Taurine, an essential ß-amino acid insulates against ketamine-induced experimental psychosis by enhancement of cholinergic neurotransmission, inhibition of oxidative/nitrergic imbalances, and suppression of COX-2/iNOS immunoreactions in mice.

Cholinergic, oxidative, nitrergic alterations, and neuroinflammation are some key neuropathological features common in schizophrenia disease. They involve complex biological processes that alter normal behavior. The present treatments used in the management of the disorder remain ineffective together with some serious side effects as one of their setbacks. Taurine is a naturally occurring essential ß-amino acid reported to elicit antipsychotic property in first episode psychosis in clinical setting, thus require preclinical investigation. Hence, we set out to investigate the effects of taurine in the prevention and reversal of ketamine-induced psychotic-like behaviors and the associated putative neurobiological mechanisms underlying its effects. Adult male Swiss mice were sheared into three separate cohorts of experiments (n = 7): drug alone, preventive and reversal studies. Treatments consisted of saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) with concomitant ketamine (20 mg/kg/i.p./day) injections between days 8-14, or 14 days entirely. Behavioral hyperactivity, despair, cognitive impairment, and catalepsy were measured. Brain oxidative/nitrergic imbalance, immunoreactivity (COX-2 and iNOS), and cholinergic markers were determined in the striatum, prefrontal-cortex, and hippocampus. Taurine abates ketamine-mediated psychotic-like episodes without cataleptogenic potential. Taurine attenuated ketamine-induced decrease in glutathione, superoxide-dismutase and catalase levels in the striatum, prefrontal-cortex and hippocampus. Also, taurine prevented and reversed ketamine-mediated elevation of malondialdehyde, nitrite contents, acetylcholinesterase activity, and suppressed COX-2 and iNOS expressions in a brain-region dependent manner. Conclusively, taurine insulates against ketamine-mediated psychotic phenotype by normalizing brain central cholinergic neurotransmissions, oxidative, nitrergic and suppression of immunoreactive proteins in mice brains.

Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory Mechanisms.

Psychosocial stress has been widely reported to contribute to psychiatric disturbances. Perturbations in the enzymes of GABAergic and cholinergic systems have been implicated as precursors in different stress-related neuropsychiatric diseases. Targeting glutamic acid decarboxylase-67 kDa (GAD67) and acetylcholinesterase (AChE) via oxidative, nitrergic, and neuroinflammatory mechanisms have been recognized as prospective strategies for the prevention of psychosocial stress-induced behavioral impairments. Naringin, a neuro-active flavonoid compound isolated from citrus fruits, has been shown to produce memory-enhancing, antiepileptic, antidepressant, and anti-inflammatory activities similarly to ginseng, a very potent adaptogen. In this communication, we assessed the effect of naringin on social-defeat stress (SDS)-induced behavioral, GABAergic, cholinergic, oxidative, nitrergic, and neuroinflammatory changes in mice using the resident-intruder paradigm. The intruder male mice were culled into six groups. Groups 1 and 2 (normal- and SDS-controls) received sterile saline, groups 3-5 were given naringin (25-100 mg/kg, i.p.) whereas group 6 had ginseng (50 mg/kg, i.p.) daily for 14 days, but followed by 10 min SDS (physical and psychological) exposure to groups 2-6 with aggressor-resident mice. Behavioral effects using Y-maze, elevated-plus maze, sociability, and tail-suspension tests were assessed on day 14. GAD67, AChE enzymes, and biomarkers of oxidative, nitrergic, and neuroinflammatory changes were assayed in the striatum, prefrontal cortex, and hippocampus. Naringin and ginseng reversed all SDS-induced behavioral impairments. Naringin increased the levels of GAD67 and decreased AChE activities in the striatum, prefrontal cortex, and hippocampus. Furthermore, naringin reduced pro-inflammatory cytokines (TNF-α, IL-6), malondialdehyde, nitrite concentrations, and increased glutathione levels in a region-dependent manner. Our study suggests that naringin attenuated SDS-induced behavioral endophenotypes of neuropsychiatric disease through increased GAD67 synthesis, inhibition of AChE activity, oxidative, nitrergic stress, and neuroinflammatory processes in stress-sensitive brain regions.

