizophrenia-like symptoms in mice. MATERIALS AND METHODS: Sixty-four male Swiss (22 ± 2 g) mice were randomly assigned into eight groups (n = 8/group) and exposed to a reversal ketamine model of schizophrenia. For 14 days, either distilled water (10 mL/kg; p.o.) or ketamine (20 mg/kg; i.p.) was administered, following possible reversal treatments with C. lutea (100, 200, 400, and 800 mg/kg; p.o.), haloperidol (1 mg/kg, p.o.), or clozapine (5 mg/kg; p.o.) beginning on days 8-14. During the experiment, a battery of behavioral characterizations defining schizophrenia-like symptoms were obtained using ANY-maze software, followed by neurochemical, oxido-inflammatory and histological assessments in the mice brains. RESULTS: A 7-day reversal treatment with C. lutea reversed predictors of positive, negative and cognitive symptoms of schizophrenia. C. lutea also mitigated ketamine-induced neurochemical derangements as evidenced by modulations of dopamine, glutamate, norepinephrine and serotonin neurotransmission. Also, the increased acetylcholinesterase activity, malondialdehyde nitrite, interleukin-6 and tumor necrosis-factor-α concentrations were reversed by C. lutea accompanied with elevated levels of catalase, superoxide dismutase and reduced glutathione. Furthermore, C. lutea reversed ketamine-induced neuronal alterations in the prefrontal cortex, hippocampus and cerebellum sections of the brain. CONCLUSION: These findings suggest that C. lutea reverses the cardinal symptoms of ketamine-induced schizophrenia in a dose-dependent fashion by modulating the oxido-inflammatory and neurotransmitter-related mechanisms.

Pretreatment with Carpolobia lutea ethanol extract prevents schizophrenia-like behavior in mice models of psychosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Carpolobia lutea decoction is widely used as a phytotherapeutic against central nervous system-related disorders including insomnia, migraine headache, and mental illness in West and Central Tropical Africa. AIM: This study was designed to investigate the antipsychotic activity of Carpolobia lutea (EECL) in mice models of psychosis. METHODS: Male Swiss mice (n = 5/group) were given EECL (100, 200, 400, and 800 mg/kg), haloperidol (1 mg/kg), clozapine (5 mg/kg) and vehicle (10 mL/kg) orally before amphetamine (5 mg/kg)-induced hyperlocomotion and stereotypy, apomorphine (2 mg/kg)-induced stereotypy, or ketamine (10, 30, and 100 mg/kg)-induced hyperlocomotion, enhancement of immobility and cognitive impairment. RESULTS: EECL (200, 400, and 800 mg/kg) prevented amphetamine- and apomorphine-induced stereotypies, as well as reduced hyperlocomotion induced by amphetamine and ketamine, all of which are predictors of positive symptoms. Regardless of the dose administered, EECL prevented the index of negative symptoms induced by ketamine. Furthermore, higher doses of EECL (400 and 800 mg/kg) also prevented ketamine-induced cognitive impairment, a behavioral phenotype of cognitive symptoms. CONCLUSION: Pretreatment with EECL demonstrated antipsychotic activity in mice, preventing amphetamine-, apomorphine-, and ketamine-induced schizophrenia-like symptoms, with 800 mg/kg being the most effective dose.

Naringenin improves depressive- and anxiety-like behaviors in mice exposed to repeated hypoxic stress through modulation of oxido-inflammatory mediators and NF-kB/BDNF expressions.

Oxidative and inflammatory signaling pathways have been identified as important targets for mitigating hypoxic stress-induced neurological complications. Thus, the effects of naringenin, a potent antioxidant, anti-inflammatory and neuroprotective bioflavonoid on hypoxic stress-induced depressive-like and anxiety-related behaviors in mice, and the underlying molecular mechanisms were evaluated in this study. Thirty-five male Swiss mice were distributed into 5 groups (n = 7). Mice in group I (non-stress control) and group 2 (stress-control) both had vehicle (5 % DMSO), while groups 3-5 received naringenin (10, 25 and 50 mg/kg), intraperitonally. Thirty minutes later, mice in groups 2-5 were subjected to 15 min hypoxic stress, daily for 14 days. Locomotor activity, anxiety and depression were evaluated on day 15. The mice brains were processed for malondialdehyde, glutathione, superoxide-dismutase (SOD), catalase, tumor necrosis factor-alpha (TNF-α) and interleukin-1ß assays. The serum corticosterone concentration and expressions of the brain immunopositive cells of inducible nitric oxide synthase (iNOS), nuclear factor kappa-B (NF-kB) and brain derived neurotrophic factor (BDNF) as well as histomorphological changes of the amygdala were also determined. Naringenin (25-50 mg/kg) ameliorated the hypolocomotion, depressive- and anxiety-like behaviors in hypoxic mice. The increased brain contents of malondialdehyde, TNF-α, interleukin-1ß, and decreased antioxidant (glutathione and SOD) status were attenuated by naringenin. Naringenin (10 mg/kg) increases BDNF expression but did not significantly (p < 0.05) alter corticosterone and catalase contents. The increased expressions of iNOS and NF-kB as well as loss of amygdala neuronal cells were reduced by naringenin (10 mg/kg). Overall, these findings suggest that naringenin improves depressive- and anxiety-like behaviors in mice exposed to hypoxic stress by modulating oxido-inflammatory insults and NF-kB/BDNF expressions.

Methyl jasmonate abrogates rotenone-induced parkinsonian-like symptoms through inhibition of oxidative stress, release of pro-inflammatory cytokines, and down-regulation of immnopositive cells of NF-κB and α-synuclein expressions in mice.

Oxidative stress and neuroinflammation play key roles in the initiation and progression of Parkinson's disease (PD), a neurodegenerative disorder, associated with the loss of nigrostriatal dopaminergic pathway. Thus, compounds that can mitigate oxidative stress and neuroinflammation are being investigated as promising agents for the treatment of PD. This study was designed to evaluate the effects of methyl jasmonate (MJ), a potent antioxidant and anti-inflammatory compound on parkinsonian-like symptoms and the underlying biochemical changes induced by rotenone (Rot) in mice. To this end, the effects of graded doses of MJ (25, 50 and100 mg/kg, i.p.) on motor dysfunctions, cognitive and depressive-like disorders induced by Rot (2.5 mg/kg, i.p.) were evaluated. The specific brain regions (striatum, prefrontal cortex and hippocampus) of the animals were processed for various biochemical studies. Rot-treated mice showed reduced motor activity, postural instability, cognitive and depressive-like disorders. Rot also increased brain levels of malondialdehyde (MDA), nitrite, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and acetyl-cholinesterase (AChE) activity. Moreover, Rot reduced the concentration of glutathione (GSH) and increased immnopositive cells of NF-κB and α-synuclein expressions in these brain regions. However, pretreatment with MJ, attenuated the parkinsonian-like symptoms and reduced the brain levels of MDA/nitrite, TNF-α and IL-6 induced by Rot. MJ also reduced AChE activity and down-regulate the expressions of NF-κB and α-synuclein in the brain of Rot-treated mice. These findings suggest that MJ has anti-parkinsonian-like activity, which may be related to the inhibition of oxidative stress, release of pro-inflammatory cytokines, and down regulation of NF-κB and α-synuclein expressions.

Clinical illness and outcomes in Nigerian children with persistent early-appearing anaemia following initiation of artemisinin-based combination treatments of uncomplicated falciparum malaria.

In non-anaemic children with malaria, early-appearing anaemia (EAA) is common following artemisinin-based combination treatments (ACTs) and it may become persistent (PEAA). The factors contributing to and kinetics of resolution of the deficit in haematocrit from baseline (DIHFB) characteristic of ACTs-related PEAA were evaluated in 540 consecutive children with malaria treated with artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine. Asymptomatic PEAA occurred in 62 children. In a multiple logistic regression model, a duration of illness ≤3 days before presentation, haematocrit <35% before and <25% one day after treatment initiation, drug attributable fall in haematocrit ≥6%, and treatment with dihydroartemisinin-piperaquine independently predicted PEAA. Overall, mean DIHFB was 5.7% (95% CI 4.8-6.6) 7 days after treatment initiation and was similar for all treatments. Time to 90% reduction in DIHFB was significantly longer in artemether-lumefantrine-treated children compared with other treatments. In a one compartment model, declines in DIHFB were monoexponential with overall mean estimated half-time of 3.9 days (95% CI 2.6-5.1), Cmax of 7.6% (95% CI 6.7-8.4), and Vd of 0.17 L/kg (95% CI 0.04-0.95). In Bland-Altman analyses, overall mean anaemia recovery time (AnRT) of 17.4 days (95% CI 15.5-19.4) showed insignificant bias with 4, 5 or 6 multiples of half-time of DIHFB. Ten children after recovery from PEAA progressed to late-appearing anaemia (LAA). Progression was associated with female gender and artesunate-amodiaquine treatment. Asymptomatic PEAA is common following ACTs. PEAA or its progression to LAA may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials. Trial registration: Pan Africa Clinical Trial Registration PACTR201709002064150, 1 March 2017 http://www.pactr.org.

