Increased Brain-Derived Neurotrophic Factor and Hippocampal Dendritic Spine Density Are Associated with the Rapid Antidepressant-like Effect of Iron-citalopram and Iron-Imipramine Combinations in Mice.

Iron supplementation previously demonstrated antidepressant-like effects in post-partum rats. The present study evaluates the possible synergistic antidepressant effect of sub-therapeutic dose of iron co-administered with citalopram or imipramine in female Institute of Cancer Research mice. Depression-like symptoms were induced in the forced swim (FST), tail suspension (TST), and open space swim (OSST) tests while open field test (OFT) was used to assess locomotor activity. Mice (n = 8) received iron (0.8-7.2 mg/kg), citalopram (3-30 mg/kg), imipramine (3-30 mg/kg), desferrioxamine (50 mg/kg) or saline in the single treatment phase of each model and subsequently a sub-therapeutic dose of iron co-administered with citalopram or imipramine. Assessment of serum brain derived neurotrophic factor (BDNF) and dendritic spine density was done using ELISA and Golgi staining techniques respectively. Iron, citalopram and imipramine, unlike desferrioxamine, reduced immobility score in the TST, FST and OSST without affecting locomotor activity, suggesting antidepressant-like effect. Sub-therapeutic dose of iron in combination with citalopram or imipramine further enhanced the antidepressant-like effect, producing a more rapid effect when compared to the iron, citalopram or imipramine alone. Iron, citalopram and imipramine or their combinations increased serum BDNF concentration, hippocampal neuronal count and dendritic spine densities. Our study provides experimental evidence that iron has antidepressant-like effect and sub-therapeutic dose of iron combined with citalopram or imipramine produces more rapid antidepressant-like effect. We further show that iron alone or its combination with citalopram or imipramine attenuates the neuronal loss associated with depressive conditions, increases dendritic spines density and BDNF levels. These finding suggest iron-induced neuronal plasticity in the mice brain.

Fast-onset effects of Pseudospondias microcarpa (A. Rich) Engl. (Anacardiaceae) hydroethanolic leaf extract on behavioral alterations induced by chronic mild stress in mice.

INTRODUCTION: Pseudospondias microcarpa (Anacardiaceae) is a plant widely used traditionally for treating various central nervous system disorders. A previous study in our laboratory confirmed that the hydroethanolic leaf extract (PME) of the plant produces an antidepressant-like effect in rodent models of behavioral despair. However, its effect on depressive-like behavior induced by chronic mild stress (CMS) and its time course of action are still unknown. In this context, the long-term effects of PME on cognitive function and depressive- and anxiety-like behavior caused by CMS were assessed. METHODS: Male ICR mice were exposed to CMS for nine weeks and anhedonia was evaluated by monitoring sucrose intake (SIT) weekly. PME (30, 100, or 300 mg kg-1) or fluoxetine (FLX) (3, 10, or 30 mg kg-1) was administered to the mice during the last six weeks of CMS. Behavioral tests-coat state, splash test, forced swimming test (FST), tail suspension test (TST), elevated plus maze (EPM), open field test (OFT), novelty suppressed feeding (NSF), EPM transfer latency, and Morris water maze (MWM)-were performed after the nine-week CMS period. RESULTS: When the mice were exposed to CMS, their SIT and grooming behavior reduced (splash test), their coat status was poor, they became more immobile (FST and TST), more anxious (OFT, EPM, and NSF), and their cognitive function was compromised (EPM transfer latency and MWM tests). Chronic PME treatment, however, was able to counteract these effects. Additionally, following two (2) weeks of treatment, PME significantly boosted SIT in stressed mice (30 mg kg-1, P<0.05; 100 mg kg-1, P<0.05; and 300 mg kg-1, P<0.001), as compared to four (4) weeks of treatment with FLX. CONCLUSION: The present findings demonstrate that PME produces a rapid and sustained antidepressant-like action and reverses behavioral changes induced by chronic exposure to mild stressors.

Gestational iron supplementation reverses depressive-like behavior in post-partum Sprague Dawley rats: Evidence from behavioral and neurohistological studies.

