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Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway

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Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway

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... G. P. B. Lima et al., 2013) -Anti-depressant (Komori et al., 1995) (Komiya et al., 2006) -Anti-nociceptive (Do Amaral et al., 2007) -Increasing motility (Buchbauer et al., 1993) -Anti-inflammatory (Lappas & Lappas, 2012) -Anti-carcinogenic (Haag et al., 1992) -Antioxidant (Roberto et al., 2010) -Antifungal, anti-bacterial -Anti-inflammatory (E. B. Russo & McPartland, 2001) -Dries excess fluids (Mihai & Holban, 2017) -May be responsible for dry mouth -Anti-microbial (Da Silva et al., 2012) -Memory enhancing (Kennedy et al., 2011) Piney, dry, woody, resinous, herbal BP:155 °C -Pinene C10H16 -Anxiolytic (Satou et al., 2014) (Yang et al., 2016) -Anti-nociceptive (Him et al., 2008) -Anti-depressant (Guzmán-Gutiérrez et al., 2015) -Bronchodilator (Falk et al. 1990) -Relaxant, anti-spasmodic (Câmara et al., 2003) -Increasing motility (Buchbauer et al., 1993) -Memory enhancing (Kennedy et al., 2011) -AChE inhibitor (F. J. B. Lima et al., 2010) -Anti-microbial, anti-cancer antiinflammatory, anti-allergic (Gil et al., 1989) -Anti-irritant, anti-inflammatory, antimicrobial, analgesic, anti-biotic (Srivastava et al., 2010) citrus, floral, sweet, spicy, peppery BP: 153°C ...
... -Relaxing (M. A. Lewis et al., 2018) -Sedative (Buchbauer et al., 1991) -Anxiolytic (E. B. Russo & McPartland, 2001) -Anti-depressive (Komori et al. 1995) (Guzmán-Gutiérrez et al., 2015 -Analgesic (Batista et al., 2010) (Peana et al., 2002) -Neuroprotective, anti-inflammatory (Pereira et al., 2018) -Anti-microbial (Carson & Riley, 1995) floweryfresh, spicy, wood ...
... Its anxiolytic and sedative effects are virtually caused by its inhibitory activity on AChE [111]. In the case of many antidepressants, the linalool mechanism of action has been found to involve interaction with dopaminergic, serotonergic, and noradrenergic pathways [112]. Upon interacting with the postsynaptic serotonin A 1 receptor (5-HT 1A receptor), the overall result is increased dopaminergic and decreased serotonergic receptor activity, which accounts for improved depression. ...
... Upon interacting with the postsynaptic serotonin A 1 receptor (5-HT 1A receptor), the overall result is increased dopaminergic and decreased serotonergic receptor activity, which accounts for improved depression. On the other hand, linalool potentiates α 2adrenergic receptor activity, reversing the state in depression [112]. ...
Chapter
Insomnia and sleep apnea represent the most prevalent sleep disorders worldwide. Incidences are discouraging, with perhaps less attention in some parts, and the complexity in the pathophysiologies of the two diseases pose a major challenge to clinicians and researchers. Mainstream therapeutic regimens are afflicted by adverse side effects, laborious, demanding enormous amounts of money, and are in particular, less accessible to the vast majority. Traditional medicine remains critically the “Hobsons’s choice” and stands out as a scaffold for the development of novel drugs with more desirable pharmacological attributes. This chapter covers the pathophysiological attributes of insomnia and sleep apnea, pointing out their interplay, possible biomarkers, and targets for both conventional and alternative therapeutic approaches. The chapter further delves more into the role of selected most important plant species in the management of insomnia and sleep apnea. Realizing the importance of phytochemistry in the drug discovery endeavor, the chapter, as well, underscores the phytochemical profile underlying the neuropharmacological relevance of each plant to its possible effectiveness in improving sleep quality.
... Diverse essential oils and other biological substances extracted from natural resources have been targets for new drug discovery and have established a wide variety of biological actions [5]. Linalool is one of the most abundant naturally occurring monoterpenes, located in the essential oil fraction of numerous plants of aromatic species [6]. Linalool has been distinguished by the Food and Drug Administration as a safe product to be used for flavoring and as an adjuvant for human consumption [7]. ...
... However, linalool can be toxic when ingested in large doses (more than 500 mg/kg/day in rodents) [8]. Linalool has been evidenced to have abundant pharmacological actions, including antidepressant [6], antifungal [9], gastro-protective [10], anti-nociceptive [11], and anti-tumor [12] activities. In addition, linalool protects against smoking-induced lung inflammation through inhibiting NF-κB activation [13] and, similarly, inhibits Lipo-polyssaccharide (LPS)-induced inflammation in BV2 microglia cells [14]. ...
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Background: Myocardial infarction (MI), a life-threatening disorder, arises from the imbalance between oxygen supply and myocardial demand. Linalool is a naturally occurring monoterpenes with proved numerous pharmacological actions. This study investigated the cardioprotective effect of Linalool on isoproterenol (ISO)-induced MI in rat models and explored part of the underlying molecular mechanisms. Methods: Rats were divided into five groups; groups I and II served as normal and linalool control groups, Group III administered ISO alone; groups V and VI received two different doses of Linalool and were challenged by ISO. Different biochemical parameters were determined, including hemodynamic, infarction size, cardiac enzymes, apoptotic markers, and inflammatory mediators. Results: Linalool limited the infarcted area size and diminished the elevated cardiac enzymes. Linalool escalated HO-1 and Nrf2, both nuclear and cytosol fractions, and reduced Keap 1. Linalool enhanced cardiac antioxidant activities, reduced inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), nuclear factor-κ-B (NF-κB), interleukin 1 beta (IL-1β), interleukin 6 (IL-6)), apoptotic markers (Caspase-3, Caspase-9, and Bax), and elevated Bcl2. Conclusion: Linalool could act as an effective cardioprotective agent in the MI model through improving the oxidative condition, probably via the Nrf2/HO-1 pathway and by abolishing both apoptotic and inflammatory responses.
... In another study, linalool was tested for antidepressant activity using a forced swimming test. The study has shown that linalool produced an anti-depressant effect by affecting the serotonergic pathway (22). ...
... Investigation of anti-depressant potential of β-pinene in mice using forced swimming test showed a marked decrease in the immobility time confirming its beneficial potential (22). ...
... Serotonins are vital as their release and reuptake levels can be altered to overcome stress (Chaouloff 2000;Guzman-Gutierrez et al. 2012). They also interact with the body's adrenergic receptors that play a key role in stressinduced behavioral changes (Guzman-Gutierrez et al. 2015). Another key finding is the interaction of dopaminergic receptors (D1 receptors) with beta-pinene and is the mechanisms followed by majority of antidepressant drugs accessible in the market (Guzman-Gutierrez et al. 2015). ...
... They also interact with the body's adrenergic receptors that play a key role in stressinduced behavioral changes (Guzman-Gutierrez et al. 2015). Another key finding is the interaction of dopaminergic receptors (D1 receptors) with beta-pinene and is the mechanisms followed by majority of antidepressant drugs accessible in the market (Guzman-Gutierrez et al. 2015). Similarly, hyperforin present in the extracts of Hypericum perforatum is another effective antidepressant terpenes and works by inhibiting the neuronal uptake of mood regulators including norepinephrine, serotonin, and dopamine. ...
Chapter
Nature is the immense source of chemical compounds or substances usually acknowledged as natural products. Plants are the considerable source of an inestimable diversity of natural products with manifold chemical structures and functionalities. These natural compounds have various healthcare benefits and are commonly termed as the primary metabolites (PPMs) and secondary metabolites (PSMs). Biogenically, there are basically four main classes of secondary metabolites: phenolics and polyphenolics, terpenes, nitrogen-containing alkaloids, and sulfur-containing compounds. The functional groups and other structural features present in a molecule are accountable for delivering a variety of characteristics including therapeutic applications and the solubility and stability of the molecules. The structural features of compounds useful to understand the relations between their molecular structures and biological or pharmacological activities are attributed to being responsible for arousing a target biological effect in the organism. This chapter will delineate the chemistry, classification, physicochemical properties, and numerous biological activities of plant secondary metabolites. In order to develop the new derivatives of therapeutic value, the present chapter would be useful for medicinal chemists to design and introduce new chemical groups into these biomedical compounds and to explore their biological effects.
... Indeed, α-pinene (0.63 mM) potentiated the response of GABA A receptors to GABA by ∼49-57% compared to GABA alone, invitro (74). In addition, β-pinene targets the serotonin 5-HT 1A , and β-adrenergic receptor sub-types to exert antidepressant effects in mice (75), suggesting that β-pinene may possess similar properties to existing anti-depressant drugs that target monoaminergic (eg serotonin and norepinephrine) signalling in the brain (76); however, further studies are needed to confirm. Furthermore, evidence suggests that pinene is neuroprotective, with anti-inflammatory and anti-oxidant properties, and may exert therapeutic benefits in the brain in multiple disease states. ...