Effects of Jobelyn® on Isoniazid-Induced Seizures, Biomarkers of Oxidative Stress and Glutamate Decarboxylase Activity in Mice.

INTRODUCTION: Isoniazid-induced seizure, often described as Status Epilepticus (SE), is an emergency condition characterized by repeated convulsive episodes that responds poorly to the currently available anticonvulsant drugs. The current study aimed at ascertaining the effect of Jobelyn® (JB), an African dietary supplement, on seizures, altered oxidative stress, and glutamate decarboxylase activity induced by isoniazid in mice. METHODS: A total of 6 mice received JB (10-50 mg/kg, PO), pyridoxine (300 mg/kg), diazepam (5 mg/kg), or distilled water (10 mL/kg) 30 minutes prior to the induction of SE with injection of isoniazid (300 mg/kg, IP). Thereafter, the mice were observed for the onset of convulsions for a period of two hours. Moreover, the effect of JB on Glutamate Decarboxylase (GAD) activity and biomarkers of oxidative stress (glutathione and malondialdehyde) was also evaluated in the brain homogenates of another set of isoniazid-treated mice. RESULTS: JB (50 mg/kg, PO) prolonged the latency to convulsions, but could not prevent the occurrence of seizure episodes caused by isoniazid. Moreover, JB neither showed any protection against death nor delayed the latency to death caused by isoniazid. However, this dose of JB positively modulated the concentrations of malondialdehyde and glutathione in the brains of mice treated with isoniazid. The activity of GAD, the enzyme responsible for GABA synthesis, increased by JB, which suggested enhanced GABAergic neurotransmission. CONCLUSION: The current study findings suggest that JB prolongs the latency to convulsions, enhances GABAergic neurotransmission, and demonstrates anti-oxidative effect in isoniazid-treated mice.

Anti-nociceptive activity of the crude extract of Myrianthus arboreus P. Beauv (Cecropiaceae) in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrianthus arboreus P. Beauv (Cecropiaceae) is a shrub or a tree plant widely distributed in Tropical Africa. In the South Eastern part of Nigeria, the leaves are used in traditional medicine as an analgesic for muscular pains, and also as an enema to relieve pain in the back and loins. Although no scientific study has been performed to validate its traditional use in pain management, this study therefore aims at investigating the anti-nociceptive activity of M. arboreus leaves extract in mice. MATERIALS AND METHODS: Anti-nociceptive activity of M. arboreus was investigated using acetic acid induced writhing, formalin induced paw licks, hot plate, and tail flick tests. Acute toxicity was determined using a slightly modified Lorkes method. RESULTS: The extract of M. arboreus produced a significant dose-dependent [F (4, 20)=13.48 p<0.001] inhibition of abdominal writhings induced by acetic acid. In the formalin paw licking test, it produced a significant dose-dependent inhibition of neurogenic and inflammatory pain [F (4, 17.5)=60.13 p<0.001]. It also produced a significant dose dependent [F (4, 20)=30.5 p<0.001; F (4, 20)=0.321 p<0.0001] prolongation of the latency and reaction time in the hot plate and tail immersion tests. Peak effect was observed at the highest dose (40 mg/kg). LD50 of the plant was found to be 894 mg/kg. CONCLUSION: M. arboreus possesses potent antinociceptive activity mediated centrally and peripherally, an effect which may justify its traditional use in the management of pain.

Studies on neuropharmacological profile of ethanol extract of Moringa oleifera leaves in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera (family Moringaceae), commonly called Horseradish or tree of life, is traditionally used for the treatment of epilepsy and neurologic conditions. AIM OF THE STUDY: The objective of this study is to investigate the neurobehavioural and anticonvulsant properties of the ethanol extract from the leaves of Moringa oleifera. MATERIALS AND METHODS: Neurobehavioural properties were evaluated using the open field, hole board, Y-maze, elevated plus maze (EPM) and pentobarbitone-induced hypnosis. Pentylenetetrazole (leptazol), picrotoxin and strychnine induced convulsion tests were used to investigate the anti-convulsive actions of Moringa oleifera. RESULTS: The result showed that the extract (250-2000mg/kg) caused a significant dose-dependent decrease in rearing, grooming, head dips and locomotion (P<0.001). It also enhanced learning and memory and increased anxiogenic effect. In addition, the extract (2000mg/kg) protected mice against pentylenetetrazol induced convulsion, but has no effect on picrotoxin and strychnine induced convulsion. The effects of the extract in the various models were comparable to those of the standard drugs used except in Y-maze, EPM and picrotoxin and strychnine induced convulsion. The LD50 obtained for the acute toxicity studied using oral route of administration was >6.4g/kg. CONCLUSION: The findings from this study suggest that the ethanol extract of Moringa oleifera leaves possesses CNS depressant and anticonvulsant activities possibly mediated through the enhancement of central inhibitory mechanism involving release γ-amino butyric acid (GABA). The results partially justified the traditional use of the extract for the treatment of epilepsy.

