Ezekiel O. Iwalewa

Neuroprotective effects of the ethanol stem bark extracts of Terminalia ivorensis in ketamine-induced schizophrenia-like behaviors and oxidative damage in mice.

Abstract Context: Schizophrenia is a heterogenous neurological disorder, which has been hypothetically linked to oxidative imbalance and associated behavioral perturbations. Preliminary evidence from animal models predictive of human psychosis suggests that Terminalia ivorensis A. Chev. (Combretaceae) has antipsychotic-like activity in mice. Objective: This study investigates the neuroprotective property of the ethanol stem bark extracts of T. ivorensis (EETI) in reversal treatment of ketamine-induced schizophrenia-like behaviors and oxidative alteration in adult male Swiss albino mice. Materials and methods: Animals were divided into six treatment groups (n = 5). Animals received distilled water or ketamine (20 mg/kg) once daily intraperitoneally (i.p.) for 14 days, and from the 8th to the 14th day, they were treated with EETI (125, 250 or 500 mg/kg), risperidone (RIS) or vehicle orally once daily. Behaviors related to positive (locomotor activity) and cognitive (Y maze) symptoms of schizophrenia were assessed. Glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, including malondialdehyde (MDA) concentration were measured in mice whole brains. Result: The LD50 of EETI was 2236.06 mg/kg, p.o. body weight. EETI (125, 250 or 500 mg/kg, p.o.) demonstrated significant (p < 0.05) inhibition of ketamine-induced hyperlocomotion and cognitive dysfunction. The extract decreased MDA concentration (39.0, 62.6 and 67.5%) in a dose-dependent manner. Moreover, EETI significantly (p < 0.05) reversed the depletion of GSH, and increased activities of SOD and CAT in brain tissues. Discussion and conclusion: These findings suggest that EETI probably exert its antipsychotic-like activity, via a neuroprotective compensatory mechanism of action, and as such, could be relevant in the management of schizophrenia.

Morin Pretreatment Attenuates Schizophrenia-Like Behaviors in Experimental Animal Models

OBJECTIVES Morin is a naturally occurring flavonoid with strong anti-oxidant and anti-inflammatory properties. Studies have shown that flavones modulate neurotransmission through enhancement of gamma amino butyric acid activity in the central nervous system; which led to the hypothesis that they could exert tranquilizing effects in rodents. Hence, this study was designed to evaluate the antipsychotic effect of morin on experimental animal models. METHODS The antipsychotic effect of morin (25, 50 and 100 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced locomotion, apomorphine-induced stereotypy, ketamine-induced stereotypy, ketamine-induced hyperlocomotion and ketamine-enhanced immobility in forced swim test (FST). Catalepsy and rota rod tests were also carried out to evaluate the extrapyramidal side effects of morin. RESULTS Morin (25, 50 and 100 mg/kg, i.p.) pretreatments significantly (p<0.05) demonstrated anti-schizophrenia-like behavior by inhibiting ketamine-induced hyperlocomotion in mice. Moreover, morin (50 and 100 mg/kg, i.p.) significantly (p<0.05) reduced spontaneous locomotor activity. Also, morin suppressed apomorphine-induced stereotypy and ketamine-induced stereotypy. The increase in immobility in FST due to ketamine administration was reduced by morin in a significant dose-dependent manner. Furthermore, the antipsychotic activity of morin was not associated with extrapyramidal side effects, as evidenced by decreased decent latency and increased motoric coordination and performance in mice. CONCLUSION The results of the study revealed that morin demonstrated antipsychotic-like property devoid of extrapyramidal side effects in experimental animal models and may be beneficial in the treatment of schizophrenia-like behaviors; particularly in patients with behavioral hyperactivity and negative symptoms.

Evaluation of the combination of Uvaria chamae (P. Beauv.) and amodiaquine in murine malaria

ETHNOPHARMACOLOGICAL RELEVANCE The leaf and fruit of Uvaria chamae P. Beauv (Annonaceae) are used in antimalarial ethnomedical preparations. Therefore, they were investigated for antimalarial activities as well as possible herb-drug interaction with amodiaquine (AQ). MATERIALS AND METHODS The methanol extracts of the leaf (UCL) and fruit (UCF) were administered orally at 100-800mg/kg/day in mice infected with chloroquine (CQ)-sensitive Plasmodium berghei NK65 using the four-day, curative and prophylactic antimalarial test models. The UCL was further evaluated at 100-800mg/kg as twice-daily doses and combinations of UCL+AQ using the four-day test. Mice infected with CQ-resistant P. berghei ANKA were treated with UCL at 400mg/kg and AQ at 10mg/kg - [UCL400+AQ10]mg/kg - in the four-day and curative test models. RESULT At 800mg/kg/day, UCL, UCF gave chemosuppression of 42, 28% (four-day test), parasite clearance of 36.3, 49.5% on day 5 (curative test) and 64.3, 82.6% (prophylactic test), respectively. The twice-daily dose of UCL at 800mg/kg showed activity of 51.50% while the combination of [UCL200+AQ5]mg/kg exhibited chemosuppression of 91.66%, which was not significantly different (p>0.05) from AQ at 10mg/kg (85.41%). In the CQ-resistant P. berghei experiment, the combination gave a chemosuppression of 45.80%, significantly lower (p<0.05) than AQ (78.40%) while the parasite clearance was not significantly different from AQ (curative test). CONCLUSION The leaf extract showed moderate chemosuppressive activity. The lower-dose combination of the leaf extract and amodiaquine had better antimalarial activity in CQ-sensitive murine malaria. However, the tested combination had no beneficial antimalarial effect in CQ-resistant murine malaria.

Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways

The involvement of oxidative, nitrergic, cholinergic and inflammatory alterations have been reported to contribute to the pathophysiology of schizophrenia, a debilitating neuropsychiatric disorder. Our previous studies have shown that doxycycline (DOX), a notable member of tetracyclines with proven antioxidant and anti-inflammatory properties, attenuated psychotic-like behaviors induced by apomophine and ketamine (KET) in mice. This present study was designed to further evaluate in detail the ability of DOX and its combination with risperidone (RIS) to prevent and reverse KET-induced schizophrenic-like behaviors and the role of oxidative/nitrergic and cholinergic pathways in mice. In the prevention protocol, mice were treated orally with DOX (25, 50 or 100 mg/kg), RIS (0.5 mg/kg), DOX (50 mg/kg) in combination with RIS, or vehicle for 14 consecutive days. In addition, the animals received intraperitoneal injection of KET (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or vehicle for 14 days prior to DOX, RIS, DOX in-combination with RIS or vehicle treatments. Schizophrenic-like behaviors consisting of positive, negative and cognitive symptoms were evaluated using open field, social interaction, Y-maze and novel object recognition tests. Thereafter, the brain levels of biomarkers of oxidative stress, nitrite and acetylcholinesterase activity were determined. DOX given alone or in combination with RIS attenuated schizophrenic-like behaviors induced by chronic injection of KET in both preventive and reversal treatment protocols. DOX significantly increased glutathione, superoxide dismutase and catalase levels in the brain of chronic KET-treated mice. However, it decreased malonyladehyde, nitrite levels and acetylcholinesterase activity when given alone or in-combination with RIS in both protocols. Taken together, these findings showed that doxycycline ameliorated schizophrenic-like behaviors induced by ketamine in both preventive and reversal treatment protocols in mice via inhibition of oxidative and nitrergic alterations, and acetylcholinesterase activity. Our data further suggests that adjunctive oral administration of doxycycline may augment the therapeutic efficacy of risperidone particularly for the treatment of negative and cognitive symptoms associated with schizophrenia.

Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine-induced schizophrenia-like behavior by morin in mice

GABAergic (Gamma-aminobutyric acid) and neurotrophic derangements have important implication in schizophrenia, a neuropsychiatric disease. Previous studies have shown that nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) alters GABAergic and neurotrophic activities via inflammatory and oxidative pathways. Thus, it has been proposed that agents with anti-oxidant and anti-inflammatory properties might be beneficial for the treatment of the disease. Morin is neuroactive bioflavonoid compound, which has been reported to demonstrate antipsychotic and anti-oxidant/anti-inflammatory activities. In this study, we further evaluated its effects on the brain markers of GABAergic, neurotrophic and oxidative alterations in the preventive and reversal of schizophrenia-like behavior induced by ketamine (KET). In the prevention protocol, adult mice were treated intraperitoneally with morin (100 mg/kg/day), haloperidol (1 mg/kg/day), risperidone (0.5 mg/kg/day), or saline (10 mL/kg/day) for 14 consecutive days. In addition, the animals were administered KET (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or saline for 14 days. From 8th to 14th days mice were additionally treated with morin, haloperidol, risperidone or saline. Schizophrenic-like behaviors consisting of positive (stereotypy test), negative (behavioral despair in forced swim test) and cognitive (novel-object recognition test) symptoms were evaluated. Afterwards, brain levels of biomarkers of GABAergic (Glutamic acid decarboxylase-67, GAD67), neurotrophic (Brain-derived neurotrophic factor, BDNF) and oxidative [NADPH-oxidase, superoxide dismutase, (SOD) and catalase (CAT)] alterations were determined in the striatum, prefrontal cortex (PFC) and hippocampus, respectively. Morin significantly (p < 0.05) prevented and reversed KET-induced increased stereotypy, behavioral despair and deficit in cognitive functions when compared with KET-treated mice respectively. Also, morin and risperidone but not haloperidol, significantly (p < 0.05) prevented and reversed the decreases in expressions of GAD67 and BDNF immunoreactivity in the striatum, PFC and hippocampus caused by KET. Moreover, morin and risperidone significantly (p < 0.05) decreased regional brain expressions of NADPH-oxidase immunopositive cells and increased endogenous anti-oxidant enzymes (SOD and CAT) in the striatum, PFC and hippocampus relative to KET controls respectively. Taken together, these findings further suggest that the antipsychotic-like activity of morin may be mediated via mechanisms related to enhancement of GABAergic neurotransmission and neurotrophic factor, and suppression of NADPH-oxidase induced oxidative damage in mice.

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.

Evaluation of the Neurobehavioral Properties of Naringin in Swiss Mice

OBJECTIVES This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice. METHOD The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test. RESULTS Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice. CONCLUSION These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice.