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.

Acute and subacute toxicological evaluation of the ethanol leaf extract of Morus mesozygia stapf. (Moraceae) in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the Morus mesozygia tree leaf has been used to manage maladies such as peptic ulcer, hyperglycemia, dermatitis, rheumatism, stomach-ache, arthritis, cough, malignancies, and malaria in parts of Africa. AIM OF THE STUDY: The study aimed to evaluate the potential of ethanol leaf extract of Morus mesozygia (EEMm) to induce toxicity by employing both acute and sub-acute oral toxicity experimental models. MATERIAL AND METHODS: The extract's cytotoxicity was studied using brine shrimps (Artemia salina) lethality assay (BSLA), while in the acute toxicity test, male and female mice were administered a single oral dose of EEMm (2000 mg/kg). Male and female Wistar rats received repeated doses of 100 or 500 mg/kg EEMm orally for 28 days in the sub-acute toxicity experiment. The phytochemical analysis of EEMm was done using the HPLC. RESULTS: The BSLA revealed a moderate cytotoxic potential of the extract, with an LC50 of 567.13 ± 0.27 µg/mL. All the animals survived the acute toxicity test, with no significant changes in the relative organ weights, suggesting that LD50 is greater than 2000 mg/kg. The animal weights did not vary significantly in the sub-acute toxicity test neither were the alterations in biochemical and hematological tests pronounced, although the histoarchitectures of the kidney, liver and spleen indicated slight anomalies in the evaluated animals. The HPLC analysis revealed the presence of quercetin, ferulic acid, rutin, caffeic acid, morin and gallic acid. CONCLUSIONS: Ethanol leaf extract of Morus mesozygia demonstrated a safe toxicity profile in rodents, supporting its broad folkloric use in African ethnomedicine.

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.

Ameliorating Effect of Morin Hydrate on Chronic Restraint Stress-induced Biochemical Disruption, Neuronal, and Behavioral Dysfunctions in BALB/c Mice.

Introduction: Morin hydrate (MH) is a bioflavonoid component of many fruits and vegetables. Our previous research demonstrated that MH provides neuroprotection in mouse models of acute restraint stress and sleep deprivation by attenuating hippocampal neuronal damage and enhancing memory. Based on these findings, our study investigated the role of MH in chronic stress-induced neuronal and biochemical perturbations in BALB/c mice. Methods: Male BALB/c mice were divided into 6 groups (n=6). Groups 1 and 2 received vehicle (10 mL/kg normal saline), groups 3-5 received MH (5, 10, 20 mg/kg IP), while group 6 received ginseng (25 mg/kg) daily and 30 minutes afterward were restrained in a plastic cylindrical restrainer for 14 days. Results: Immobility time in the forced swim test increased in the MH-treated group, indicating an antidepressant-like effect. Also, a reduction in frequency and duration of open arms exploration was observed in the elevated plus-maze (EPM) test in stressed mice, and administration of MH (5, 10, 20 mg/kg, IP) reversed these effects. An increase in blood levels of glucose, triglycerides, total cholesterol, and brain malondialdehyde and nitrite levels was observed in the stressed groups, which was reversed by MH. Furthermore, MH reversed the stress-induced reduction in HDL cholesterol and glutathione (GSH) levels and attenuated stress-induced alterations in the prefrontal cortex and hippocampus. Conclusion: Our findings suggest that MH attenuated chronic restraint stress-behavioral and biochemical perturbations, probably due to its capability to decrease oxidative stress and brain neuronal damage. Highlights: Chronic stress perturbs physiological and psychological homeostasis;Morin hydrate normalized chronic stress-induced biochemical disruptions;Morin hydrate attenuated structural changes in prefrontal cortex and hippocampus. Plain Language Summary: Stress is a state of being overwhelmed by demands exceeding the personal and social means of coping. Exposure to excessive stress has resulted in disruption of neurochemical and physiological processes, which sometimes manifest as behavioural abnormalities. Therefore to cope with the stressful life style, there is need to develop a therapeutic agent of plant origin. Morin hydrate is a flavonoid with known antioxidant and neuroprotective properties; however, its effect in a stressful condition has not been studies. The study thus evaluated ameliorating effect of Morin hydrate on chronic restraint stress-induced biochemical disruption, neuronal and behavioral dysfunctions in BALB/c mice. To achieve this, mice were exposed to chronic restraint stress protocol for fourteen days. Behavioural changes were examined using various techniques. The vital parameters like antioxidant, glucose and nitrite levels were also taken. Our findings show that Morin hydrate prevented behavioral abnormalities and damage to the brain cells. It also inhibited stress-induced biochemical disturbance.