Jobelyn® pretreatment ameliorates symptoms of psychosis in experimental models.

BACKGROUND: Psychosis is a chronic neurological disorder and it remains a major medical and social problem in most African countries. Individuals with psychotic illness in this region tend to seek help from traditional medical practitioners, who prescribe herbal remedies as alternative forms of treatment for the disease. Jobelyn® (JB) is a commercial polyherbal formulation that has been acclaimed to show beneficial effects in neurological disorders. However, its usefulness in psychosis has not been scientifically validated. Thus, this study was undertaken to evaluate its effects on animal models predictive of human psychosis. METHODS: Antipsychotic activity of JB was assessed based on the inhibition of stereotyped behavior induced by amphetamine or apomorphine in mice. Amphetamine-induced hyperactivity and lethality in aggregated mice were additional tests employed to further evaluate the antipsychotic property of JB. The effect of JB on catalepsy was also assessed, using the inclined plane paradigm. RESULTS: JB (5-50 mg/kg, p.o.) significantly (p<0.05) inhibited stereotypy induced by amphetamine (10.0 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.), which suggests antipsychotic activity. Furthermore, JB (5-50 mg/kg, p.o.) reduced lethality in aggregated mice and inhibited hyperactivity induced by amphetamine, respectively. However, JB (5-50 mg/kg, p.o.) did not cause cataleptic behavior, as it failed to alter the duration of stay of the animals on the inclined plane. CONCLUSIONS: Taken together, these findings suggest that JB exhibits antipsychotic-like activity, devoid of the adverse effect of cataleptic behavior, and may offer some beneficial effects in the symptomatic relief of psychotic ailments.

Ameliorative potential of ethanol extract of Calyptrochilum emarginatum leaves on scopolamine-induced amnesia in male swiss mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Calyptrochilum emarginatum (Afzel. Ex Sw.) Schltr. (Orchidaceae) is a traditional medicinal plant known for its antimicrobial properties and efficacy in managing convulsive fever and menstrual disorders and addressing conditions such as malaria, tuberculosis, and cough. AIM OF THE STUDY: The study aims to examine the memory-enhancing and neuroprotective properties of ethanol extract of Calyptrochilum emarginatum leaves (EECEL) in scopolamine-induced amnesia mice model. MATERIALS AND METHODS: Forty-two male mice were divided into six groups (n = 7). Group 1 served as control, administered distilled water (10 mL/kg, p. o), group 2 received scopolamine only (3 mg/kg, i. p.), groups 3 to 6 received pretreatments of EECEL (50, 100, and 200 mg/kg, p. o.) and donepezil (1 mg/kg, p. o.) 30 min before scopolamine (3 mg/kg), for seven days. Following treatments, behavioral (learning and memory) assessments were carried out, while biochemical (acetylcholinesterase activity, oxidative stress markers, inflammatory cytokines markers) and histological evaluations were done after euthanasia. RESULTS: Scopolamine significantly impaired spatial, long term and recognition memory. Nevertheless, administration of EECEL (50, 100, and 200 mg/kg orally) enhanced memory function in mice, as observed in the Y maze [F (5, 30) = 20.23, p < 0.0001], Morris water maze [F (10, 90) = 3.105, p = 0.0019; [F (5, 30) = 21.13, p < 0.0001]], and novel object recognition tasks [F (5, 30) = 37.22, p < 0.0001)]. Scopolamine-treated mice exhibited significant dysfunction in the cholinergic system, as evidenced by elevated AChE activity [0.099 ± 0.005 vs. 0.063 ± 0.004 mol/min/g] with an elevation in oxidative stress. On the other hand, administration of EECEL counteracted these consequences by reducing AChE activity, mitigating oxidative damage, reducing pro-inflammatory cytokines, and preventing degeneration of neurons. CONCLUSION: The results demonstrated that EECEL effectively mitigates scopolamine-induced memory impairment via an oxido-inflammatory mechanism and modulation of the central cholinergic system.