... There was also an increase in striatal dopamine [with no change in dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)] and reduced norepinephrine in the treated mice compared to the anxiogenic controls (145). Guzmán-Gutiérrez et al. (75) showed antidepressant-like effects (i.e., increased mobility in the forced swim test) following linalool administration that were blocked by pre-treatment with 5-HT 1A receptor antagonist, WAY 100635, but not 5-HT synthesis inhibitor, para-chlorophenylalanine, demonstrating a role for the 5-HT1A receptor in the antidepressant mechanisms of action of linalool. Another study reported reduced immobility of mice in the tail suspension test following (-)-linalool in a dose-dependent manner (100 and 200 mg/kg i.p., not 10, 50 mg/kg i.p.) (146). ...
Article
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“Medicinal cannabis” is defined as the use of cannabis-based products for the treatment of an illness. Investigations of cannabis compounds in psychiatric and neurological illnesses primarily focus on the major cannabinoids, cannabidiol (CBD) and Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), which are hypothesised to benefit multiple illnesses manifesting cognitive impairment, neurodegeneration and neuro-inflammation, as well as chronic pain, epilepsy and post-traumatic stress disorder, respectively. The cannabis plant contains >500 compounds, including terpenes responsible for the flavour and fragrance profiles of plants. Recently, research has begun providing evidence on the potential use of certain plant-derived terpenes in modern medicine, demonstrating anti-oxidant, anti-inflammatory, and neuroprotective effects of these compounds. This review examined the effects of two key terpenes, pinene and linalool, on parameters relevant to neurological and psychiatric disorders, highlighting gaps in the literature and recommendations for future research into terpene therapeutics. Overall, evidence is mostly limited to preclinical studies and well-designed clinical trials are lacking. Nevertheless, existing data suggests that pinene and linalool are relevant candidates for further investigation as novel medicines for illnesses, including stroke, ischemia, inflammatory and neuropathic pain (including migraine), cognitive impairment (relevant to Alzheimer's disease and ageing), insomnia, anxiety, and depression. Linalool and pinene influence multiple neurotransmitter, inflammatory and neurotrophic signals as well as behaviour, demonstrating psycho-activity (albeit non-intoxicating). Optimising the phytochemical profile of cannabis chemovars to yield therapeutic levels of beneficial terpenes and cannabinoids, such as linalool, pinene and CBD, could present a unique opportunity to discover novel medicines to treat psychiatric and neurological illnesses; however, further research is needed.
... After preprocessing, fast Fourier transformation converted the signals from the time domain to the frequency domain, where frequencies were used to separate different rhythmic brain activities. Signals were categorized into five frequency bands: delta (1-4 Hz), theta (5-8 Hz), alpha (9-12 Hz), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and gamma (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Additionally, the strength of the brain waves detected by each electrode were normalized by the average value, and a brain map was created using these values in order to obtain the mean value for each electrode. ...
... In previous reports, higher levels of 2-ethyl-1-hexanol were detected also in the volatiles of both fresh tzitzilché flower (14.6%) and tree peony flower (19.76%), which was similar to the results of this study [37,38]. Furthermore, d-limonene and pinene are also commonly used in aromatherapy to relieve anxiety emotion and have some sedative effects [39]. Terpineol and eucalyptol have also been reported to have medicinal value in the treatment of anxiety emotion [40]. ...
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Coriander is a popular herb with versatile applications. However, the current research about coriander medicinal values have been mainly focusing on its extracts while lacking in the relationship between living coriander plants and emotion. Therefore, this study aims to investigate the effects of coriander plants on human emotions and physiological activities. The results showed that the main Volatile organic compounds (VOCs) of coriander plants were 2-ethyl-1-hexanol, d-limonene, eucalyptol, benzyl alcohol, Isophorone, dimethyl glutarate, α-terpineol, styrene, methyl methacrylate, α-pinene. Coriander plants could significantly reduce the angry sub-scores, alpha amylase and amino acids (arginine, proline, histidine, and taurine) concentrations in saliva. Theta (4–8 Hz) band activity of the cerebral cortex was significantly enhanced. Moreover, taurine significantly positively correlated with anger and negatively correlated with vigor. All the results signified that coriander plant could influence the activity of brain electrophysiological and salivary secretion through its VOCs to improve people’s negative emotions.
... There are data regarding the antimicrobial properties of β-pinene, used either as a purified chemical or as a constituent of essential oils [12,13]. Some studies have also demonstrated that β-pinene and trans-pinocarveol, contained in the oils, show various biological effects [14][15][16][17][18]. ...
Article
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Mutagenesis and adaptation of the psychrotrophic fungus Chrysosporium pannorum A-1 to the toxic substrate β-pinene were used to obtain a biocatalyst with increased resistance to this terpene and improved bioconversion properties. Mutants of the parental strain were induced with UV light and N-methyl-N′-nitro-N-nitrosoguanidine. Mutants resistant to β-pinene were isolated using agar plates with a linear gradient of substrate concentrations. Active mutants were selected based on their general metabolic activity (GMA) expressed as oxygen consumption rate. Compared to the parental strain, the most active mutant showed an enhanced biotransformation ability to convert β-pinene to trans-pinocarveol (315 mg per g of dry mycelium), a 4.3-fold greater biocatalytic activity, and a higher resistance to H2O2-induced oxidative stress. Biotransformation using adapted mutants yielded twice as much trans-pinocarveol as the reaction catalyzed by non-adapted mutants. The results indicate that mutagenesis and adaptation of C. pannorum A-1 is an effective method of enhancing β-bioconversion of terpenes.
... In addition, Lavandula angustifolia essential oil is rich in linalool, which has been reported to interact with the serotonergic system and have an antidepressant effect in rodents. 38 , 48 In our study, this component was observed in higher concentration in relation to the ISO 3515:2002, 49 which might aided in its therapeutic properties. ...
Article
Background: To evaluate the effect of Lavandula angustifolia essential oil inhalation on sleep and menopausal symptoms in postmenopausal women with insomnia. Participants: 35 postmenopausal women with a clinical diagnosis of insomnia were included, 17 in Aroma Group (AG) and 18 in Placebo Group (PG). Methods: In this double-blind, randomized controlled trial, PG participants inhaled sunflower oil and AG participants inhaledLavandula angustifolia essential oil, for 29 days. Both groups received sleep hygiene guidelines before the intervention and weekly follow-up during it. Evaluations were performed before and after intervention. All statistical analyses and intention-to-treat test were performed in SPSS 22. Sleep quality (Primary outcome) was measured by Pittsburgh Sleep Quality Index. Secondary outcomes were polysomnography data, severity of insomnia, anxiety and depression symptoms, and postmenopausal symptoms. Results: There were no significant differences between groups after intervention in the primary outcome (P = 0.22; effect size=0.69); however, a tendency of improvement in wake after sleep onset (WASO) was observed (P = 0.07; effect size=0.81; B = 42.2). Both groups presented better sleep quality over time (AG P < 0.001; PG P = 0.011). AG participants showed a significant decrease in sleep onset latency (P = 0.001), depression levels (P = 0.025), hot flashes (P < 0.001), postmenopausal symptoms (P < 0.001) and, in polysomnography data, increased sleep efficiency (P = 0.002) compared to baseline. Conclusion: Although no significant differences were observed between groups, our data presented a tendency of improvement in WASO. Moreover, AG participants had enhanced overall sleep pattern, quality and sleep efficiency. Weekly follow-up and sleep hygiene instructions were essential for both groups to show improvement in almost all outcomes. Clinical trial registration: Brazilian Registry of Clinical Trials, www.ensaiosclinicos.gov.br, RBR-5q5t5z.
... Recently, α-pinene, β-pinene, car-3-ene, borneol, verbenol, pinocarveol and linalool, when inhaled, have shown anti-depressive and anxiolytic functions (Linck et al., 2010;Souto-Maior et al., 2011;Kessler et al., 2014;Guzmán-Gutiérrez et al., 2015;Woo and Lee, 2020). ...
Article
The Mediterranean basin represents one of the key hotspots in terms of biodiversity and endemic floristic richness in the world (i.e., a reservoir of plant biodiversity). With ongoing climate change, the Mediterranean vegetation is increasingly exposed to different sources of environmental stresses, such as drought, heat, and solar irradiance. To cope with these severe abiotic stresses, beside morpho-anatomical traits, Mediterranean endemic species enhance the production of secondary metabolites, especially terpenes and polyphenols. These compounds have different roles in plants. Terpene and polyphenol compounds play a key antioxidant function (quenching Reactive Oxygen Species) thus improving ozone and drought tolerance, while also acting as pollinator attractors and repellents for dangerous herbivorous insects (contributing to the taste and odour of different plant tissues). In addition to their roles in plants, these bioactive compounds provide multiple health-promoting benefits for humans. Indeed, they can be used in different types of industries, such as pharmaceutical, nutraceutical, green (as supplements to fossil fuel and insecticides) and cosmetic industries. In conclusion, these compounds may be considered as key innovative components in different technological domains
... The first one primarily emits α-pinene, mycrene and ∆ 3 carene, caryophyllene and β-pinene [87,88], while the second one emits limonene [89]. Though current research on the mental health effects of these volatile organic compounds is mostly focused on animal experiments, the results indicate that these terpenes have antidepressant/anxiolytic functions and contribute to mood regulation [89][90][91][92][93][94]. However, mechanisms and pathways through which terpenes contribute to human health remain unclear [82,95]. ...