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.

Morus mesozygia leaf extract ameliorates behavioral deficits, oxidative stress and inflammation in Complete Freund's adjuvant-induced arthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Morus mesozygia Stapf (Moraceae), otherwise referred to as African mulberry, is utilized domestically as a remedy for a variety of inflammatory disorders including rheumatism. AIM: The anti-arthritic effect of the ethylacetate fraction of M. mesozygia leaf extract (EAFMm) was assessed on complete Freund's adjuvant (CFA)-induced arthritis in male Wistar rats. METHOD: Groups of male Wistar rats were injected with CFA (0.2 mL; 10 mg/mL) in the plantar surface of their right hind paws and treated orally with EAFMm (50 and 100 mg/kg) or its vehicle daily for 28 days. The effect on joint inflammation and mechanical nociception threshold, behavioral deficits (spontaneous motor activity in the open field test and depressive-like symptoms in the forced swim test) was evaluated. The levels and activities of the biomarkers of oxidative-nitrosative stress (reduced glutathione, superoxide dismutase, nitrite, and malondialdehyde) and inflammatory markers [TNF-α, IL-6, COX-2, NFκB and myeloperoxidase] were also analysed. RESULTS: The EAFMm at the doses of 50 and 100 mg/kg produced a dose dependent reduction in joint inflammation and mechanical hyperalgesia, and as well improved behavioral deficits like spontaneous motor activity and depressive-like behavior. The EAFMm also significantly reduced oxido-nitrosative stress response in the joint and brain tissues. It also decreased TNF-α, interleukin-6 levels and myeloperoxidase enzyme activities in joints and brain tissues of rats. Furthermore, EAFMm attenuated the activity of NFκB and reduced the cyclooxygenase -2 protein expression level in joint tissues. CONCLUSION: The ethylacetate fraction of Morus mesozygia leaf extract demonstrated anti-arthritic activity and ameliorated co-morbid depressive-like behavior via inhibition of oxidative stress and inflammation in a rat model of arthritis.

Jobelyn® extends the life span and improves motor function in Drosophila melanogaster exposed to lipopolysaccharide via augmentation of antioxidant status.

Jobelyn® (JB), a dietary supplement, derived from polyphenol-rich leaf sheath of Sorghum bicolor, has been reported to attenuate sensorimotor deficits and oxidative stress evoked by complete Freund-adjuvant in mice. This present study evaluated its effects on the life span, motor function and changes in oxidative stress parameters as well as acetylcholinesterase activity in Drosophila melanogaster exposed to lipopolysaccharide (LPS). The flies (50 per vial), in 5 replicates were fed with LPS (250 µg/kg diet) alone or in combination with JB (0.25-1.0 mg/kg diet) daily for 7 days. The mortality rate and motor function were evaluated on day 7. The flies were afterwards processed for determination of oxidative stress parameters and acetylcholinesterase activity. The effects of JB (0.25-1.0 mg/g diet) on the longevity of Drosophila was also investigated wherein the flies were monitored daily for mortality throughout their lifespan. The flies exposed to LPS (250 µg/kg diet) had reduced life span and elevated oxidative stress when compared with control. However, JB (0.25 and 1.0 mg/kg diet) improved the motor function and also reduced the mortality rate of the flies exposed to LPS. It also restored the cellular antioxidant status and reduced acetylcholinesterase activity, accumulation of hydrogen peroxide as well as nitric oxide in Drosophila fed with LPS. JB also extended the longevity of the flies relative to control. The findings that JB improves motor function and extended the lifespan of Drosophila flies by boosting the antioxidant status and cholinergic function, suggest it might be helpful in delaying the onset of neuropsychiatric illnesses associated with the aging processes.

The antioxidant and neuroprotective effects of the Psychotria camptopus Verd. Hook. (Rubiaceae) stem bark methanol extract contributes to its antiepileptogenic activity against pentylenetetrazol kindling in male Wistar rats.

