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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.
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Adaptation to psychosocial stress is psychologically distressing, initiating/promoting comorbidity with alcohol use disorders. Emerging evidence moreover showed that ethanol (EtOH) exacerbates social-defeat stress (SDS)-induced behavioral impairments, neurobiological sequelae, and poor therapeutic outcomes. Hence, this study investigated the effects of geraniol, an isoprenoid monoterpenoid alcohol with neuroprotective functions on EtOH escalated SDS-induced behavioral impairments, and neurobiological sequelae in mice. Male mice chronically exposed to SDS for 14 days were repeatedly fed with EtOH (2 g/kg, p. o.) from days 8-14. From days 1-14, SDS-EtOH co-exposed mice were concurrently treated with geraniol (25 and 50 mg/kg) or fluoxetine (10 mg/kg) orally. After SDS-EtOH translational interactions, arrays of behavioral tasks were examined, followed by investigations of oxido-inflammatory, neurochemicals levels, monoamine oxidase-B and acetylcholinesterase activities in the striatum, prefrontal-cortex, and hippocampus. The glial fibrillary acid protein (GFAP) expression was also quantified in the prefrontal-cortex immunohistochemically. Adrenal weights, serum glucose and corticosterone concentrations were measured. EtOH exacerbated SDS-induced low-stress resilience, social impairment characterized by anxiety, depression, and memory deficits were attenuated by geraniol (50 and 100 mg/kg) and fluoxetine. In line with this, geraniol increased the levels of dopamine, serotonin, and glutamic-acid decarboxylase enzyme, accompanied by reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal-cortex, hippocampus, and striatum. Geraniol inhibited SDS-EtOH-induced adrenal hypertrophy, corticosterone, TNF-α, IL-6 release, malondialdehyde and nitrite levels, with increased antioxidant activities. Immunohistochemical analyses revealed that geraniol enhanced GFAP immunoreactivity in the prefrontal-cortex relative to SDS-EtOH group. We concluded that geraniol ameliorates SDS-EtOH interaction-induced behavioral changes via normalization of neuroimmune-endocrine and neurochemical dysregulations in mice brains.
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Monoterpenos Acíclicos , Etanol , Estresse Psicológico , Terpenos , Animais , Monoterpenos Acíclicos/farmacologia , Monoterpenos Acíclicos/uso terapêutico , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/complicações , Camundongos , Etanol/toxicidade , Etanol/farmacologia , Terpenos/farmacologia , Terpenos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Derrota SocialRESUMO
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.
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Etanol , Esquizofrenia , Animais , Masculino , Camundongos , Acetilcolinesterase/metabolismo , Antipsicóticos/farmacologia , Etanol/farmacologia , Ketamina/efeitos adversos , Receptores de N-Metil-D-Aspartato , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismoRESUMO
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.
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Antipsicóticos , Ketamina , Transtornos Psicóticos , Esquizofrenia , Anfetamina , Animais , Antipsicóticos/farmacologia , Apomorfina/farmacologia , Etanol/uso terapêutico , Ketamina/farmacologia , Masculino , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/prevenção & controle , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controleRESUMO
INTRODUCTION: Lead is the most used nonphysiological neurotoxic heavy metal in the world that has been indicated to interfere with the cognitive and noncognitive processes via numerous mechanisms. The neuroprotective effect of melatonin is well known, but the effect of its interaction with lead in the brain remains inconclusive. OBJECTIVE: To assess the therapeutic role of melatonin on cognitive deficit, anxiety and depressive-like symptoms in matured male Wistar rats exposed to a subchronic lead chloride (PbCl2 ). METHODS: Twenty male Wistar rats were blindly randomized into four groups (n = 5/group): group 1 to 4 underwent intragastric administration of physiological saline (10 ml/kg; vehicle), PbCl2 (50 mg/kg), melatonin (10 mg/kg) and PbCl2 + melatonin respectively for a period of 4 weeks during which neurobehavioral data were extracted, followed by neurochemical and histopathological evaluations. RESULTS: Exposure to PbCl2 reduced cognitive performance by increasing the escape latency and average proximity to the platform zone border, decreasing average path length in the platform zone, cognitive score, and time spent in probing. It raised the thigmotaxis percentage, time spent in rearing, number of pellet-like feces, and time spent in the dark compartment of a bright/dark box which are predictors of anxiety. It also induced depressive-like behavior as immobility time was enhanced. PbCl2 deranged neurochemicals; malondialdehyde, interlukin-1ß, and tumor necrotic factor-α were increased while superoxide dismutase and acetylcholinesterase were decreased without remarkable alteration in reduced glutathione and nitric oxide. Administration of PbCl2 further disrupted neuronal settings of hippocampal proper and dentate gyrus. In contrast, the supplementation of melatonin reversed all the neurological consequences of PbCl2 neurotoxicity by eliciting its properties against oxidative and nonoxidative action of PbCl2 . CONCLUSION: These findings suggest that melatonin down-regulates neurotoxicant interplays in the brain systems. Therefore, this study suggests the use of melatonin as an adjuvant therapy in neuropathological disorders/dysfunctions.