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This study evaluated the short-term responses of physiological and psychological indices and examined the human senses that are mostly engaged during a green space and urban exposure in residents of Athens, Greece. The forest had beneficial effects for human physiology, anxiety and mood states and was also associated with all five senses and positive reactions, while the opposite was observed in the urban center. The difference of pre- and post-green space exposure salivary cortisol was correlated with the participants’ environmental profile and body mass index. Green spaces can alleviate stress and improve overall mood, while helping individuals experience their surroundings with all five senses.
... Among the top ten compounds, the content of limonene (57.98%) is greatest, which has been considered to be the most important active component of the herb's anti-depressant effects [16,30] . Encouragingly, linalool (9.63%), another major component of essential oils, has also been shown to have antidepressant activity in previous experiments [31,32] . Moreover, although presented at a lower proportion, β-Caryophyllene, which is identi ed in CREOs, has been found it to signi cantly improve depression-like effects [33,34] . ...
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Citrus reticulata , has been used for various diseases such as cough. According to previous studies, the essential oil of C. reticulata (CREOs) have been shown to be effectively alleviate depression-like behaviors in mice. This study is aimed to investigate the antidepressant-like effect of CREOs in the rapid reserpine-induced depression model mice as well as its possible mechanisms. The experiment was conducted in six groups, each with four mice. The essential oil group and the control group were administered by sniffing (1h/d), while the reserpine group and fluoxetine group by intraperitoneal injection. Body weight, forced swimming test (FST) and tail suspension test (TST) were used to assess depressive behavior. The compositions and contents of CREOs were analyzed by GC-MS. The results indicated that reserpine could reduce the weight of mice and prolong the immobility time of FST and TST. Moreover, the level of 5HT-1A, GR and Nissl bodies in the brain tissue were significantly reduced, while the level of BDNF was increased in reserpine-treated mice. The administration of CREOs could effectively inhibit the weight loss and the prolongation of immobility time caused by reserpine. In addition, the treatment of CREOs has also been shown to reverse the changes in Nissl body, 5-HT, GR and BDNF levels. Limonene was the main active component of CREOs and might be related to the reduction of BDNF. By up-regulating the level of BDNF, CREOs could regulate the hyperexcitability of the HPA axis, thereby increasing the level of neurotransmitters and restoring neurons.
... Baik β-Pinen maupun α-Pinen juga ditemukan dalam jumlah besar pada penelitian Moronkola et al., 2007) dan (Lamaty et al., 1991). Senyawa tersebut telah dilaporkan memiliki aktivitas antibakteri (Silva et al., 2012) dan antidepresan (Guzmán-Gutiérrez et al., 2015). Senyawa β-Felandren terdapat dalam jumlah kecil pada penelitian ini dan Moronkola et al. (2007). ...
Article
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ABSTRAK Daun Insulin (Tithonia diversifolia) merupakan salah satu tanaman obat tradisional yang digunakan masyarakat Kalimantan Selatan untuk mengatasi glikemia. Analisis komposisi Kimia penyusun minyak atsiri dari daun Insulin yang berasal dari Kalimantan Selatan belum dilakukan. Oleh karena itu, penelitian ini bertujuan untuk menentukan komponen kimia penyusun minyak atsiri Daun Insulin (T. diversifolia) untuk melengkapi data dasar daun Insulin yang diperoleh dari Kalimantan Selatan. Sampel daun Insulin diperoleh tumbuh liar dari Desa Hulu Pasar, Kabupaten Hulu Sungai Utara Kalimantan Selatan, Indonesia. Sebelum didistilasi, daun dikeringanginkan kemudian dikeringkan dengan oven pada suhu 50 ᵒC selama 30 menit. Metode distilasi rebus digunakan untuk mendapatkan minyak atsiri daun Insulin. Sampel didistilasi selama 48 jam sehingga diperoleh minyak bening berwarna kekuningan dengan rendemen minyak 0,02% (b/b). Minyak hasil distilasi selanjutnya dianalisis dengan Kromatografi Gas-Spektra Masa (KG-SM). Hasil kromatogram minyak atsiri daun Insulin menunjukkan adanya 6 puncak yang teridentifikasi melalui spektra massa merupakan senyawa limonen (32,14%), β pinen (24,88%), α pinen (21,73%), trans kariofilen (11,68%), bisiklogermakren (5,24%), dan β felandren (4,33%). Komponen kimia penyusun minyak atsiri daun Insulin termasuk dalam golongan monoterpena dan seskuiterpena hidrokarbon. Kata-kata kunci: daun Insulin; distilasi; limonen; minyak atsiri; Tithonia diversifolia PENDAHULUAN Daun Insulin (Tithonia diversifolia) merupakan salah satu tanaman obat tradisional yang digunakan masyarakat untuk mengatasi glikemia. Karena khasiatnya, masyarakat Kalimantan Selatan menyebutnya dengan tanaman "Insulin" yang merujuk pada hormon yang memiliki peran pada kontrol kadar glukosa pada darah. Beberapa penelitian melaporkan tentang aktivitas biologis dari T. diversifolia yaitu antihiperglikemia (Zhao et al.
... Similarly, linalool has been demonstrated as an important active compound with antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects (Levenberg et al., 2020). Further evaluation of β-pinene and linalool in mice demonstrated that L. glaucescens exert their antidepressant-like activity through interaction with the monoaminergic system, as demonstrated by suppression of the pharmacological activity in the presence of WAY100635 (antagonist of 5-HT1A and agonist of D4), yohimbine (α2 receptor antagonist), propranolol (β receptor antagonist), SCH23390 (D1 receptor antagonist) and neurotoxin DSP-4 (noradrenergic neurotoxin) but not in the presence of PCPA (a serotonin synthesis inhibitor) (Guzmán-Gutiérrez et al., 2015;Munir et al., 2020). Neuroprotective properties of an ethanolic extract and an isolated compound, 5,7,30,40-tetrahydroxy-isoflavone, demonstrated an anti-inflammatory activity by inhibiting carrageenan-induced paw edema and by reducing the influx of leucocytes in a model of persistent pain induced by partial sciatic nerve ligation (Simão Da . ...
Article
Ethnopharmacological relevance For thousands of years, different cultural groups have used and transformed natural resources for medicinal purposes focused on psychological or neurological conditions. Some of these are recognized as central nervous system (CNS) disorders and diseases, whereas other ethnopsychiatric interpretations are explained in culture-specific terms. In traditional Mayan medicine, several herbs have been part of treatments and rituals focused on cultural and ethnomedical concepts. Aim of review This study aims to provide a comprehensive overview of the medicinal plants used in Mesoamerica by traditional healers and Mayan groups to CNS disorders and associate the traditional use with demonstrated pharmacological evidence to establish a solid foundation for directing future research. Methods A systematic search for primary sources of plant use reports for traditional CNS-related remedies of Mesoamerica were obtained from library catalogs, thesis and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct), and entered in a database with data analyzed in terms of the usage frequency, use by ethnic groups, plant endemism, and pharmacological investigation. Results A total of 155 plants used for ethnopsychiatric conditions in Mesoamerica by Mayan groups were found, encompassing 127 native species. Of these, only 49 native species have reported in vitro or in vivo pharmacological analyses. The most commonly reported ethnopsychiatric conditions are related to anxiety, depression, memory loss, epilepsy, and insomnia. The extent of the scientific evidence available to understand the pharmacological application for their use against CNS disorders varied between different plant species, with the most prominent evidence shown by Annona cherimola, Justicia pectoralis, J. spicigera, Mimosa pudica, Persea americana, Petiveria alliacea, Piper amalago, Psidium guajava, Tagetes erecta and T. lucida. Conclusion Available pharmacological data suggest that different plant species used in traditional Mayan medicine may target the CNS, mainly related to GABA, serotonin, acetylcholine, or neuroprotective pathways. However, more research is required, given the limited data regarding mechanism of action at the preclinical in vivo level, identification of active compounds, scarce number of clinical studies, and the dearth of peer-reviewed studies.
... 22 is slightly less common in Cannabis plants than 19 (Nuutinen 2018). Its antidepressant action is, similar to that of synthetic drugs, mediated mainly by influencing the serotonergic system (Guzmán-Gutiérrez et al. 2015). ...
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
... The pretreatment with WAY100635 (an antidepressant drug) and yohimbine stopped the antidepressant effect of linalool. The antidepressant effect of linalool is mediated through the receptors of the serotonergic and monoaminergic systems [104]. ...