A substantial number of epileptic patients are resistant to the current medication thus necessitating the search for alternative therapies for intractable forms of the disease. Previous studies demonstrated the acute anticonvulsant properties of the methanol extract of the stem bark of Psychotria camptopus (MEPC) in rats. This study investigated the effects of MEPC on pentylenetetrazole-kindled Wistar rats. Kindling was induced by intraperitoneal injection of pentylenetetrazole (37.5 mg/kg) on every alternate day, 1 h after each daily oral pretreatment of rats (8 ≤ n ≤ 10) with MEPC (40, 80 and 120 mg/kg), vehicle or diazepam (3 mg/kg) for 43 days. The kindling development was monitored based on seizure episodes and severity. Rats' brains were collected on day 43 for the determination of oxidative stress parameters. The histomorphological features and neuronal cell viability of the prefrontal cortex (PFC) and hippocampus were also assessed using H&E and Cresyl violet stains. Chronic administration of pentylenetetrazole time-dependently decreased the latency to myoclonic and generalized seizures, and increased seizure scores and the number of kindled rats. MEPC and diazepam significantly increased the latencies to myoclonic jerks and generalized tonic-clonic seizures. These substances also reduced seizure score and the number of rats with PTZ-kindling. MEPC improved glutathione status and decreased lipid peroxidation in the brains of kindled rats. MEPC also exhibited neuroprotection against pentylenetetrazole-induced hippocampal and PFC neuronal damages. These results suggest that P. camptopus has antiepileptogenic activity, which might be related to the augmentation of antioxidant and neuroprotective defense mechanisms, and further confirm its usefulness in the management of epilepsy.

Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice.

Objectives Diosmin (DSM), commonly isolated from various plants, is a citrus nutrient that has been shown to increase intracellular antioxidant capacity and assuage symptoms associated with neurological disorders. Deficiency in the antioxidant system has been implicated in the pathogenesis of schizophrenia. The use of antioxidants as neuroprotectants to suppress schizophrenia pathology is increasingly being sought. Hence, this study investigated the effects of DSM on schizophrenia-like behavior and the underlying changes in biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in mice. Methods The acute antipsychotic effect of DSM (25, 50, and 100 mg/kg, intraperitoneally [i.p.]), haloperidol (1 mg/kg, i.p.), and risperidone (RIS) (0.5 mg/kg, i.p.) was investigated on stereotyped behaviors induced by apomorphine (2 mg/kg, i.p.) and ketamine (10 mg/kg, i.p.). The effect of DSM on ketamine-induced hyperlocomotion, immobility enhancement, and its woodblock cataleptogenic potential was evaluated. Also, the subacute antipsychotic potential of DSM was assessed following intraperitoneal injection of DSM (25-100 mg/kg, i.p.) alone and in combination with ketamine (20 mg/kg, i.p.) for 10 days. The behaviors of the animals were assessed in the open-field, Y-maze, and forced swim tests. Brains of the animals were afterward processed for spectrophotometric assay of oxidative stress and AChE contents. Results DSM (25, 50, and 100 mg/kg) attenuated apormorphine-induced stereotypy and devoid of cataleptogenic effect. DSM and RIS reversed acute and subacute ketamine-induced schizophrenia-like behaviors. Disomin alone increased cognitive function and reduced despair-like phenotype. Furthermore, DSM increased superoxide dismutase and glutathione and decreased malondialdehyde and AChE levels in naïve and ketamine schizophrenic mice. Conclusions DSM prevents schizophrenia-like behavior, attenuates oxidative stress, and AChE activity in naïve and ketamine schizophrenic mice.

Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention by treatment with a neuroactive flavonoid, morin.