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.

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.

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.

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.

Possible Mechanisms Involved in Attenuation of Lipopolysaccharide-Induced Memory Deficits by Methyl Jasmonate in Mice.

This present study was carried out to investigate the likely mechanisms by which methyl jasmonate (MJ), 'an agent widely used in aromatherapy for neurological disorders, attenuates lipopolysaccharide (LPS)-induced memory deficits in mice. Mice were given intraperitoneal administration of LPS (250 µg/kg) alone or in combination with MJ (10-40 mg/kg), donepezil, DP (1 mg/kg), or vehicle for 7 successive days. Thereafter, memory was assessed using object recognition test (ORT). Acetylcholinesterase and myeloperoxidase activities were estimated in brain tissue homogenates. Brain levels of nitric oxide and markers of oxidative stress as well as histopathologic changes of the prefrontal cortex and cornu ammonis 1 (CA1) of the hippocampal region were also assessed. MJ (10-40 mg/kg) attenuated LPS-induced memory impairment in ORT. Moreover, the increased brain activities of acetylcholinesterase and myeloperoxidase enzymes were suppressed by MJ when compared with control (p < 0.05). Increased brain oxidative stress and nitric oxide levels in LPS-treated mice were significantly decreased by MJ. It offers protection against LPS-induced neuronal degeneration of the prefrontal cortex and CA1 of the hippocampus, suggesting neuroprotective effect. Taken together, these findings showed that MJ offers protection against LPS-induced memory deficits via mechanisms related to inhibition of acetylcholinesterase, myeloperoxidase, oxidative stress and neuronal degeneration.

Effect of Jobelyn® on intruder- and isolation-induced aggressive behavior in mice.

BACKGROUND: Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn® (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. METHODS: Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p-chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. RESULTS: JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. CONCLUSIONS: These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system.

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.

Evaluation of the effect of jobelyn(®) on chemoconvulsants-induced seizure in mice.

INTRODUCTION: Epilepsy is a common central nervous system (CNS) disorder characterized by seizures resulting from episodic neuronal discharges. The incidence of toxicity and refractoriness has compromised the clinical efficacy of the drugs currently used for the treatment of convulsions. Thus, there is a need to search for new medicines from plant origin that are readily available and safer for the control of seizures. Jobelyn(®) (JB) is a unique African polyherbal preparation used by the natives to treat seizures in children. This investigation was carried out to evaluate whether JB has anti-seizure property in mice. METHODS: The animals received JB (5, 10 and 20 mg/kg, p.o) 30 min before induction of convulsions with intraperitoneal (i.p.) injection of picotoxin (6 mg/kg), strychnine (2 mg/kg) and pentylenetetrazole (85 mg/kg) respectively. Diazepam (2 mg/kg, p.o.) was used as the reference drug. Anti-seizure activities were assessed based on the ability of test drugs to prevent convulsions, death or to delay the onset of seizures in mice. RESULTS: JB (5, 10 and 20 mg/kg, p.o) could only delay the onset of seizures induced by pentylenetetrazole (85 mg/kg, i.p.) in mice. However, it did not did not offer any protection against seizure episodes, as it failed to prevent the animals, from exhibiting tonic-clonic convulsions caused by pentylenetetrazole (85 mg/kg, i.p.), strychnine (2 mg/kg) or picrotoxin (6 mg/kg, i.p.). On the other hand, diazepam (2 mg/kg, i.p.), offered 100% protection against convulsive seizures, induced by pentylenetetrazole (85 mg/kg, i.p.). However, it failed to prevent seizures produced by strychnine (2 mg/kg, i.p.) or picrotoxin (6 mg/kg, i.p.). DISCUSSION: Our results suggest that JB could not prevent the examined chemoconvulsants-induced convulsions. However, its ability to delay the latency to seizures induced by pentylenetetrazole suggests that JB might be effective in the control of the seizure spread in epileptic brains.