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Background Depression is a most common mental disorder. The symptoms of depression include loss of energy, changes in appetite, more or less sleep, anxiety, low concentration, uncertainty, restlessness, feelings of worthlessness, guilt, or despair, and thoughts of self-harm or suicide. In order to provide safe, efficient and cost-effective medication, the plants based principles in isolation or in combination with traditional antidepressants are attracting increasing attention for depression therapy. Method The information regarding the present review and its contents such as collected from published literature materials in different international journals. We have used different search engines such as PubMed, Medline, ResearchGate Google Semantic Scholar and ScienceDirect. For this purpose, the data obtained were properly organized and suitably analyzed to include in this article. Results Most of the phytomolecules isolated from the medicinal plants display antidepressant effect through the synaptic regulation of levels of neurotransmitters such as dopamine, serotonin, and noradrenaline in different parts of the brain. The mechanism of action of phytomolecules also involves negative regulation of the activities of monoamine oxidase (MAO) and acetylcholinesterase (AChE) and prevention of hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis. In addition, the strong antioxidative and antiinflamatory potential of these phytochemicals offer synergy to their antidepressant as well as antipsychosomatic functions. Conclusion The application of phytochemicals has proved it to be a safe, cost effective and efficient therapeutic agent to treat the patients suffering from mild to severe state of depression and other psychiatric disorders. The potential phytochemicals may be further optimized using in silico tools to develop better antidepressants and antisychotic agents in future.
... Similar effects are reported for borneol, verbenol, isopulegol, and pinocarveol [92,93]. Moreover, inhaled linalool and β-pinene have shown anxiolytic [94,95] and antidepressive [96,97] properties in different animal models. ...
Article
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The aim of this research work is to analyze the chemistry and diversity of forest VOCs (volatile organic compounds) and to outline their evidence-based effects on health. This research work was designed as a narrative overview of the scientific literature. Inhaling forest VOCs like limonene and pinene can result in useful antioxidant and anti-inflammatory effects on the airways, and the pharmacological activity of some terpenes absorbed through inhalation may be also beneficial to promote brain functions by decreasing mental fatigue, inducing relaxation, and improving cognitive performance and mood. The tree composition can markedly influence the concentration of specific VOCs in the forest air, which also exhibits cyclic diurnal variations. Moreover, beneficial psychological and physiological effects of visiting a forest cannot be solely attributed to VOC inhalation but are due to a global and integrated stimulation of the five senses, induced by all specific characteristics of the natural environment, with the visual component probably playing a fundamental role in the overall effect. Globally, these findings can have useful implications for individual wellbeing, public health, and landscape design. Further clinical and environmental studies are advised, since the majority of the existing evidence is derived from laboratory findings.
... As a result, participants who inhaled cypress orientation had significantly decreased depression than in the pre-test, while those who did not inhale orientation had increased depression compared to the pre-test. In addition, although it is a preclinical study of animal behavior models, BVOCs showed anti-anxiety [110,111] and antidepressant properties [112,113]. It has been proven that tactile stimulation caused by the contact of bark and plant leaves of trees can also relax and stimulate parasympathetic nerve activity more than touching other materials [114,115]. ...
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... Se encuentra en altitudes que van de 800 m a 2880 m s.n.m. Se han identificado 45 componentes en los aceites esenciales del laurel y demostrado actividad antidepresiva y ansiolítica a dosis de 100 mg/kg y 300 mg/kg (Guzmán-Gutiérrez et al., 2015). Los monoterpenos b-pineno y linalol fueron identificados como los principios activos del aceite, pudiendo tener gran potencial para su actividad en el sistema nervioso central. ...
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... The volatile compounds α-pinene and β-pinene were also found in high concentrations in the present study and have been evaluated for biological activities. Both compounds presented antibacterial, antiviral, antifungal and hypotensive activities [48], α-pinene presented anti-inflammatory, hypoglycemic [49], and gastroprotective activities [50] whereas β-pinene showed antidepressant [51] and antiviral [52] properties. ...
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... Linalool was reported to reduce blood pressure and has been suggested to have direct effects on vascular smooth muscle leading to vasodilation in the rabbit carotid artery [27]. In addition, linalool has been demonstrated to be an antidepressant in mice [28]. Linalyl acetate has been reported to have antihypertensive properties in a hypertension-related ischaemic injury model in rodents [29] and has also been shown to induce the recovery of the acute nicotine-induced cardiovascular disruptions in rodents [30]. ...
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... Herein, antidepressant activities of (+)-limonene epoxide were demonstrated using the forced swimming and tail suspension protocols. Both of them are routinely applied to search for compounds with antidepressant action (Guzmán-Gutiérrez et al. 2015;Yan et al. 2015). The behavior of immobility exhibited by mice under subjected inevitable and/or inescapable stress reflects behavioral despair, which in turn may mimic behavioral disorders in humans, such as depression (Zhen et al. 2012). ...
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... Considering the effects of the plant alkaloids during elevated plus maze, FST and TST models, we opined that our study model of sub-chronic exposure to CSAE, DSAE, NTAE, and CMAE may be used to study anxiety and depression in a rat model as the changes observed were absent in the control group of the same experiment. The major neurochemical process in depressive disorder is the impairment of the monoaminergic neurotransmission, with a concomitant depleted serotonin and dopamine concentration (Guzmán-Gutiérrez et al. 2015). The ability of CSAE, DSAE, NTAE, and CMAE to reduce MAO activity in the present study is consistent with a previous study where the alkaloid extracts inhibited brain MAO activities in a concentration-dependent manner during an ex vivo study (Fasakin et al. 2021). ...
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This study investigated the modulatory effects of alkaloid extracts of Cannabis sativa (CSAE), Datura stramonium (DSAE), Nicotiana tabacum (NTAE) and male Carica papaya (CMAE) on neurotransmitter, neurotrophic and neuro-inflammatory systems linked to anxiety and depression. Male Wistar rats were orally administered the alkaloid extracts in doses of 5, 50, 500, and 2000 mg/kg for 90 days. On day 91, neurobehavioural studies were evaluated, rats were sacrificed, brain hippocampus removed and tissue homogenate prepared. Biochemical, cytokine and neurotransmitter metabolisms were estimated in the hippocampus. Expressions of genes linked to anxiety and depression were evaluated by RT-qPCR. Results showed CSAE, NTAE and CMAE act as anxiolytic and antidepressant agents by depleting TNF-α, IL-1β and reactive oxygen species concentrations, and monoamine oxidase, angiotensin 1-converting enzyme and acetylcholinesterase activities while elevating IL-10 and dopamine concentrations and glutamate dehydrogenase activity at doses of 5, 50 and 500. Same doses of CSAE, NTAE and CMAE also depleted the gene expressions of GSK3β, JNK, NF-ĸB, and Nesfatin-1 while increasing expressions of CREB, BDNF, serotonin and Nrf2. However, administration of DSAE and 2000 mg/kg CSAE, NTAE and CMAE had adverse modulatory effects on the neurochemical concentrations and activities as well as the gene expressions of the evaluated neurotransmitter, neurotrophic and inflammatory systems. In conclusion, the study established the sub-chronic instrumentalization potential of CSAE, CMAE, and NTAE for anxiolytic and anti-depressive moods, though their use may be associated with dependence and addiction, which may result in more detrimental effects than any therapeutic potential they may proffer.
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Depression and anxiety are the most common disorders among all age groups. Several antidepressant drugs including benzodiazepine, antidepressant tricyclics, azapirone, noradrenaline reuptake inhibitors, serotonin selective reuptake inhibitors, serotonin, noradrenaline reuptake inhibitors, and monoamine oxidase inhibitors have been used to treat these psychiatric disorders. However, these antidepressants are generally synthetic agents and can cause a wide range of side effects. The potential efficacy of plant-derived alkaloids has been reviewed against various neurodegenerative diseases including Alzheimer's disease, Huntington disease, Parkinson's disease, schizophrenia, and epilepsy. However, data correlating the indole alkaloids and antidepressant activity are limited. Natural products, especially plants and the marine environment, are rich sources of potential new drugs. Plants possess a variety of indole alkaloids, and compounds that have an indole moiety are related to serotonin, which is a neurotransmitter that regulates brain function and cognition, which in turn alleviates anxiety, and ensures a good mood and happiness. The present review is a summary of the bioactive compounds from plants and marine sources that contain the indole moiety, which can serve as potent antidepressants. The prospects of naturally occurring as well as synthetic indole alkaloids for the amelioration of anxiety and depression-related disorders, structure-activity relationship, and their therapeutic prospects have been discussed.
