Neuropharmacology Potential of the Hydroalcoholic Extract from the Leaves of Piper cernuum: Anxiolytic, Hypnotic, and Antidepressant-Like Effects.

Aim: The use of medicinal plants in the treatment of mental illnesses is a reality that accompanies the history of civilizations, and the Piper genus exhibits many species with pharmacologically proven central effects. Then, this study evaluated the neuropharmacological effects of the hydroalcoholic extract from Piper cernuum (HEPC) leaves to validate its uses in folk medicine. Materials and Methods: Primarily Swiss mice (female, 25-30 g) were pretreated with HEPC (50-150 mg/kg, p.o.), vehicle, or the positive control, and submitted to open-field test (OFT), inhibitory avoidance test (IAT), tail suspension test (TST), and forced swim test (FST). Also, mice were exposed to pentylenetetrazol- and strychnine-induced seizure assay, pentobarbital-induced hypnosis test, and elevated plus-maze (EPM). The GABA levels and MAO-A activity were measured in the animal's brain after 15 days of HEPC administration (150 mg/kg, p.o.). Results: Mice pretreated with HEPC (100 and 150 mg/kg) and exposed to pentobarbital presented decreased sleep latency and increased sleep duration (HEPC 150 mg/kg). In EPM, the HEPC (150 mg/kg) increased the frequency of entry and the time of exploration of mice in the open arms. The antidepressant-like properties of HEPC were demonstrated by the decrease in the mice's immobility time when tested in FST and TST. The extract did not show anticonvulsant activity, in addition to not improving the memory parameters of animals (IAT) or interfering with their locomotor activity (OFT). Besides, HEPC administration decreased the MAO-A activity and increased the GABA levels in the animal's brain. Conclusion: HEPC induces sedative-hypnotic, anxiolytic-, and antidepressant-like effects. These neuropharmacological effects of HEPC could be, at least in part, related to the modulation of the GABAergic system and/or MAO-A activity.

Antidepressant-Like Effect and Phenolic Profile of Brazilian Native and Exotic Species from Psidium Genus.

Depression is one of the disorders involving mental health that most affects the population worldwide. Considering the available pharmacological therapies for the treatment of depression are ineffective in most patients, the search for new alternatives is crucial. In line with this, we investigated the phenolic profile, antidepressant-like, and antioxidant effects triggered by the administration of aqueous extracts from Psidium guajava L. (GUA), Psidium cattleianum Sw. (CAT), and Psidium guineense Sabine (GUI) leaves in mice. Our results show that quercetin is the major compound of GUA and GUI, and o-coumaric acid in CAT extracts. The acute and subchronic administrations of the three plant extracts exerted an antidepressant-like effect in mice exposed to the tail suspension test, without changes on locomotor performance evaluated by the open field test. Furthermore, the GUI and CAT decreased oxidative stress markers, mainly lipid peroxidation and nitrites in the hippocampus, prefrontal cortex, liver, and plasma. Notably, GUA and CAT increased non-protein thiols in all tissues. Therefore, the Psidium extracts demonstrated an antidepressant-like effect in mice, and the antioxidant capacity of the extracts seems to underlie the behavioral effect.

Phenolic profile, antidepressant-like and neuroprotective effects of Maclura tinctoria leaves extract.

Considering the drawbacks elicited by the conventional antidepressants, the interest in natural products for the management of major depressive disorder has increased in the last years. Therefore, this study investigated the phenolic profile of Maclura tinctoria leaf aqueous extract (MtAE) and its possible antidepressant-like effect in mice. The LC-MS/MS analysis demonstrated MtAE has epicatechin as the major phenolic, followed by catechin, gallic acid, quercetin, syringaldehyde, ferulic acid, and syringic acid. Moreover, the acute treatment of MtAE elicited an antidepressant-like response in mice. Importantly, this antidepressant-like effect produced by MtAE was reinforced in the chronic corticosterone (20 mg/kg p.o.) administration model. MtAE treatment was also effective to protect hippocampal and cerebrocortical slices against glutamatergic excitotoxicity. Our results indicated that MtAE displayed antidepressant-like and neuroprotective effects and these responses could be associated with the presence of the phenolic compounds identified.