Background: Postpartum depression is a mood disorder that affects about 9-20% of women after child birth. Reports suggest that gestational iron deficiency can cause a deficit in behavioral, cognitive and affective functions and can precipitate depressive symptoms in mothers during the postpartum period. The present study examined the effect of iron supplementation on depressive behavior during postpartum period in a rat model. Method: Female Sprague-Dawley rats were crossed. Pregnant rats received iron, fluoxetine, desferrioxamine or vehicle throughout the period of gestation. During the postpartum period, mothers from all groups were taken through the open field test (OFT), forced swim test (FST), novelty-induced hypophagia (NIH) and sacrificed for histological examination of the brains. Results: Results showed that rats treated with iron-chelating agent, desferrioxamine, and vehicle during gestation exhibited increased immobility scores in the FST, increased latency to feed and reduced feeding in the NIH with corresponding decreased number of neurons and dendritic branches in the cortex of the brain. These depression-related effects were attenuated by perinatal iron supplementation which showed decreased immobility scores in the FST comparable to rats treated with fluoxetine, a clinically effective antidepressant. Iron treatment also decreased latency to feeding while increasing feeding behavior in the NIH. Iron-treated dams had a higher number of neurons with dendritic connections in the frontal cortex compared to vehicle- and desferrioxamine-treated groups. Conclusion: The results suggest that, iron supplementation during gestation exerts an antidepressant-like effect in postpartum Sprague-Dawley rats, attenuates neuronal loss associated with depression and increases dendritic spine density.

Antidepressant Potentials of Components from Trichilia monadelpha (Thonn.) J.J. de Wilde in Murine Models.

Trichilia monadelpha is a common medicinal plant used traditionally in treating central nervous system conditions such as epilepsy, depression, pain, and psychosis. In this study, the antidepressant-like effect of crude extracts of the stem bark of T. monadelpha was investigated using two classical murine models, forced swimming test (FST) and tail suspension test (TST). The extracts, petroleum ether, ethyl acetate, and hydroethanolic extracts (30-300 mg/kg, p.o.), standard drug (imipramine; fluoxetine, 3-30 mg/kg, p.o.), and saline (vehicle) were given to mice one hour prior to the acute study. In a separate experiment the components (flavonoids, saponins, alkaloids, tannins, and terpenoids; 30-300 mg/kg, p.o.) from the most efficacious extract fraction were screened to ascertain which components possessed the antidepressant effect. All the extracts and components significantly induced a decline in immobility in the FST and TST, indicative of an antidepressant-like activity. The extracts and some components showed increase in swimming and climbing in the FST as well as a significant enhancement in swinging and/or curling scores in the TST, suggesting a possible involvement of monoaminergic and/or opioidergic activity. This study reveals the antidepressant-like potential of the stem bark extracts and components of T. monadelpha.

Toxicological Assessment of Pseudospondias microcarpa (A. Rich.) Engl. Hydroethanolic Leaf Extract in Rats: Haematological, Biochemical, and Histopathological Studies.

Pseudospondias microcarpa is used traditionally for treating various diseases. However, although parts of the plant are extensively used in African traditional medicine, no scientific study has been reported on its toxicity. Therefore, this study evaluated the acute and subacute toxicity studies of the ethanolic extract of P. microcarpa in rats. Male Sprague-Dawley rats (120-150 g) were treated orally with the extract (30, 100, 300, 1000, and 3000 mg kg-1) or distilled water (10 ml kg-1) for 2 weeks and observed daily for general appearance and signs of toxicity. In addition, blood was collected for both biochemical and haematological assays. Sections of tissues from liver, kidney, spleen, brain, and stomach were also used for histopathological examination. Administration of the extract for 14 consecutive days caused no deaths, with an LD50 above 3000 mg kg-1. Except for lymphocytes (%) that showed a significant decrease (F5,23 = 3.93, P = 0.013), all other haematological parameters remained unaffected by the extract. The extract at 100 mg kg-1 showed a significant decrease in the levels of triglyceride and very-low-density lipoproteins (both at P < 0.05). Weight change as well as histological evaluation of the organs indicated no toxicity. The study demonstrates that an ethanolic extract of P. microcarpa given orally to rats is safe.

An extract of Synedrella nodiflora (L) Gaertn exhibits antidepressant properties through monoaminergic mechanisms.