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Chapter
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Numerous studies have indicated the pharmacological properties of linalool, a volatile terpene alcohol found in many flowers and spice plants, including anti‐nociceptive, anti‐inflammatory, and neuroprotective activities. The aim of this study was to explore the mechanisms of neuroprotection provided by (±) linalool and its enantiomer, (R)‐(−) linalool against oxygen, and glucose deprivation/reoxygenation (OGD/R) in PC12 cells. PC12 cells were treated with (±) linalool and (R)‐(−) linalool before exposure to OGD/R condition. Cell viability, reactive oxygen species (ROS) production, malondialdehyde (MDA) level, DNA damage, and the levels of proteins related to apoptosis were evaluated using MTT, comet assay, and western blot analysis, respectively. IC50 values for the PC12 cells incubated with (±) linalool and (R)‐(−) linalool were 2700 and 2600 μM after 14 h, as well as 5440 and 3040 μM after 18 h, respectively. Survival of the ischemic cells pre‐incubated with (±) linalool and (R)‐(−) linalool (100 μM of both) increased compared to the cells subjected to the OGD/R alone (p < .001). ROS and MDA formation were also decreased following incubation with (±) linalool and (R)‐(−) linalool compared to the OGD/R group (p < .01). In the same way, pre‐treatment with (±) linalool and (R)‐(−) linalool significantly reduced OGD/R‐induced DNA injury compared to that seen in OGD/R group (p < .001). (±) Linalool and (R)‐(−) linalool also restored Bax/Bcl‐2 ratio and cleaved caspase‐3 and caspase‐9 (p < .001, p < .01) following ischemic injury. The neuroprotective effect of linalool against ischemic insult might be mediated by alleviation of oxidative stress and apoptosis. This study indicated, for the first time, that (±) linalool and its enantiomer, (R)‐(‐) linalool protected PC12 cells against injury induced by oxygen and glucose deprivation/reoxygenation (OGD/R) via the mitigation of oxidative stress and the downregulation of Bax/Bcl‐2, caspase‐3 and caspase‐9, resulting in decreased apoptotic cell death.
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Autonomic nervous system disorders have many causes, and thus, no effective remedy for these disorders has been established. In this study, we conducted animal experiments with essential oil from Pelargonium graveolens (EOPG, geranium essential oil), which may regulate the autonomic nervous system. EOPG was administered to awake mice by inhalation. Heart rate variability (HRV) was analyzed from the pulse wave of the mice on an elevated platform, and the ratio of sympathetic to parasympathetic nerve activity was determined. The results showed that inhalation of EOPG did not affect the heart rate but made activity of the parasympathetic nervous system dominant. This effect was thought to be due to linalool, a component of EOPG that was transferred into the brain and body.
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INTRODUCTION The drugs currently available for treatment of anxiety and depression act through modulation of the neu-rotransmission systems involved in the neurobiology of the disorder, yet they often present side effects, which can impair patient adherence to treatment. METHOD This, has driven the search for new molecules with anxiolytic and antidepressant potential. Aromatic plants are rich in essential oils, and their chemical constituents, such as monoterpenes, are being studied for these disorders. This study aims to evaluate the anxiolytic and antidepressant-like potential of the monoterpene tetrahydrolinalool in in vivo animal models, and review pharmacological targets with vali-dation through molecular docking. Male Swiss mice (Mus musculus) were treated with THL (37.5-600 mg kg-1 p.o.) and submitted to the elevated plus maze, open field, rota rod, and forced swim tests. In the elevated plus-maze, THL at doses of 37.5 and 75 mg kg-1 induced a significant increase in the percent-age of entries (72.7 and 64.3% respectively), and lengths of stay (80.3 and 76.8% respectively) in the open arms tests. RESULT These doses did not compromise locomotor activity or motor coordination in the animals. In the open field, rota rod tests, and the forced swimming model, treatment with THL significantly reduced immobil-ity times at doses of 150, 300, and 600 mg kg-1, and by respective percentages of 69.3, 60.9 and 68.7%. CONCLUSION In molecular docking assay, which investigated potential targets, THL presented satisfactory energy val-ues for: nNOs, SGC, IL-6, 5-HT1A, NMDAr, and D1. These demonstrate the potential of THL (a de-rivative of natural origin) in in vivo and in silico models, making it a drug candidate.
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The legal cannabis market worldwide is facing new challenges regarding innovation in the production of cannabinoid-based drugs. The usual cannabinoid production involves growing Cannabis sativa L. outdoor or in dedicated indoor growing facilities, followed by isolation and purification steps. This process is limited by the growth cycles of the plant, where the cannabinoid content can deeply vary from each harvest. A game change approach that does not involve growing a single plant has gained the attention of the industry: cannabinoids fermentation. From recombinant yeasts and bacteria, researchers are able to reproduce the biosynthetic pathway to generate cannabinoids, such as (-)-∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and (-)-∆9-tetrahydrocannabivarin (∆9-THCV). This approach avoids pesticides, and natural resources such as water, land, and energy are reduced. Compared to growing cannabis, fermentation is a much faster process, although its limitation regarding the phytochemical broad range of molecules naturally present in cannabis. So far, there is not a consolidated process for this brand-new approach, being an emerging and promising concept for countries in which cultivation of Cannabis sativa L. is illegal. This survey discusses the techniques and microorganisms already established to accomplish the task and those yet in seeing for the future, exploring upsides and limitations about metabolic pathways, toxicity, and downstream recovery of cannabinoids throughout heterologous production. Therapeutic potential applications of cannabinoids and in silico methodology toward optimization of metabolic pathways are also explored. Moreover, conceptual downstream analysis is proposed to illustrate the recovery and purification of cannabinoids through the fermentation process, and a patent landscape is presented to provide the state-of-the-art of the transfer of knowledge from the scientific sphere to the industrial application.
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An essential oil is an extraction of the volatile plant molecules that confer distinctive colors, flavors, and aromas to different plant species (aka the “volatiome” of a plant). This diverse group of molecules are produced by all plants and are considered secondary metabolites. While primary metabolites are those substances created to meet the basic survival needs of the plant, secondary metabolites provide adaptive and protective mechanisms for plants, while also regulating the plant’s development and metabolism, and are classified by nitrogen content. The non-nitrogen containing secondary metabolites include cannabinoids, terpenes, flavonoids, lignans, saponins, and fatty acids (Wink 2010). The volatile molecules of particular interest in cannabis for clinical and therapeutic use are terpenes and flavonoids. These molecules provide each variety of cannabis its distinctive color, aroma, and flavor profile, while potentially conferring therapeutic benefits in their own rights.
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In an emergency, drug repurposing is the best alternative option against newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, several bioac-tive natural products have shown potential against SARS-CoV-2 in recent studies. The present study selected sixty-eight broad-spectrum antiviral marine terpenoids and performed molecular docking against two novel SARS-CoV-2 enzymes (main protease or M pro or 3CL pro) and RNA-dependent RNA polymerase (RdRp). In addition, the present study analysed the physiochemical-toxicity-pharmacokinetic profile, structural activity relationship, and phylogenetic tree with various computational tools to select the 'lead' candidate. The genomic diversity study with multiple sequence analyses and phylogenetic tree confirmed that the newly emerged SARS-CoV-2 strain was up to 96% structurally similar to existing CoV-strains. Furthermore, the anti-SARS-CoV-2 potency based on a protein−ligand docking score (kcal/mol) exposed that the marine terpenoid brevione F (−8.4) and stachyflin (−8.4) exhibited similar activity with the reference antiviral drugs lopinavir (−8.4) and darunavir (−7.5) against the target SARS−CoV−M pro. Similarly, marine terpenoids such as xiamycin (−9.3), thyrsiferol (−9.2), liouvilloside B (−8.9), liouvilloside A (−8.8), and stachyflin (−8.7) exhibited comparatively higher docking scores than the referral drug remdesivir (−7.4), and favipiravir (−5.7) against the target SARS-CoV-2−RdRp. The above in silico investigations concluded that stachyflin is the most 'lead' candidate with the most potential against SARS-CoV-2. Previously, stachyflin also exhibited potential activity against HSV-1 and CoV-A59 within IC50, 0.16-0.82 µ M. Therefore, some additional pharmacological studies are needed to develop 'stachyflin' as a drug against SARS-CoV-2.
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Background and aim Campomanesia xanthocarpa Berg. (Myrtaceae) present several pharmacological actions, but there are no reports on its antidepressant-like potential. This study investigated the antidepressant-like effect and mechanism of action of Campomanesia xanthocarpa seeds extract obtained from supercritical CO2 (40 °C, 250 bar). Experimental procedure Mice were orally treated with the extract 1 h before the TST. To investigate the involvement of the monoaminergic system in the antidepressant-like activity of the extract, pharmacological antagonists were administered prior to the acute oral administration of the extract (60 mg/kg). Also, the interaction of the extract with antidepressants was assessed in the tail suspension test (TST). The in vitro inhibitory potential of C. xanthocarpa seeds extract towards MAO A and MAO B enzymes was tested in vitro. Results and conclusion Animals treated with Campomanesia xanthocarpa seeds extract showed a significant reduction in the immobility time in the TST. Mice pretreatment with SCH23390, sulpiride, prazosin, yohimbine, and p-chlorophenylalanine prevented the anti-immobility effect of the extract in the TST. The combined administration of sub-effective doses of the extract with imipramine, bupropion and fluoxetine significantly reduced mice immobility time in the TST. The extract showed MAO A inhibitory activity (IC50 = 151.10 ± 5.75 μg/mL), which was greater than that toward MAO B (IC50 > 400 μg/mL). The extract of Campomanesia xanthocarpa seeds obtained by supercritical CO2 shows antidepressant-like activity, which relies on the activation of the monoaminergic neurotransmission (serotoninergic, dopaminergic and noradrenergic), suggesting that this species might represent a resource for developing new antidepressants.