Antidepressant-like effect of caffeic acid: Involvement of the cellular signaling pathways

Abstract Caffeic acid is a phenolic compound widely distributed in plants and beverages such as coffee. Although its mechanism of action is poorly understood, caffeic acid reportedly induces antidepressant-like and neuroprotective effects. This study aimed to investigate the involvement of cellular signaling pathways in acute antidepressant-like effect induced by caffeic acid in mice. All procedures were approved by the Institutional Animal Ethics Committee of the UNIVALI n. 021/2013. Female Swiss mice were administered with vehicle, caffeic acid (5 mg/ kg, p.o.), inhibitor (H-89, U0126, chelerythrine, or PD9859, i.c.v.) or caffeic acid plus inhibitor. The behavioral effects were evaluated 1h after the administration of compounds to mice using tail suspension test (TST) and open field test (OFT). The results showed that the antidepressant- like effect of caffeic acid in mice was possibly mediated by the activation of PKA, MEK 1/2, PKC and MAPK (as assessed using TST), without compromising their locomotor activity (as assessed using OFT). Our results demonstrated, at least in part, the pathways involved in the neuroprotective and behavioral effects of caffeic acid.

Myrsinoic acid B from Myrsine coriacea reverses depressive-like behavior and brain oxidative stress in streptozotocin-diabetic rats.

AIMS: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects. MAIN METHODS: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats. KEY FINDINGS: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats. SIGNIFICANCE: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect.

Antidepressant-like effect of hydroalcoholic extract from barks of Rapanea ferruginea: Role of monoaminergic system and effect of its isolated compounds myrsinoic acid A and B.

Major Depressive Disorder (MDD) is a highly disabling condition and has been linked to increased inflammatory mediators. Hydroalcoholic extract from barks of Rapanea ferruginea (HEBRF) and the majoritary compounds-myrsinoic acid A (MAA) and B (MAB)-have been studied due to their anti-inflammatory potential, but there is no evidence about its antidepressant-like effects. This research investigated the HEBRF, MAA, and MAB antidepressant-like effect, besides the involvement of the monoaminergic system and MAO-A activity in the HEBRF antidepressant-like effect. HEBRF (50-300 mg/kg, p.o.), MAA (5-30 mg/kg, p.o.) or MAB (3-60 mg/kg, p.o.) were administrated to mice, and behavioral parameters were assessed using the tail suspension test (TST), splash test (ST) and open field test (OFT). The involvement of monoaminergic system in the HEBRF antidepressant-like effect was established through the pretreatment of mice with antagonists. The influence triggered by HEBRF in the monoamine oxidase A (MAO-A) activity was evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of mice. HEBRF (100-300 mg/kg) promoted antidepressant-like effect in the TST and augmented the total time of grooming in the ST, without compromising the locomotor activity. Pretreatment of mice with serotoninergic, dopaminergic, and noradrenergic antagonists, reversed the HEBRF antidepressant-like effect. Besides, HEBRF inhibited the MAO-A activity in the HIP and PFC. Moreover, MAA (5 mg/kg) and MAB (3 mg/kg) also promoted antidepressant-like and anti-anhedonic effects in mice. Data showed that monoaminergic system is involved in the HEBRF antidepressant-like effect, besides MAA and MAB possibly could be responsible for these pharmacological effects.

Red cabbage (Brassica oleracea L.) extract reverses lipid oxidative stress in rats.

Red cabbage (Brassica oleracea L. var. capitata f. rubra DC.) extract has been demonstrated hypolipidemic and antioxidant capacity. Herein, we investigated the effect of red cabbage aqueous extract (RC) or fenofibrate (FF) in oxidative stress induced by Triton WR-1339 in rats. The antioxidant capacity was evaluated through the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and, thiobarbituric reactive species (TBARS) and protein carbonyl (PC) levels in erythrocytes, liver, kidneys, cerebral cortex and hippocampus of male rats. The alterations promoted by Triton WR-1339 in enzymatic antioxidant defense in the liver, kidneys and hippocampus were reversed by RC or FF treatments. The TBARS and PC levels increased in the liver, cerebral cortex and hippocampus of hyperlipidemic rats were decreased by the treatments with RC or FF. These findings demonstrated that RC is a potential therapy to treat diseases not only involving dyslipidemic condition but also oxidative stress.

Morus nigra leaves extract revokes the depressive-like behavior, oxidative stress, and hippocampal damage induced by corticosterone: a pivotal role of the phenolic syringic acid.