Synedrella nodiflora (SNE) has been used traditionally for many neurological conditions and some of these neuroactive effects have been scientifically substantiated. The usefulness of SNE in depression has however not been investigated despite the availability of data in other disease models indicating it may be useful. The present study therefore examined the effect of SNE in acute murine models of depression and the possible mechanisms mediating its activities in these models. Preliminary qualitative phytochemical and high performance liquid chromatography (HPLC) screening were conducted on SNE. The behavioural effects of SNE (100, 300 and 1000 mg/kg) pre-treated mice were examined in the forced swimming (FST) and tail suspension (TST) tests. Behavioural events such as mobility (swimming, climbing, curling and climbing), and immobility, were scored. The possible involvement of monoamines in the effects of SNE was assessed in the TST by pre-treating mice with α-methyldopa, reserpine and para-chlorophenylalanine (pCPA) in separate experiments. Flavonoids, tannins, saponins, alkaloids, cardiac glycosides, coumarins, triterpenes, sterols, anthraquinones and phenolic compounds were present in SNE. HPLC analysis revealed the presence of two major constituents observed at retention times 42.56 and 46.51 min, with percentage composition of 45.72% and 36.88% respectively. SNE significantly reduced immobility scores in both FST and TST, suggesting antidepressant effects. The antidepressant properties of SNE were reversed by the pre-treatment of α-methyldopa, reserpine and pCPA, suggesting a possible involvement of monoamines (noradrenaline and serotonin) in its mechanism(s) of actions. SNE exhibits antidepressant effects, possibly mediated through an interplay of enhancement of noradrenergic and serotoninergic mechanisms.

Medicinal Plants Used in the Treatment of Mental and Neurological Disorders in Ghana.

ETHNOPHARMACOLOGICAL RELEVANCE: Mental and neurological disorders are a serious public health challenge globally, particularly in developing countries where cultural factors and limited access to standard healthcare have led to a reliance on traditional medicines. However, ethnopharmacological characterization of traditional medicines used to treat these diseases is lacking. In this study, an ethnobotanical description of plant species used in treating mental and neurological disorders in Ghana and an update of their experimentally validated pharmacological relevance are provided. MATERIALS AND METHODS: Two hundred herbalists agreed to participate but sixty-six specialized in treating mental and neurological disorders were interviewed on their traditional medical practice. Literature review was conducted to verify the experimentally validated pharmacological importance of the reported plants. RESULTS: Thirty-two plant species belonging to twenty-eight families were identified. Most plant species had either analgesic (50%), anxiolytic (18.8%), or anticonvulsant (15.6%) properties. Others had reported sedative, anti-Alzheimer's disease, motor coordination, antipsychotic, antidepressant, cognitive enhancement, and neuroprotective properties. While Ageratum conyzoides L. (Asteraceae) and Ocimum gratissimum L. (Lamiaceae) were the most commonly mentioned species with analgesic properties, Lantana camara L. (Verbenaceae) was the most-reported anxiolytic product, with Cymbopogon citratus DC. (Gramineae), Mangifera indica L., Tetrapleura tetraptera Schum Taub. (Fabaceae), and Persea Americana Mill (Lauraceae) being the most studied anticonvulsants. CONCLUSIONS: This study provides the first report specifically on medicinal plants used in treating mental and neurological disorders in Ghana. Most of the identified plants have been scientifically confirmed to possess neuro- and psychopharmacological properties and may serve as templates for drug development.

Psychotropic Effects of an Alcoholic Extract from the Leaves of Albizia zygia (Leguminosae-Mimosoideae).

BACKGROUND: Albizia zygia is used in Ghanaian traditional medicine for the management of mental disorders. The present study tested the hypothesis that an extract of the leaves of Albizia zygia (AZE) may possess antipsychotic and antidepressant properties. METHOD: The novelty- and apomorphine-induced locomotor and rearing behaviours of AZE in mice were explored in an open-field observational test system. The effects of AZE in apomorphine-induced cage climbing test, extract-induced catalepsy, and haloperidol-induced catalepsy on mice were also investigated. Lastly, the forced swimming and tail suspension tests in mice were employed to screen the possible antidepressant effects of AZE. RESULTS: AZE (100-3000 mg/kg) showed signs of central nervous system (CNS) depression under observation, with no lethality, 24 h after treatment in mice. AZE (100-1000 mg/kg) produced a significant decrease in the frequency of novelty- and apomorphine-induced locomotor activities in mice. The extract also significantly decreased the frequency and duration of apomorphine-induced climbing activities in mice. AZE, while failing to produce any cataleptic event in naïve mice, significantly enhanced haloperidol-induced catalepsy at a dose of 1000 mg/kg. However, AZE did not produce any significant antidepressant effects in the test models employed. CONCLUSION: The extract of Albizia zygia exhibited an antipsychotic-like activity in mice.

Analgesic effects of a hydro-ethanolic whole plant extract of Synedrella nodiflora (L.) Gaertn in paclitaxel-induced neuropathic pain in rats.