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Essential oils (EOs) absorbed via inhalation are consistently reported to produce anxiolytic effects. The underlying neurochemical mechanisms, however, are not well understood. High concentrations of ascorbate in the human brain (∼10 mM in neurons) implicates this compound as a key signaling molecule and regulator of oxidative stress. In this study, we demonstrate the significant in vitro capacity of ascorbate to produce H2O2 in the presence of oxygen at physiological pH values, peaking at ∼400 μM for ascorbate levels of 1.0 mg/mL. In comparison, individual EOs and selected neurotransmitters at similar concentrations produced <100 μM H2O2. Systematic studies with binary and ternary mixtures containing ascorbate indicated that EOs and neurotransmitters could variably enhance (pro-oxidant, POX) or suppress (anti-oxidant, AOX) the production of H2O2 versus the ascorbate control, depending on the concentration ratios of the components in the mixture. Moreover, the AOX/POX chemistry observed with binary mixtures did not necessarily predict effects with ternary mixtures, where the POX ascorbate chemistry tended to dominate. A model is proposed to account for the ability of compounds with electron-donating capacity to catalytically regenerate ascorbate from intermediate oxidized forms of ascorbate, thus driving H2O2 production and exerting a net POX effect; whilst compounds that irreversibly reacted with oxidized forms of ascorbate suppressed the production of H2O2 and produced an overall AOX effect. Since the anxiolytic effects of different EOs, including extracts of Lavendula angustifolia (lavender) and Salvia rosmarinus (rosemary), were associated with AOX regulation of H2O2 production by ascorbate, it can be concluded that these anxiolytic effects are potentially related to the AOX properties of EOs. In contrast, EOs driving POX effects (eg, Junipenus communis (Juniper) berry EO) are proposed to be more useful for their potential anti-microbial or cancer cytotoxic applications.
Chapter
Terpenoids (isoprenoids) are the most diverse class of natural products among plants’ innumerable compounds. Terpenoids possess many pharmacological activities. These activities include anticancer, antibacterial, antiviral, antioxidant, and antifungal. The diverse collections of terpenoid structures and functions have increased interest in their commercial use resulting in some with established medical applications. This chapter describes the health effects of terpenoids on humans.
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The genus Litsea (Lauraceae) comprises eight species in the American Continent collectively known as “laurel”. Here, we review their botany, ethnobotany, ecology, chemistry and pharmacology to promote their international recognition, and to outline their use as condiments and as potential sources of novel phytomedicines. “Laurel” leaves are widely used as a spice and in traditional medicine throughout Mexico and Central America. The leaves of these species are harvested mainly from wild populations in temperate forests. The most used and studied species is L. glaucescens, which is listed as endangered in Mexico. Its leaves are traded throughout the country and even exported. However, in an international context, they are considered substitutes for the Mediterranean “bay leaf” (Laurus nobilis). Several folk medicinal applications of L. glaucescens and other species of Litsea have been experimentally validated in vitro. Although most active principles are yet to be discovered, some species may be suitable to develop new phytomedicines, especially as antidepressants and anti-inflammatory. However, research on the systematics, phytochemistry, ecology and genetics of the American species of Litsea is scarce. Further research will allow the development of such phytomedicines through the rational exploitation of natural populations or the establishment of plantations, thus avoiding “laurel” to follow the fate of numerous Mesoamerican floristic resources which have been depleted, while their economic and medicinal potential remained largely untapped.
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Hemp is a crop that has been used since ancient times for its medicinal and textile applications, which is experiencing a resurgence today. This growing interest is due to the fact that hemp is a crop with multipurpose applications: a source of cellulosic and woody fibers, produces oil-rich seeds, is a raw material for phytochemicals and is driven by consumer demand for more natural and sustainable products. Residues recovered during the harvesting and processing of hemp fibers and/or seeds can be utilized to obtain an essential oil rich in phytochemicals with multiple applications. We review the recent progress and developments in hemp essential oil as a complex mixture of bioactive compounds with antiinflammatory, antibacterial, insecticidal and therapeutic properties, and whose exploitation can add value to hemp cultivation. Essential oils are widely used globally, and their use is constantly increasing. This could boost the utilization and market value of hemp essential oil.
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For a long time, Cannabis sativa has been used for therapeutic and industrial purposes. Due to its increasing demand in medicine, recreation, and industry, there is a dire need to apply new biotechnological tools to introduce new genotypes with desirable traits and enhanced secondary metabolite production. Micropropagation, conservation, cell suspension culture, hairy root culture, polyploidy manipulation, and Agrobacterium-mediated gene transformation have been studied and used in cannabis. However, some obstacles such as the low rate of transgenic plant regeneration and low efficiency of secondary metabolite production in hairy root culture and cell suspension culture have restricted the application of these approaches in cannabis. In the current review, in vitro culture and genetic engineering methods in cannabis along with other promising techniques such as morphogenic genes, new computational approaches, clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR/Cas9-equipped Agrobacterium-mediated genome editing, and hairy root culture, that can help improve gene transformation and plant regeneration, as well as enhance secondary metabolite production, have been highlighted and discussed.
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Depression is one of the most common mental disorders worldwide. The genetic factors are linked to depression and anti-depressant outcomes. Traditional Persian medicine (TPM) manuscripts have provided various anti-depressant remedies, which may be useful in depression management. This review has studied the bioactive compounds, underlying mechanisms, and treatment outcomes of the medicinal plants traditionally mentioned effective for depression from “The storehouse of medicament” (a famous pharmacopeia of TPM) to merge those with the novel genetics science and serve new scope in depression prevention and management. This review paper has been conducted in two sections: (1) Collecting medicinal plants and their bioactive components from “The storehouse of medicament,” “Physician's Desk Reference (PDR) for Herbal Medicines,” and “Google scholar” database. (2) The critical key factors and genes in depression pathophysiology, prevention, and treatment were clarified. Subsequently, the association between bioactive components' underlying mechanism and depression treatment outcomes via considering polymorphisms in related genes was derived. Taken together, α-Mangostin, β-carotene, β-pinene, apigenin, caffeic acid, catechin, chlorogenic acid, citral, ellagic acid, esculetin, ferulic acid, gallic acid, gentiopicroside, hyperoside, kaempferol, limonene, linalool, lycopene, naringin, protocatechuic acid, quercetin, resveratrol, rosmarinic acid, and umbelliferone are suitable for future pharmacogenetics-based studies in the management of depression.
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Depression is a potentially life-threatening disorder affecting millions of people across the globe. It is a huge burden to both the individual and society, costing over £9 billion in 2000 alone: the World Health Organisation (WHO) cited it as the third leading cause of global disability in 2004 (first in the developed world), and project it will be the leading cause by 2030. The serendipitous discovery of antidepressants has revolutionized both our understanding and management of depression: however, their efficacy in the treatment of depression has long been debated and recently been brought very much into the public limelight by a controversial publication by Kirsch, in which the role of placebo response in antidepressant efficacy trials is highlighted. Whilst antidepressants offer benefits in both the short and long term, important problems persist such as intolerability, delayed therapeutic onset, limited efficacy in milder depression and the existence of treatment-resistant depression.
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Humans can detect and discriminate a vast number of odours. The number perceived as distinguishable is estimated to be more than ten thousand. Humans are capable of distinguishing even slight alterations in the structure of an odorous molecule. A pair of enantiomers of an odorant, which possess the same molecular structures except for the chiral position, can trigger profoundly different odour perceptions. How precisely can humans and their olfactory system detect and discriminate such a great variety of odours and such subtle differences in the molecular structures? In a series of studies, we have attempted to examine the relationship between mood change, odour and its physiological effects, by focusing on the possible verbal and non-verbal changes in humans induced by smelling the fragrances of essential oils as well as linalool and its enantiometric isomers. In this article, we provide an overview of our recent verbal and non-verbal studies. We then discuss how our findings may contribute to the assessment of psychophysiological responses of essential oils as well as how our research can contribute to the study of human chemoreception science, by shedding light on the sophistication of the olfactory system in its ability to detect and discriminate odors.
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(-)-Linalool is a monoterpene compound commonly found as a major component of the essential oil of several aromatic species. It has been shown to exert several actions in the central nervous system (CNS) and is able to inhibit glutamate receptors. This study investigated the effect of (-)-linalool in depression and genotoxicity models. Mice were given (-)-linalool (10, 50, 100 or 200 mg/kg i.p.) and were evaluated using the tail suspension test (TST). Genotoxic and antigenotoxic effects in blood and brain were investigated using the alkaline comet assay. In the TST, the animals that received doses of 100 and 200 mg/kg presented a decrease in immobility times. No increase in DNA damage was observed in either tissue, and resistance to DNA oxidative damage induced by hydrogen peroxide did not increase. (-)-Linalool showed an antidepressant-like activity in the TST and was unable to cause damage/protection to DNA in brain tissue and peripheral blood. This investigation provides evidence of an important effect of (-)-linalool on the CNS; however, more studies are necessary to support its possible clinical uses.
