Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies.

Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

Sintocalmy, a Passiflora incarnata Based Herbal, Attenuates Morphine Withdrawal in Mice.

Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200 mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100 mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50 mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

Objective: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. Methods: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. Results: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. Conclusion: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review.

OBJECTIVE: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. METHODS: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. RESULTS: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. CONCLUSION: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice

Objective: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. Methods: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. Results: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. Conclusion: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice.

OBJECTIVE: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. METHODS: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. RESULTS: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. CONCLUSION: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.

Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida).

Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.

N-acetylcysteine prevents increased amphetamine sensitivity in social isolation-reared mice.

Treating individuals at risk to develop schizophrenia may be strategic to delay or prevent transition to psychosis. We verified the effects of N-acetylcysteine (NAC) in a neurodevelopmental model of schizophrenia. C57 mice were reared in isolation or social groups and treated with NAC from postnatal day 42-70; the locomotor response to amphetamine was assessed at postnatal day 81. NAC treatment in isolated mice prevented the hypersensitivity to amphetamine, suggesting neuroprotection relevant to striatal dopamine. Considering its safety and tolerability profile, complementary studies are warranted to further evaluate the usefulness of NAC to prevent conversion to schizophrenia in at-risk individuals.

Medical knowledge exchanges between Brazil and Portugal: an ethnopharmacological perspective.

ETHNOPHARMACOLOGICAL RELEVANCE: Like many traditional medical systems found at Latin America, the very existence of a Brazilian traditional medical system is debated. Despite the absence of written material and organized knowledge, there is little doubt that Brazilians from all regions and all social classes recognize and access an estimated 4000 plant species with alleged therapeutic purposes as well as medicinal practices ranging from bone setting to spiritual healing. This "Brazilian folk medicine" is usually described as a rich mixture of African, European, and Indigenous medical traditions. AIM OF THE STUDY: This study questions this view, and argues it is both simplistic and Eurocentric. MATERIALS AND METHODS: By scrutinizing the origins of the medical uses of Zingiberis officinale, Curcuma longa, Ruta officinalis, Cephaelis ipecacuanha, Pilocarpus pinnatifolius, and curare (Chondrodendron, Abuta and Curarea), we illustrate the intense circulation of materials during imperial times. We further discuss how these practices articulated with local medical knowledge, and exemplify some of the ways by which knowledge was produced, transformed, incorporated, and resignified over time. DISCUSSION: Though not a systematic or comprehensive analysis of Brazilian folk medicine development, these selected examples show that, in opposition to usual simplistic descriptions, complex and convoluted manners of medicinal plant development occurred over time to compound both the Brazilian and European pharmaceutical armamentarium.

In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants.

Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes.

Alstonine as an antipsychotic: effects on brain amines and metabolic changes.

Managing schizophrenia has never been a trivial matter. Furthermore, while classical antipsychotics induce extrapyramidal side effects and hyperprolactinaemia, atypical antipsychotics lead to diabetes, hyperlipidaemia, and weight gain. Moreover, even with newer drugs, a sizable proportion of patients do not show significant improvement. Alstonine is an indole alkaloid identified as the major component of a plant-based remedy used in Nigeria to treat the mentally ill. Alstonine presents a clear antipsychotic profile in rodents, apparently with differential effects in distinct dopaminergic pathways. The aim of this study was to complement the antipsychotic profile of alstonine, verifying its effects on brain amines in mouse frontal cortex and striatum. Additionally, we examined if alstonine induces some hormonal and metabolic changes common to antipsychotics. HPLC data reveal that alstonine increases serotonergic transmission and increases intraneuronal dopamine catabolism. In relation to possible side effects, preliminary data suggest that alstonine does not affect prolactin levels, does not induce gains in body weight, but prevents the expected fasting-induced decrease in glucose levels. Overall, this study reinforces the proposal that alstonine is a potential innovative antipsychotic, and that a comprehensive understanding of its neurochemical basis may open new avenues to developing newer antipsychotic medications.

Omega-3 fatty acids deprivation affects ontogeny of glutamatergic synapses in rats: relevance for behavior alterations.