BACKGROUND: Synedrella nodiflora is used by traditional healers in Ghana for the management of epilepsy and pain. The hydro-ethanolic extract of the whole plant has demonstrated antinociceptive effect in various animal models of pain. This study investigated the potential benefit of the hydro-ethanolic extract in a rat model of paclitaxel-induced neuropathic pain. METHODS: Neuropathy was induced in rats by a continuous intraperitoneal administration of paclitaxel (2 mg/kg) for 5 days. Baseline latencies to thermal pain were recorded before the first injection of paclitaxel and during the 5 day induction period. Following the induction, the rats in designated treatment group were treated with the hydro-ethanolic extract (100, 300 and 1000 mg/kg, p.o) or pregabalin (10, 30 and 100 mg/kg) or vehicle (distilled water) and their responses to thermal hyperalgesia measured every 30 for a total period of 3 h. RESULTS: There was a significant difference between the baseline reaction latency and what was observed on the 5th day of the induction of neuropathy. Two days after the induction of neuropathy, the extract and pregabalin significantly and dose-dependently produced antinociceptive effect during the 3-h test period. CONCLUSION: The hydro-ethanolic extract of the whole plant of Synedrella nodiflora possess analgesic effect in paclitaxel-induced neuropathy in rats.

Analgesic properties of aqueous leaf extract of Haematostaphis barteri: involvement of ATP-sensitive potassium channels, adrenergic, opioidergic, muscarinic, adenosinergic and serotoninergic pathways.

BACKGROUND: Pain is the most common cause of patients seeking medical advice as a result of its association with different pathologies. This study evaluated the antinociceptive property of Haematostaphis barteri as well as the possible mechanism(s) associated with its antinociceptive property. METHODS: Mice were administered H. barteri (30-300 mg kg-1; p.o.), followed by intraplantar injection of 10 µL of 5% formalin into the hind paws. The pain score was determined for 1 h in the formalin test. The possible nociceptive pathways involved in the antinociceptive action of H. barteri were determined by pre-treating mice with theophylline (5 mg kg-1, a non-selective adenosine receptor antagonist), naloxone (2 mg kg-1, a non-selective opioid receptor antagonist), glibenclamide (8 mg kg-1; an ATP-sensitive K+ channel inhibitor), and atropine (3 mg kg-1; non-selective muscarinic antagonist). RESULTS: H. barteri (30-300 mg kg-1) significantly and dose dependently precluded both first and second phases of nociception. Pre-treatment with naloxone had no effect on the analgesic activities of H. barteri in the first phase. Again, pre-treatment with atropine and glibenclamide did not significantly reverse the neurogenic antinociception of the extract in phase 1. However, theophylline reversed the analgesic effect of the extract in the first phase. In phase 2, theophylline had no effect on the analgesic activities of the extract. Naloxone, atropine, and glibenclamide significantly blocked the antinociception of H. barteri in the inflammatory phase of the formalin test. CONCLUSIONS: H. barteri possesses antinociceptive property mediated via the opioidergic, adrenergic, muscarinic, ATP-sensitive K+ channels, and adenosinergic nociceptive pathways.

Antidepressant-Like Effect of the Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway.

Depression continues to be a major global health problem. Although antidepressants are used for its treatment, efficacy is often inconsistent. Thus, the search for alternative therapeutic medicines for its treatment is still important. In this study, the antidepressant-like effect of Pseudospondias microcarpa extract (30-300 mg kg(-1), p.o.) was investigated in two predictive models of depression--forced swimming test and tail suspension test in mice. Additionally, the mechanism(s) of action involved were assessed. Acute treatment with the extract dose dependently reduced immobility of mice in both models. The antidepressant-like effect of the extract (100 mg kg(-1), p.o.) was blocked by p-chlorophenylalanine and cyproheptadine but not prazosin, propranolol, or yohimbine. Concomitant administration of D-cycloserine and the extract potentiated the anti-immobility effect. In contrast, D-serine, a full agonist of glycine/NMDA receptors, abolished the effects. Anti-immobility effects of PME were prevented by pretreatment of mice with L-arginine (750 mg kg(-1), i.p.) and sildenafil (5 mg kg(-1), i.p.). On the contrary, pretreatment of mice with L-NAME (30 mg kg(-1), i.p.) or methylene blue (10 mg kg(-1), i.p.) potentiated its effects. The extract produces an antidepressant-like effect in the FST and TST that is dependent on the serotoninergic system, NMDA receptor complex, and the nitric oxide pathway.