The pathophysiology of depression includes glucocorticoids excess, glutamatergic excitotoxicity, and oxidative stress impairment. Previous study demonstrated Morus nigra L. leaves extract and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid), its major phenolic compound, administered orally for 7 days, decreased the immobility time in the tail suspension test, without locomotor alteration. Therefore, the purpose of this study was to investigate the antidepressant-like effects, antioxidant effects, and neuroprotective effects of M. nigra leaves extract and syringic acid in an animal model of depression induced by corticosterone. Herein, corticosterone administered in male Swiss mice, 60-90 days of age, at 20 mg/kg, once a day, for 21 days, was effective to induce depressive-like phenotype. This alteration was accompanied by the increase of oxidative stress markers (lipid peroxidation, nitrite, and protein carbonyl) and the decrease in nonprotein thiols level, besides impairment in the hippocampus. Conversely, the treatment with M. nigra leaves extract (10 mg/kg), syringic acid (1 mg/kg), or fluoxetine (10 mg/kg), administered once a day for the last 7 days of the corticosterone treatment, was able to abolish the behavioral alterations elicited by corticosterone, reinforcing evidence of the M. nigra leaves extract and syringic acid having antidepressant-like effect. Both treatments also exerted antioxidant property in the mice's brain, reducing the amount of oxidative stress and abolishing the corticosterone-induced damage in the hippocampal slices. In addition, the treatments protected the hippocampus against the damage induced by the association between corticosterone administration and glutamate excess. In conclusion, M. nigra leaves extract and syringic acid revoke depressive-like behavior induced by corticosterone via inhibition of oxidative stress and hippocampal damage.

Involvement of PI3K/Akt/GSK-3ß signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid.

Depression is a common neuropsychiatric disorder whose pathophysiology has been associated with glutamatergic excitotoxicity. Thus, the research for new antidepressant strategies with the ability to mitigate glutamate toxicity has received growing attention. Given this background, the present study sought to investigate the antidepressant-like and neuroprotective effects of Morus nigra (MN) and its major phenolic, syringic acid (SA), against glutamate-induced damage, as well as, the role of the PI3K/Akt/GSK-3ß signaling pathway in these effects. Treatment with MN (3 mg/kg) and SA (1 mg/kg) for 7 days, similar to fluoxetine (10 mg/kg), triggered an antidepressant-like effect. Moreover, the treatments evoked neuroprotection against glutamatergic excitotoxicity in hippocampal slices, and MN treatment also afforded protection in cerebrocortical slices. Notably, ex vivo neuroprotective effect of MN and SA was mediated, at least in part, by PI3K/Akt/GSK-3ß signaling pathway. Furthermore, the ability of MN and SA to counteract the glutamate-induced damage were evaluated in three different in vitro experiments. The hippocampal slices pretreated with MN (0.05 and 0.1 µg/mL) or SA (0.01-0.1 µg/mL) as well as the concomitant treatment with MN (0.01 and 0.05 µg/mL) or SA (0.05 and 0.1 µg/mL) exhibited protection against glutamate toxicity. Interestingly, post-treatment with MN in all doses (0.01-0.1 µg/mL) and SA at dose of 0.1 µg/mL were capable of preventing glutamate-induced cell death. In vitro neuroprotective effect of SA, but not MN, involves the activation of Akt, since the pretreatment with LY294002 completely abolished the protective effect. Overall, MN and SA presented antidepressant-like and neuroprotective effects against glutamatergic excitotoxicity via PI3K/Akt/GSK-3ß.

Taraxerol as a possible therapeutic agent on memory impairments and Alzheimer's disease: Effects against scopolamine and streptozotocin-induced cognitive dysfunctions.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death, characteristic of the effect of time on biochemical neuronal function. The use of medicinal plants as an alternative form of prevention, or even as a possible treatment of AD, is therefore interesting areas of research, since the standard drugs have many side effects. Taraxerol (TRX) is a triterpene that has been isolated from several plant species, and its various pharmacological properties have already been identified, such the acetylcholinesterase (AChE) inhibition activity in vitro. There is a lack of information in literature that confirms the effect of TRX in an animal AD-like model. Seeking to fill this gap in the literature, in the present work we assessed the effect of TRX on AChE activity in the animals' encephalon and hippocampus. We also investigated the effect of TRX (1.77 µM/side, 0.5 µL) isolated from leaves of Eugenia umbelliflora Berg. on aversive memory impairments induced by scopolamine (2 µg/side, 0.5 µL) infused into rat hippocampus, and the effect of TRX (0.89 and 1.77 µM/side, 0.5 µL) on aversive memory impairments induced by streptozotocin (STZ) (2.5 mg/mL, 2.0 µL) infused i.c.v. into mice, using the step-down inhibitory avoidance task. We found that TRX significantly inhibited AChE activity in the animal's hippocampus. Furthermore, TRX significantly improved scopolamine and STZ-induced memory impairment. Taking together, these results confirms its AChE activity inhibition in animals and indicate that TRX has anti-amnesic activity that may hold significant therapeutic value in alleviating certain memory impairments observed in AD.

Evaluation of phenolic compounds and lipid-lowering effect of Morus nigra leaves extract.

Morus nigra L. (Moraceae) is a tree known as black mulberry and the leaves are used in folk medicine in the treatment of diabetes, high cholesterol and menopause symptoms. The aim of this study was to evaluate the M. nigra leaves phytochemical profile in different extractions and the hypolipidemic effect of the infusion comparing to the fenofibrate. Morus nigra infusion (MN) showed higher amounts of phenolics and flavonoids (83.85 mg/g and 79.96 µg/g, respectively), as well as antioxidant activity (83.85%) than decoction or hydromethanolic extracts. Although, decoction showed the best result for ascorbic acid (4.35 mg/100 g) than hydromethanolic or infusion (2.51 or 2.13 mg/100 g, respectively). The phenolic acids gallic, chlorogenic and caffeic and the flavonoids quercetin, rutin and catechin were found in the M. nigra extracts. Hyperlipidemic rats treated with 100, 200 or 400 mg/kg of MN decreased serum cholesterol, triglycerides and normalized lipoproteins. Furthermore, MN inhibited lipid peroxidation in liver, kidney and brain of hyperlipidemic rats. This study provides evidence that M. nigra leaves extracts are rich in polyphenols, mainly chlorogenic acid, which normalized hyperlipidemic disturbance. The results suggest a potential therapeutic effect of the M. nigra leaves infusion on dislipidemic condition and related oxidative stress.

Evaluation of phenolic compounds and lipid-lowering effect of Morus nigra leaves extract

ABSTRACT Morus nigra L. (Moraceae) is a tree known as black mulberry and the leaves are used in folk medicine in the treatment of diabetes, high cholesterol and menopause symptoms. The aim of this study was to evaluate the M. nigra leaves phytochemical profile in different extractions and the hypolipidemic effect of the infusion comparing to the fenofibrate. Morus nigra infusion (MN) showed higher amounts of phenolics and flavonoids (83.85 mg/g and 79.96 µg/g, respectively), as well as antioxidant activity (83.85%) than decoction or hydromethanolic extracts. Although, decoction showed the best result for ascorbic acid (4.35 mg/100 g) than hydromethanolic or infusion (2.51 or 2.13 mg/100 g, respectively). The phenolic acids gallic, chlorogenic and caffeic and the flavonoids quercetin, rutin and catechin were found in the M. nigra extracts. Hyperlipidemic rats treated with 100, 200 or 400 mg/kg of MN decreased serum cholesterol, triglycerides and normalized lipoproteins. Furthermore, MN inhibited lipid peroxidation in liver, kidney and brain of hyperlipidemic rats. This study provides evidence that M. nigra leaves extracts are rich in polyphenols, mainly chlorogenic acid, which normalized hyperlipidemic disturbance. The results suggest a potential therapeutic effect of the M. nigra leaves infusion on dislipidemic condition and related oxidative stress.

Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride.

Psychiatric diseases affect more than 350 million people all over the world, and medicinal plants have been considered the basis for pharmacological research. The study investigates the anticonvulsant and antidepressant-like activities and acute toxicological effects of ethanolic extract of Allamanda cathartica flowers, and plumieride. The extract was analyzed by HPLC and plumieride was isolated. Toxicity studies were carried out on females Wistar rats (2000 mg/kg). Toxicity was evaluated by measuring biochemical parameters and conducting histopathological analysis. For pharmacological evaluation different doses of the extract (100, 150 and 300 mg/kg, p.o.) and plumieride (0.5, 1 and 2 µg/kg, i.p.) were administered before the Forced-Swimming Test (FST), pentylenetetrazole seizure test (PTZT) or Tail-Suspension Test (TST) in mice. Furthermore, hemolytic activity, cytotoxicity and micronucleus test were performed. In addition, mutagenicity and reproductive/developmental toxicity were estimated by TEST-software analysis. Data show that both treatments induce significant antidepressive-like effect in FST and TST, but not anticonvulsant effect. The effect of plumieride last up to 4 h after treatment. No signs of toxicity, mutagenicity, cytotoxicity or hemolytic activity were observed. The TEST-software demonstrated that plumieride present reproductive/developmental toxicity. Together, the data obtained show that the flowers extract and plumieride present antidepressant-like effect and did not present signals of acute toxicity.