Essential omega-3 polyunsaturated fatty acids (omega3) are crucial to brain development and function, being relevant for behavioral performance. In the present study we examined the influence of dietary omega3 in the development of the glutamatergic system and on behavior parameters in rats. Female rats received isocaloric diets, either with omega3 (omega3 group) or a omega3 deficient diet (D group). In ontogeny experiments of their litters, hippocampal immunocontent of ionotropic NMDA and AMPA glutamatergic receptors subunits (NR2 A\B and GluR1, respectively) and the alpha isoform of the calcium-calmodulin protein kinase type II (alphaCaMKII) were evaluated. Additionally, hippocampal [(3)H]glutamate binding and uptake were assessed. Behavioral performance was evaluated when the litters were adult (60 days old), through the open-field, plus-maze, inhibitory avoidance and flinch-jump tasks. The D group showed decreased immunocontent of all proteins analyzed at 02 days of life (P2) in comparison with the omega3 group, although the difference disappeared at 21 days of life (except for alphaCaMKII, which content normalized at 60 days old). The same pattern was found for [(3)H]glutamate binding, whereas [(3)H]glutamate uptake was not affected. The D group also showed memory deficits in the inhibitory avoidance, increased in the exploratory pattern in open-field, and anxiety-like behavior in plus-maze. Taken together, our results suggest that dietary omega3 content is relevant for glutamatergic system development and for behavioral performance in adulthood. The putative correlation among the neurochemical and behavioral alterations caused by dietary omega3 deficiency is discussed.

Antidepressant profile of Ptychopetalum olacoides Bentham (Marapuama) in mice.

Depression has become of universal major importance, and it is therefore vital to expand the armamentarium for treating the condition. Lack of motivation and lassitude are major symptoms treated with the use of Marapuama (Ptychopetalum olacoides, PO) remedies by communities in the Brazilian Amazon. Considering the prominence of such symptoms in depression, the present study was designed to verify the effects of a standardized PO ethanol extract (POEE) on the forced swimming (FST) and tail suspension tests (TST). POEE i.p. (15-100 mg/kg) and oral (300 mg/kg) resulted in a significant and dose-related anti-immobility effect. We further examined the involvement of dopamine, noradrenaline and serotonin in these antidepressant-like effects. POEE effects were prevented when catecholamine synthesis was inhibited by -alpha-methyl-rho-tyrosine (AMPT) (100 mg/kg, i.p.), while inhibition of serotonin synthesis with rho-chlorophenylalanine methyl ester hydrochloride (PCPA) (100 mg/kg, i.p.) was devoid of effect. The blockade of beta-adrenergic (propranolol 2 mg/kg, i.p.) and D(1) dopamine (SCH 23390 0.5 mg/kg, i.p.) receptors prevented POEE anti-immobility effects; by contrast, blockade of D(2) dopamine (sulpiride 2 and 50 mg/kg, i.p.) receptors was ineffective. Consistent with traditional use, the results indicate that POEE possesses antidepressant-like effects, possibly mediated by beta-adrenergic and D(1) dopamine receptors.

Inhaled linalool-induced sedation in mice.

Linalool is a monoterpene often found as a major component of essential oils obtained from aromatic plant species, many of which are used in traditional medical systems as hypno-sedatives. Psychopharmacological evaluations of linalool (i.p. and i.c.v.) revealed marked sedative and anticonvulsant central effects in various mouse models. Considering this profile and alleged effects of inhaled lavender essential oil, the purpose of this study was to examine the sedative effects of inhaled linalool in mice. Mice were placed in an inhalation chamber during 60 min, in an atmosphere saturated with 1% or 3% linalool. Immediately after inhalation, animals were evaluated regarding locomotion, barbiturate-induced sleeping time, body temperature and motor coordination (rota-rod test). The 1% and 3% linalool increased (p<0.01) pentobarbital sleeping time and reduced (p<0.01) body temperature. The 3% linalool decreased (p<0.01) locomotion. Motor coordination was not affected. Hence, linalool inhaled for 1h seems to induce sedation without significant impairment in motor abilities, a side effect shared by most psycholeptic drugs.

MK801- and scopolamine-induced amnesias are reversed by an Amazonian herbal locally used as a "brain tonic".