Psychosocial stress and biological predispositions are linked to mood and personality disorders related to psychiatric behaviors. Targeting neuroinflammation and oxidative stress has been recognized as a potential strategy for the prevention of psychosocial stress-induced psychiatric disorders. Morin, a bioactive compound isolated from mulberry leaf has been shown to produce antiamnesic, antipsychotic and anti-inflammatory effects relative to ginseng, a well-known adaptogen. Hence, the present study investigated the effect of morin on social-defeat stress (SDS)-induced behavioral, neurochemical, neuroimmune and neurooxidative changes in mice using intruder-resident paradigm. The intruder male mice were distributed into 6 groups (n = 10). Groups 1 (normal-control) and 2 (SDS-control) received normal saline, groups 3-5 had morin (25-100 mg/kg) while group 6 received ginseng (50 mg/kg) intraperitoneally daily for 14 days. Thirty minutes after treatment from days 7-14 onwards, mice in groups 2-6 were exposed to SDS for 10 min physical and psychological confrontations respectively with aggressive-resident mice. Neurobehavioral effects (locomotor activity, cognitive performance, anxiety- and depressive-like behavior) were assessed on day 14. Biomarkers of oxidative/nitrergic stress and neuroinflammation; acetylcholinesterase (AChE) and glutamic-acid decarboxylase-67 (GAD67) were measured in the striatum, prefrontal-cortex and hippocampus. Behavioral deficits induced by SDS were attenuated by morin and ginseng. Both morin and ginseng decreasedmalondialdehyde, nitrite levels and increased glutathione concentrations in the brain regions. They also reduced inflammatory mediators (TNF-α, IL-6, COX-2 and NF-κB), AChE activity and Nox-2 expression in the specific brain regions. However, morin increased the levels of GAD67 in the striatum, prefrontal-cortex and hippocampus in contrast to ginseng. Our results suggest that morin mitigates SDS-induced neurobehavioral deficits through enhancement of GAD67, inhibition of AChE activity, oxidative stress, Nox-2 and neuroinflammatory pathways.

Anti-nociceptive and anti-inflammatory activities of ethanol extract and fractions of Morus mesozygia Stapf (Moraceae) leaves and its underlying mechanisms in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Morus mesozygia Stapf (Moraceae), commonly known as African mulberry, is traditionally used for the treatment of inflammatory disorders such as rheumatism and dermatitis. AIM: This work aimed to evaluate the anti-nociceptive and anti-inflammatory effects of its ethanol (EEMm) extract, and ethylacetate fraction (EAFMm). METHODS: The anti-nociceptive and anti-inflammatory effect of ethanol extracts of M. mesozygia (EEMm), and its ethylacetate (EAFMm) and residual aqueous fraction (RAFMm) was evaluated in hotplate, acetic acid and formalin tests and as well in membrane stabilizing assay and carrageenan-induced paw oedema models. Mechanism of anti-inflammation of EAFMm was investigated in the carrageenan-induced air-pouch model. RESULTS: In the hot plate test of nociception, only the EAFMm showed significant (p < 0.05) anti-nociceptive activity. The extract and fractions significantly reduced number of writhing with EAFMm (400 mg/kg) showing highest inhibition (66.5%) in the acetic acid-induced writhing in mice. EEMm and EAFMm (400 mg/kg) significantly reduced the paw licking time in the early and late phases of the formalin test. The extract and fractions showed good membrane stabilizing activity comparable to indomethacin. EAFMm (100 and 400 mg/kg) showed the highest inhibition of paw oedema (53.4% and 58.1%) in the carrageenan-induced paw oedema model. The EAFMm (100 and 400 mg/kg) reduced exudate volume relative to carrageenan-control (2.64 ± 0.22, 2.08 ± 0.15 vs 3.83 ± 0.18 mL) and neutrophils (8.98 ± 1.36, 8.00 ± 0.22 vs 20.51 ± 1.14) in carrageenan-induced pouch. EAFMm significantly reduced exudate volume, pro-inflammatory cytokines and the expression of COX-2 and NFκB. CONCLUSION: M. mesozygia leaves demonstrated anti-nociceptive and anti-inflammatory activities by suppressing oxidative stress, pro-inflammatory cytokines, cyclooxygenase-2, and nuclear factor kappa B.

Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice.