Morus nigra and its major phenolic, syringic acid, have antidepressant-like and neuroprotective effects in mice.

Depression is a disorder with a high incidence that has been increasing worldwide although the pathophysiology remains unclear. Moreover, some studies revealed a higher concentration of glutamate and oxidative stress in the patients' brain, which causes cell death by excitotoxicity. Morus nigra L. is known as black mulberry and its leaves are popularly used to treat affections related to menopause, obesity and high cholesterol. M. nigra leaves are a rich fount of phenolics which well-known by the antioxidant property. Herein, we examined the phenolic profile and the antidepressant-like effect of the Morus nigra aqueous extract (MN) and its major phenolic constituent, syringic acid (SA). Furthermore, the involvement of antioxidant and neuroprotective activities were further evaluated. Our results show that acute and subchronic MN or SA administration exerted antidepressant-like property in the behavioral testes in mice. The results suggest that the antidepressant-like effect of MN, at least in part, could be due to the SA influence. Moreover, the observed effect involves the nitro-oxidative system modulation in both the serum and brain of mice. Furthermore, MN or SA was able to contain the glutamate-induced cell death in the hippocampal and cortical slices implicating the neuroprotection activity in the antidepressant-like effect.

Avaliação psicofarmacológica do óleo essencial de Piper amplum / Psychopharmacology analysis of essential oil Piper amplum

Espécies do gênero Piper são utilizadas na medicina popular e carecem de validação farmacológica. Estudos científicos com a espécie Piper amplum são concentrados principalmente nos efeitos antimicrobianos e pouco se sabe sobre suas ações sobre o sistema nervoso central (SNC), apesar da planta ser utilizada de forma etnofarmacológica em processos neurológicos. Portanto, para avaliar os efeitos sobre o SNC, o óleo essencial obtido de Piper amplum (OEPA) (50, 100, 150 mg/kg, v.o.) foi administrado em camundongos fêmeas Swiss (25-30 g/ n=8-10 animais) e 60 minutos após os mesmos foram submetidos a testes de: depressão (teste do nado forçado, TNF), deambulação motora (campo aberto, TCA e Rotarod), convulsão e hipnose. Grupos controle-positivo (fármacos usados na terapêutica) e negativo (veículo no qual o OEPA foi dissolvido) foram utilizados nas mesmas condições experimentais. Os resultados demonstraram que o tratamento com OEPA não afetou a deambulação e atividade exploratória dos animais no TCA, assim como não afetou o sistema motor no Rotarod. Não foram detectados efeitos anticonvulsivante, hipnótico e ansiolítico do OEPA, entretanto, verificou-se atividade antidepressiva no TNF nas doses testadas. Diante dos efeitos do OEPA sobre o SNC, pode-se considerar o mesmo como alvo potencial para maiores estudos relacionados a atividade antidepressiva.(AU)

Species of the genus Piper used are in folk medicine and need pharmacological validation. Scientific studies with Piper amplum species are mainly concentrated on antimicrobial effects, little known is about their actions on the central nervous system (CNS), although the plant is ethnopharmacological used in neurological processes. Therefore, to evaluate the effects on the CNS, the essential oil obtained from Piper amplum (OEPA) (50, 100-150 mg/kg, p.o.) was administered in Swiss female mice (25-30 g/ n=8-10 animals) and 60 minutes after, the same were submitted to tests: depression forced swimming test, FST), motor ambulation (open field, OFT and Rotarod), seizure and hypnosis. Control-positive (drugs used in therapy) and negative (vehicle in which OEPA was dissolved) control groups were used under the same experimental conditions. The results showed that OEPA treatment did not affect the ambulation and exploratory activity of the animals in the OFT, and did not it affect the motor system in Rotarod. No anticonvulsive, hypnotic and anxiolytic effects of OEPA detected were, however, antidepressant activity in TNF at all doses tested. In view of the effects demonstrated by the OEPA on the CNS, it be can considered the same as a potential target for further studies related to antidepressant activity.(AU)