RATIONALE: Traditional remedies prepared from Ptychopetalum olacoides (PO) are used throughout the Amazon to alleviate age-related conditions. These formulas are mainly used by elders, and alleged effects may be related to the anticholinesterase properties identified in a standardized ethanol extract of this species [P. olacoides standardized ethanol extract (POEE)]. OBJECTIVES: To further characterize the potential of this extract for developing drugs useful to treat cognitive deficits, the effects of POEE on scopolamine (scop)- and MK801-induced amnesias (acquisition, consolidation, and retrieval) in mice were investigated. RESULTS: Scop (3.0 mg/kg, ip) significantly impaired memory (all three phases) in the step-down inhibitory avoidance protocol. As expected, MK801 (0.1 mg/kg, ip) was amnesic regarding acquisition and consolidation, but not retrieval. POEE (100 mg/kg, ip) reversed the scop-induced impairment in all three phases of long-term and short memories, whereas only the memory consolidation deficit was reversed with MK801-induced amnesia. CONCLUSIONS: This study complements previously reported promnesic properties of this plant extract and suggests that POEE may be further developed for treating conditions associated with cognitive deficits, especially those linked with cholinergic malfunction.

Effects of Marapuama in the chronic mild stress model: further indication of antidepressant properties.

ETHNOPHARMACOLOGY RELEVANCE: Ptychopetalum olacoides Bentham (PO) (Olacaceae), known as Marapuama, is regarded as a "nerve tonic" in the Amazon. Traditional uses include states of lassitude with noticeable lack of desire/motivation, and to manage particularly stressful (physical and/or psychological) circumstances. Suggestive of antidepressant activity, we have established that a specific PO ethanol extract (POEE) significantly decreases immobility in the tail suspension and forced swimming tests. AIM OF THE STUDY: The aim of this study was to verify the effects of POEE in the unpredictable chronic mild stress (UCMS) depression model in mice, given the construct and face values of the UCMS as an experimental model of depression and the traditional use of this species. MATERIALS AND METHODS: Over 6 weeks BALB/c mice were subjected to the UCMS protocol. The effects of POEE (50, 100, 300mg/kg, p.o.) and imipramine (20mg/kg, i.p.) were evaluated in relation to coat state, splash-test grooming, and corticosterone levels. RESULTS: The coat state degradation, decreased grooming and increased serum corticosterone induced by UCMS were prevented by POEE and imipramine treatments. CONCLUSION: In addition to supporting traditional claims and previously reported antidepressant properties for POEE, this study shows that POEE prevents stress-induced HPA hyperactivity.

Serotonin receptors contribute to the promnesic effects of P. olacoides (Marapuama).

Nootropic, antioxidant, and neuroprotective properties have been shown in a standardized ethanol extract of Ptychopetalum olacoides (POEE), a medicinal plant traditionally used by the Amazonian elderly population. It has been revealed that POEE mechanisms of action include anticholinesterase effects, and involve beta-adrenergic and dopamine D(1) receptors. The purpose of this study was to verify the role of serotonin receptors in the promnesic effects of this standardized extract. The step-down task in mice and selective serotonin antagonists were used. The study reveals that POEE promnesic effects on short-term (acquisition, consolidation and retrieval) and long-term (retrieval) declarative aversive memories are increased by 5HT(2A) (but not 5HT(1A)) serotonin antagonists (spiperone and pindolol, respectively). The observed synergism between POEE and spiperone can be interpreted as the combined effects of two subeffective doses of two 5HT antagonists, or the known synergism between an acetylcholinesterase inhibitor (POEE) and a 5HT antagonist. In conclusion it is suggested that 5HT(2A) serotonin receptors are relevant for the promnesic effects of this extract, adding to its multiple mechanisms of action.

Beyond the myth of expensive clinical study: assessment of traditional medicines.

Clinical studies with human subjects represent the only assessment of effectiveness and safety that can translate into medical practice, and national or local health policy. There are several reasons why traditional medicines (in fact medicinal plants and other alternative or complementary medicines) should be subjected to more clinical research with patient observation and follow-up: firstly, this would help to select products of interest for further investigations in ethnopharmacology; secondly, it could translate into immediate recommendations for the population using the assessed local treatments. Contrary to a commonly held myth, clinical studies can be conducted at relatively low cost, if one works with local/regional research institutes and with doctoral students, focusing on meaningful clinical measures rather than sophisticated laboratory analyses. This paper describes special designs of clinical studies, appropriate for traditional medicines and tested in the field, including: the retrospective treatment-outcome population survey, the prognosis- outcome method (with modern physicians observing progress of patients treated by a traditional healer), the dose-escalating prospective study (detecting a dose-response phenomenon in humans). It is suggested that this approach offers the best cost-effective course of action for obtaining maximal benefits from traditional medicines, especially those used for treating endemic diseases.