OBJECTIVES: Diosmin (DSM), commonly isolated from various plants, is a citrus nutrient that has been shown to increase intracellular antioxidant capacity and assuage symptoms associated with neurological disorders. Deficiency in the antioxidant system has been implicated in the pathogenesis of schizophrenia. The use of antioxidants as neuroprotectants to suppress schizophrenia pathology is increasingly being sought. Hence, this study investigated the effects of DSM on schizophrenia-like behavior and the underlying changes in biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in mice. METHODS: The acute antipsychotic effect of DSM (25, 50, and 100 mg/kg, intraperitoneally [i.p.]), haloperidol (1 mg/kg, i.p.), and risperidone (RIS) (0.5 mg/kg, i.p.) was investigated on stereotyped behaviors induced by apomorphine (2 mg/kg, i.p.) and ketamine (10 mg/kg, i.p.). The effect of DSM on ketamine-induced hyperlocomotion, immobility enhancement, and its woodblock cataleptogenic potential was evaluated. Also, the subacute antipsychotic potential of DSM was assessed following intraperitoneal injection of DSM (25-100 mg/kg, i.p.) alone and in combination with ketamine (20 mg/kg, i.p.) for 10 days. The behaviors of the animals were assessed in the open-field, Y-maze, and forced swim tests. Brains of the animals were afterward processed for spectrophotometric assay of oxidative stress and AChE contents. RESULTS: DSM (25, 50, and 100 mg/kg) attenuated apormorphine-induced stereotypy and devoid of cataleptogenic effect. DSM and RIS reversed acute and subacute ketamine-induced schizophrenia-like behaviors. Disomin alone increased cognitive function and reduced despair-like phenotype. Furthermore, DSM increased superoxide dismutase and glutathione and decreased malondialdehyde and AChE levels in naïve and ketamine schizophrenic mice. CONCLUSIONS: DSM prevents schizophrenia-like behavior, attenuates oxidative stress, and AChE activity in naïve and ketamine schizophrenic mice.

Involvement of l-arginine-nitric oxide pathway in the antidepressant and memory promoting effects of morin in mice.

l-Arginine-nitric oxide pathway has been reported to be involved in the mediation of the psychopharmacological effects of many psychotropic drugs. Previous studies have shown that morin, a psychotropic compound isolated from mulberry leaf produces functional psychopharmacological effects indicative of antidepressant, antipsychotic, anxiolytic and nootropic properties. However, the role of l-arginine-nitric oxide pathway in the psychotropic effects of morin has not been fully investigated, hence, the need for this study. Male Swiss mice were pretreated individually or in combination with nitric oxide precursor [l-arginine (750 mg/kg, i.p.)], competitive nonselective nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methyl ester (l-NAME, i.p) (50 mg/kg)] or selective neuronal NOS inhibitor [methylene blue (3.75 mg/kg, i.p)] prior to morin (100 mg/kg, i.p.) or saline (10 mL/kg, i.p.) treatment. Psychopharmacological activities were then evaluated 30 min later using open field, Y-maze, and forced swim tests. l-Arginine significantly reversed the effects of morin on locomotion, memory and depression in mice. The reduced motor activity and enhanced memory function produced by morin were significantly attenuated by methylene blue but augmented the antimobility activity of morin in the FST. Moreover, l-NAME potentiated the psychopharmacological effects of morin in the open field and forced swim tests but reduced its memory promoting effect. Meanwhile, morin supplementation reversed the effects of l-arginine on l-NAME-treated mice in all behavioral models. The results of this study suggest that l-arginine-nitric oxide pathway might play a role in the modulation of the antidepressant and memory promoting effects of morin in mice.

Evaluation of neurotoxicity and hepatotoxicity effects of acute and sub-acute oral administration of unripe ackee (Blighia sapida) fruit extract.

Ackee (Blighia sapida) is a commonly eaten fruit that is indigenous to West Africa and Jamaica. Ackee poisoning in young children have been reported in parts of Nigeria due to consumption of the unripe fruits. This study was designed to identify potential mechanisms of acute and sub-acute toxicity of unripe B. sapida fruit extract (BSE). Acute toxic effect was investigated in mice of either sex administered BSE 2000 mg/kg. The sub-acute toxicity effects were investigated in mice of either sex that received 28 days repeated administration of BSE (100 and 500 mg/kg, p.o.). Locomotor activity and memory performance were measured as well as seizure vulnerability in PTZ-induced model. Liver enzymes were assessed in the serum. Acetylcholinesterase, oxidative stress parameters and histopathological changes were assessed in the brain and liver tissues. Signs and symptoms of toxicity such as urination, tremor, depressed locomotion and death were observed in acute toxicity test. Sub-acute dosing caused significant impairment in locomotor activity and memory performance in mice. Seizure threshold was shortened in BSE-treated compared to control mice. Brain acetylcholinesterase activity was significantly increased. Alkaline phosphatase (ALP) was significantly elevated in mice that received BSE (500 mg/kg). Furthermore, BSE caused significant increase in oxidative stress expressed in nitrite, malondialdehyde, reduced glutathione and catalase in the brain and liver tissues. Histological staining revealed neuronal damage of brain hippocampus and hepatocellular swelling and necrosis. Blighia sapida unripe fruit extract increased susceptibility to seizure and impaired locomotor and memory function. The biochemical and histopathological findings revealed potential toxicity mechanisms related to neurotoxicity and hepatotoxicity.

Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia.

Neuroinflammation plays a prominent role in the pathophysiology and progression of schizophrenia. Thus, suppression of neuroinflammation may retard the progression of the disease. This study was designed to investigate whether morin, a bioactive compound with antipsychotic-like activity could reduce biomarkers of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)- and ketamine (KET)-induced schizophrenic-like behavior in mice. Animals were treated once daily intraperitoneally with morin (100 mg/kg), haloperidol (1 mg/kg), risperidone (0.5 mg/kg), or saline (10 mL/kg) in combination with LPS (0.1 mg/kg) for 14 consecutive days. However, from days 8-14, overt schizophrenia-like episode was produced with i.p. injection of KET (20 mg/kg) once daily. Schizophrenic-like behaviors: positive (open-field test), negative (social-interaction and social-memory tests) and cognitive (Y-maze test) symptoms were assessed on day 14. Thereafter, the levels and expressions of biomarkers of neuroinflammation were estimated in the striatum (ST), prefrontal cortex (PFC) and hippocampus (HC) using spectrophotometry, ELISA and immunohistochemistry. The effects of morin on cortical pyramidal neurons were estimated using Golgi-impregnation staining technique. LPS in combination with KET significantly (p < 0.05) induced schizophrenia-like behaviors, which was attenuated by morin. Morin significantly (p < 0.05) decreased tumor necrosis factor-α, interleukine-6 levels and myeloperoxidase activity in the ST, PFC and HC of mice treated with LPS + KET. Moreover, morin reduced regional brain expressions of cyclooxygenase-2, inducible nitric oxide synthase and nuclear factor kappa-B, and also rescued loss of pyramidal neurons in the PFC. Taken together, these findings suggest that morin reduces schizophrenic-like symptoms induced by LPS + KET via mechanisms related to inhibition of the release of pro-inflammatory mediators and suppression of degeneration of cortical pyramidal neurons in mice.

Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice.

Rapid eye movement sleep deprivation distorts the body's homeostasis and results in oxidative breakdown which may be responsible for a variety of neurological disorders. Some naturally occurring compounds of plant origin with antioxidant and neuroprotective properties are known to attenuate the detrimental effects of REM sleep deprivation. Morin hydrate, a flavonoid from Mulberry has demonstrated antioxidant and neuroprotective activities but its effect in sleep disturbed mice is unknown. The study was designed to explore the neuroprotective effect of Morin hydrate on 48 h. REM sleep deprivation-induced behavioural impairments and neuronal damage in mice. Mice were allotted into six treatment groups (n = 6): groups 1 and 2 received vehicle (10 ml/kg normal saline), groups 3-5 received Morin hydrate (5, 10, 20 mg/kg i.p) while group 6 received ginseng (25 mg/kg) which served as the reference drug. Treatment was performed daily for 5 days and animals were sleep-deprived on the last 48 h. Various behavioural tests (Elevated plus maze, Y-maze, locomotor activity) followed by oxidative parameters (malondialdehyde, nitric oxide, reduced glutathione) and histolopathological changes in the Cornu ammonis 1 (CA1) region of the hippocampus were assessed. Data were analysed using ANOVA at α0.05. Morin hydrate (5, 10, 20 mg/kg) significantly enhanced memory performance, improves anxiolytic-like behaviour, reverses hyperlocomotion, restored depleted reduced glutathione, attenuated raised malondialdehyde and nitric oxide levels as compared to control animals and protects against loss of hippocampal neurons. Results of this present study suggest that Morin hydrate possess neuroprotective effects against sleep deprivation-induced behavioural impairments, oxidative stress and neuronal damage.

Possible neuroprotective mechanisms of action involved in the neurobehavioral property of naringin in mice.

Flavonoids are naturally occurring bioactive phytochemical metabolites widely known to prevent and suppress several human diseases, and are important sources of therapeutic compounds from plants. Evidence derived from previous studies suggests that naringin, a neuroactive flavonoid possess functional beneficial neurobehavioral effects including anxiolytic, antidepressant and memory enhancing properties. However, literature search revealed that no studies have been carried out to evaluate the possible biochemical mechanisms involved in the neurobehavioral property of naringin alone following repeated treatment. Hence, this study was designed to evaluate the possible neuro-biochemical mechanisms involved in the neurobehavioral property of naringin following repeated administration in mice. The effects of naringin (2.5, 5 and 10 mg/kg), diazepam (2 mg/kg), imipramine (15 mg/kg) and donepezil (1 mg/kg) or vehicle on neurobehavioral and biochemical effects were evaluated in mice following repeated intraperitoneal injection for 7 consecutive days. Neurobehavioral activities consisting of open-field (locomotor), elevated-plus maze (anxiolytic), forced swim and social interaction (antidepressant and social preference), and Y-maze (memory enhancing) tests were assessed. Thereafter, brains levels of biomarkers of oxidative, nitrosative and cholinergic parameters were determined. Repeated treatment with naringin produced increased locomotor activity, and demonstrated antidepressant-like effects evidenced by decreased immobility time in forced swim test and increased % social preference in the social interaction test relative to controls. Also, naringin induced anxiolytic-like effect and increased cognitive performance in mice. Mechanistically, naringin significantly increased the activities of superoxide dismutase and catalase, and glutathione concentration relative to vehicle-controls. However, naringin significantly decreased malondialdehyde and nitrite contents, and reduced brain acetylcholinesterase activity in mice brains in a significant manner relative to controls. Taken together, these findings suggest that treatment with naringin might be useful to produce functional behavioral effects via mechanisms related to enhancement of cholinergic transmission, antioxidant defense systems, inhibition of lipid peroxidation and nitrosative processes.

Probable mechanisms involved in the antipsychotic-like activity of morin in mice.

Evidence derived from preliminary studies suggests that morin, a neuroactive flavonoid with proven antioxidant and antiinflammatory properties possess antipsychotic-like activity. The present study was designed to evaluate the probable mechanisms involve in the antipsychotic-like activity of morin in ketamine model of schizophrenia. The effects of morin, haloperidol and risperidone on neurobehavioral and anti-schizophrenia-like effects were evaluated in mice (n = 7) following intraperitoneal (i.p.) administration of morin (25-100 mg/kg), haloperidol (1 mg/kg) and risperidone (0.5 mg/kg) alone or in combination with ketamine (20 mg/kg, i.p.) for 10 days. Neurobehavioral and schizophrenia-like activities consisting of open-field (positive symptoms), Y-maze, novel-object recognition (cognitive symptoms), social interaction (negative symptoms) tests were assessed. Also, wood-block catalepsy and rota-rod tests were employed to evaluate extrapyramidal side effects of morin. Thereafter, brain levels of biomarkers of oxidative, nitrergic and acetylcholinesterase alterations as well as histomorphological changes in the striatum and prefrontal-cortex were determined. Administration of morin and risperidone alone but not haloperidol significantly (p > 0.05) prevented ketamine-induced hyperlocomotion, social withdrawal and cognitive impairments relative to controls, and were devoid of extrapyramidal side effects. Morin alone or in combination with ketamine significantly increased glutathione concentration, superoxide dismutase and catalase activities compared with saline- or ketamine-treated mice. Moreover, morin alone or in combination with ketamine also significantly decreased malondialdehyde, nitrite and acetylcholinesterase alterations in mice brains. Furthermore, morin prevented ketamine-induced brain neuronal alterations in the striatum and prefrontal-cortex. Together, our findings suggest that morin may demonstrate antipsychotic-like therapeutic effect via modulation of oxidative/nitrergic, cholinergic actions and neuroprotection.