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Essential Oils in Mexican Bays ( Litsea spp . , Lauraceae): Taxonomic Assortment and Ethnobotanical Implications. The seven species of Litsea found in Mexico, all of them popularly known as “laurel,” were surveyed by gas chromatography-mass spectrometry for their foliar essential oils composition and related ethnobotanical applications. Litsea glaucescens is in high demand as a condiment, and is sold in rural and urban markets all over Mexico. However, four other species are also locally used for food seasoning. Litsea guatemalensis is the species most used in traditional medicine, especially to treat fever, chills, infectious diseases of the digestive system, and arthritis. No reports of culinary, medicinal, or other applications were located for L. muelleri, and L. pringlei. This is the first report on the essential oils for L. neesiana, L. muelleri, L. parvifolia, L. pringlei, and L. schaffneri. The terpenoids commonly found in all the Litsea species studied were 1,8-cineole, linalool, α-pinene, β-pinene, m-cymene, terpinen-4-ol, α-terpineol, caryophyllene, and caryophyllene oxide. Nevertheless, each species can be distinguished by its characteristic assortment of terpenoids. According to hierarchical cluster analysis, three groups of species were recognized: (1) 1,8-cineole group (C-10 terpenes), consisting of L. glaucescens, L. schaffnerii, L. pringlei, and L. muelleri; (2) limonene-rich group (C-10 oxygenated terpenes), including L. guatemalensis, and L. neesiana, and (3) oxygenated sesquiterpenes-rich group (C-15 oxygenated terpenes), comprising L. parvifolia. The chemical profiles of L. glaucescens and L. guatemalensis suggest a correlation with the culinary and medicinal uses of these species due to the known properties of their main constituents.
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The goal of our study was to assess the monoaminergic changes in locus coeruleus (LC) and dorsal raphe nucleus (DRN) following noradrenaline (NA) depletion. Seven days after a single N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) intraperitoneal administration in mice, we observed a decrease of NA in both the LC and DRN, as well as in prefrontal cortex (PFC) and hippocampus (HIPP). Moreover, an increase of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) was detected at LC level, while no change was found in DRN. DSP-4 also caused a significant decrease of dopamine (DA) tissue content in HIPP and DRN, without affecting the LC and the PFC. A decrease of DA metabolite, homovanillic acid (HVA), was found in the DRN of NA-depleted mice. These results highlight that the neurotoxic action of DSP-4 is not restricted to LC terminal projections but also involves NA depletion at the cell body level, where it is paralleled by adaptive changes in both serotonergic and dopaminergic systems.
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The forced swimming test (FST) in mice has failed to predict antidepressant activity for drugs having beta adrenoreceptor agonist activity and for serotonin uptake inhibitors. We investigated the potential for clonidine to render the FST sensitive to antidepressants by using a behaviorally inactive dose of this agent (0.1 mg/kg). All antidepressants studied (tricyclics, 5-HT uptake inhibitors, iprindole, mianserin, viloxazine, trazodone) showed either activity at lower doses or activity at previously inactive doses. The effect appeared specific because it did not appear with drugs other than antidepressants (diazepam, chlorpromazine, sulpiride, atropine), except for amphetamine and apomorphine which have a strong effect on the dopaminergic system. The use of behaviorally subactive doses of clonidine may thus provide an important means of increasing the sensitivity of the forced swimming test.
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Linalool is a monoterpene compound reported to be a major component of essential oils in various aromatic species. Several Linalool-producing species are used in traditional medical systems, including Aeolanthus suaveolens G. Dom (Labiatae) used as anticonvulsant in the Brazilian Amazon. Psychopharmacological in vivo evaluation of Linalool showed that this compound have dose-dependent marked sedative effects at the Central Nervous System, including hypnotic, anticonvulsant and hypothermic properties. The present study reports an inhibitory effect of Linalool on Glutamate binding in rat cortex. It is suggested that this neurochemical effect might be underlining Linalool psychopharmacological effects. These findings provide a rational basis for many of the traditional medical use of Linalool producing plant species.
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We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.
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Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either (11)C or (18)F and some of these are successful myocardial imaging agents, only two (S-1'-(18)F-fluorocarazolol and S-1'-(18)F-fluoroethylcarazolol) could actually visualize beta-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for beta-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral beta-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-(11)C-CGP12388. Another approach to target beta-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as (11)C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored.
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Salvia elegans Vahl (Lamiaceae), popularly known as "mirto", is a shrub that has been widely used in Mexican traditional medicine for the treatment of different central nervous system (CNS) diseases, principally, anxiety. Nevertheless, the available scientific information about this species is scarce and there are no reports related to its possible effect on the CNS. In this work, the antidepressant and anxiolytic like effects of hydroalcoholic (60%) extract of Salvia elegans (leaves and flowers) were evaluated in mice. The extract, administered orally, was able to increase the percentage of time spent and the percentage of arm entries in the open arms of the elevated plus-maze, as well as to increase the time spent by mice in the illuminated side of the light-dark test, and to decrease the immobility time of mice subjected to the forced swimming test. The same extract was not able to modify the spontaneous locomotor activity measured in the open field test. These results provide support for the potential antidepressant and anxiolytic activity of Salvia elegans.
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Clonidine is an adrenergic agonist with high affinity for alpha (2) adrenoceptors that also has affinity for imidazoline receptors. Clonidine has previously been shown to reduce immobility in the forced swim test (FST) in mice. In the present study, this effect was blocked by idazoxan (0.06 mg/kg s.c.) and by yohimbine (1.0 mg/kg s.c.) suggesting that clonidine's effects in this test are mediated via its action at alpha (2) sites. Imidazoline I-2 site ligands have been shown to inhibit monoamine oxidase and thus may also have antidepressant activity. Three compounds with selective affinity for I-2 receptors (BU224, BU239, BDF 8082) were also tested in the FST. These compounds showed no activity either alone or in combination with a subthreshold dose of imipramine in the FST. These results suggest that It receptor ligands do not show antidepressant-like activity in the FST in mice. Furthermore the activity of the mixed alpha (2)/I-1 agonist clonidine is most likely to be due to its action at alpha (2) sites.
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In order to investigate the pharmacodynamic basis of the previously-established anticonvulsant properties of linalool, we examined the effects of this compound on behavioral and neurochemical aspects of glutamate expression in experimental seizure models. Specifically, linalool effects were investigated to determine its inhibition of (i) L-[H-3]glutamate binding at CNS (central nervous system membranes), (ii) N-methyl-D-aspartate (NMDA)-induced convulsions, (iii) quinolinic acid (QUIN)-induced convulsions, and the behavioral and neurochemical correlates of PTZ-kindling. The data indicate that linalool modulates glutamate activation expression in vitro (competitive antagonism of L-[H-3]glutamate binding) and in vivo (delayed NMDA convulsions and blockage of QUIN convulsions). Linalool partially inhibited and significantly delayed the behavioral expression of PTZ-kindling, but did not modify the PTZ-kindling-induced increase in L-[H-3]glutamate binding.
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: Preclinical neurochemical studies indicate that buspirone and gepirone bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-hydroxytryptamine1A (5-HT1A) receptor binding sites. Furthermore, in functional neurochemical and electrophysiologic receptor studies, azapirones in general display partial agonist activity at postsynaptic 5-HT1A receptors linked negatively to adenyl cyclase and appear to demonstrate a similar profile on hippocampal CA1 pyramidal neurons sensitive to the effects of 5-HT. Through their action at presynaptic 5-HT1A receptors, these agents have been shown to dose-dependently inhibit cortical and hippocampal 5-HT synthesis while inhibiting the firing of 5-HT-containing dorsal raphe neurons, both in vitro and in vivo. These results suggest that the efficacy seen in clinical trials of anxiety and depression may be related to buspirone's and gepirone's complex interaction with presynaptic and postsynaptic 5-HT1A receptors, which initiate long-term changes in central 5-HT neurotransmission.
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Litsea glaucescens (Lauraceae) has been used in Mexican Traditional Medicine to relieve illness related to central nervous system, such as epilepsy, fright and sadness. In this study, L. glaucescens essential oil properties on central nervous system were evaluated in mice using different behavioral tests. The essential oil was obtained by hydrodistillation and analyzed by GC/MS. Identification of major compounds was also carried out by comparison with authentic samples. The psychopharmacological profile of L. glaucescens essential oil, and some its major compounds, were evaluated in mice using several experimental models: forced swimming test (FST: Antidepressant-like activity), open field test (OFT: Spontaneous locomotor activity), elevated plus-maze (EPM: Anxiolytic-like activity), exploratory cylinder (ECT: Sedative-like activity), rotarod (motor coordination) and traction performance (myo-relaxant effect) the essential oil and active principles was administered intraperitoneally. The essential oil showed antidepressant-like activity at doses of 100 and 300mg/Kg. The monoterpenes β-pinene and linalool were identified as the two main active principles of the essential oil, and showed antidepressant-like and sedative-like activity. Eucalyptol, limonene and α-pinene they did not show antidepressant-like activity, and were not further tested. L. glaucescens essential oil showed antidepressant activity, β-pinene and linalool were identified as its active principles. These results support the use of L. glaucescens in Mexican Traditional Medicine for the treatment of sadness.
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Dracocephalum moldavica is used as a tranquilizer and as remedy for nervous conditions relief in the Mexican traditional medicine. Despite its intensive use no literature reported neuropharmacological studies on Dracocephalum moldavica as yet. The sedative, anxiolytic-like and antidepressant-like effects of the aqueous extract of aerial parts of Dracocephalum moldavica (Lamiaceae) (DM) were evaluated in behavioral models in mice. The general toxic effects of DM were evaluated as well as their chemical analysis was performed. DM effects were evaluated on pentobarbital-induced sleeping time (SPT), the hole-board (HBT), and the avoidance exploratory behavior (AEBT) tests and on the forced swimming test (FST). General activity and motor coordination were evaluated in the open field (OFT) and Rota-rod tests, respectively. The acute toxicity of DM was determinate by its LD(50) dose. The chemical analyses DM were performed by chromatographic and HPLC-ESI-MS techniques. DM prolonged the pentobarbital-induced sleeping time, induced sedation in the HBT, decreased spontaneous activity and produced motor coordination impairment in mice. However, DM did not show anxiolytic effects in the AEBT or HBT and it was not effective in FST. The DM-treatment produced mortalities with LD(50)=470 mg/kg body weight. The HPLC-ESI-MS analysis of DM revealed that (acacetin, apigenin and luteolin)-7-O-β-D-(6″-O-malonyl)-glucoside derivates are the main compounds of DM. DM induced sedative actions and a general inhibition of CNS activity observed by the decrease of animals' general activity, motor coordination and exploration.
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Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressants--the triple reuptake inhibitors--is under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal.
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Clonidine, 0.05, 0.1 and 0.5 mg/kg administered i.p. as a three-injection course but not as single doses, significantly reduced the immobility of rats in the forced swimming test. Doses of 0.1 and 0.5, administered the same way, significantly reduced activity in an open field. The effect of 0.05 and 0.5 mg/kg clonidine on immobility was prevented by 1 mg/kg idazoxan, an alpha 2-adrenoceptor antagonist, but not by 3 mg/kg prazosin, which blocks alpha 1-adrenoceptors. An infusion of 6 micrograms/microliters 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, did not modify the effect of 0.05 and 0.5 mg/kg clonidine on immobility. Chronic treatment with 5 mg/kg i.p. desipramine or 0.1 mg/kg i.p. clonidine, twice daily for 15 days, did not modify the effect of a three-injection course with 0.1 mg/kg clonidine. It is suggested that clonidine exerts antidepressant-like effects on rats in the forced swimming test by acting on central alpha 2-adrenoceptors outside the locus coeruleus and presumably postsynaptically to noradrenaline-containing neurons. No tolerance or sensitization of the clonidine effect was found after chronic treatment with desipramine or clonidine. These findings are of significance for the effects of clonidine in subgroups of depressed patients.
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Preclinical neurochemical studies indicate that buspirone and gepirone bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-hydroxytryptamine1A (5-HT1A) receptor binding sites. Furthermore, in functional neurochemical and electrophysiologic receptor studies, azapirones in general display partial agonist activity at postsynaptic 5-HT1A receptors linked negatively to adenyl cyclase and appear to demonstrate a similar profile on hippocampal CA1 pyramidal neurons sensitive to the effects of 5-HT. Through their action at presynaptic 5-HT1A receptors, these agents have been shown to dose-dependently inhibit cortical and hippocampal 5-HT synthesis while inhibiting the firing of 5-HT--containing dorsal raphe neurons, both in vitro and in vivo. These results suggest that the efficacy seen in clinical trials of anxiety and depression may be related to buspirone's and gepirone's complex interaction with presynaptic and postsynaptic 5-HT1A receptors, which initiate long-term changes in central 5-HT neurotransmission.
Article
Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. Buspirone, chlordiazepoxide and imipramine are all anxiolytic and have all been shown to decrease the frequency of RSA. All these compounds have been suggested to affect, directly or indirectly, 5-HT metabolism and function. The present experiments tested the possibility that buspirone, chlordiazepoxide and imipramine reduce RSA frequency via 5-HT1A autoreceptors. Rats received buspirone (10 mg/kg), chlordiazepoxide (5 mg/kg) and imipramine (30 mg/kg) after 5-HT depletion with p-chlorophenylalanine (pCPA, 100 mg/kg/day for 3 days or 350 mg/kg/day for 2 days) or after pretreatment with 5-HTP (40 mg/kg, to replete 5-HT) as well as pCPA. The frequency-reducing effects produced by buspirone and chlordiazepoxide were unchanged by either dose of pCPA, whereas the frequency-reducing effect of imipramine was completely eliminated by the high dose of pCPA. Pindolol, but not beta-blockers (a combination of metoprolol and ICI118,551), was able to block the effect of imipramine on RSA frequency. Pindolol has been reported to block the effects of buspirone but not chlordiazepoxide. These data suggest that: (1) buspirone obtains its frequency-reducing effects via pre- or post-synaptic 5-HT1A receptors rather than 5-HT1A autoreceptors; (2) chlordiazepoxide obtains its frequency-reducing effect via benzodiazepine receptors and GABA with no direct or indirect involvement of 5-HT systems; and (3) imipramine obtains its frequency-reducing effect by increasing the availability of 5-HT at 5-HT1A receptors which are not autoreceptors.
Article
Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT2 receptors, and hippocampal 5HT1A receptors were studied (using the ligands [3H]-dihydroalprenolol, [3H]-ketanserin and [3H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10 mg/kg per day). CMS increased Bmax for all three receptor systems. Imipramine decreased Bmax, reversing the effect of CMS, for beta-adrenergic and 5HT2 receptor binding, but increased Bmax for 5HT1A receptor binding. KDs were unaffected by either treatment. The beta-receptor and 5HT2 receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data.
Article
1. The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2. 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (< or = 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3. The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3-10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4. The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response. Antagonists at 5-HTlc/5-HT2 receptors (ketanserin; 0.1-3.0 mg kg-1, p.o.),5-HT3 receptors (ondansetron; 0.03-10mg kg-1, p.o.), at-adrenoceptors (prazosin; 1-3mgkg-1, p.o.),alpha2 -adrenoceptors (idazoxan; 3-30mg kg-1, p.o.), alpha 1-adrenoceptors (metoprolol; 1-30mgkg-1, p.o.),beta 2-adrenoceptors (ICI 118,551; 1-30 mg kg-1, p.o.), dopamine D2 receptors (sulpiride; 10-300mg kg-',p.o.) and opiate receptors (naloxone; 3-100 mg kg-', p.o.) had no effect on the 8-OH-DPAT response.5. Selective destruction of 5-HT neurones with 5,7-dihydroxytryptamine or inhibition of 5-HT synthesis with p-chlorophenylalanine did not change the 8-OH-DPAT response in the Porsolt test. This response was also unaltered by pretreatment with the noradrenergic neurotoxin, DSP-4.6. Administration of 8-OH-DPAT (3 mg kg-1, s.c.) twice-daily for 10 days attenuated the hypothermia,but not the increased mobility, induced by 8-OH-DPAT (3 mg kg-1, s.c.). Similarly, repeated administration of amitriptyline (3-30 mg kg-1), desipramine (3-30 mg kg-1) or dothiepin (10-100 mg kg-1) also attenuated the former, but not the latter, response.7. We conclude that 8-OH-DPAT produces an antidepressant-like effect in the Porsolt test which is mediated via postsynaptic 5-HT1A receptors.
Article
This review reports anatomical studies evaluating central and peripheral alpha 2- and beta-adrenoceptors. The results suggest abnormalities exist in the noradrenergic system in depressed patients. Most animal models involve the use of stress to simulate depression in man. All models that have been developed lead to differential changes in noradrenergic function. We have assessed the effects of reboxetine, a novel, selective noradrenaline-reuptake inhibitor (NARI) in olfactory bulbectomised rats, a procedure that induces significant changes in amygdala function. Reboxetine is an effective antidepressant in the forced swim test and open field test in bulbectomised rats. Unlike the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is selective for the noradrenergic system. Owing to the abnormalities that occur in depression, it would seem sensible to target the noradrenergic system for treatment of this condition.
Article
In order to investigate the pharmacodynamic basis of the previously-established anticonvulsant properties of linalool, we examined the effects of this compound on behavioral and neurochemical aspects of glutamate expression in experimental seizure models. Specifically, linalool effects were investigated to determine its inhibition of (i) L-[3H]glutamate binding at CNS (central nervous system membranes), (ii) N-methyl-D-aspartate (NMDA)-induced convulsions, (iii) quinolinic acid (QUIN)-induced convulsions, and the behavioral and neurochemical correlates of PTZ-kindling. The data indicate that linalool modulates glutamate activation expression in vitro (competitive antagonism of L-[3H]glutamate binding) and in vivo (delayed NMDA convulsions and blockage of QUIN convulsions). Linalool partially inhibited and significantly delayed the behavioral expression of PTZ-kindling, but did not modify the PTZ-kindling-induced increase in L-[3H]glutamate binding.
Article
In a previous study, we have recently shown that chronic treatment with desipramine either reduced or potentiated the locomotor response to the dopamine D(2)-like receptor agonist quinpirole, a behavioural response mediated by the mesolimbic dopamine system, depending on whether the animals were subjected, respectively, to repeated restraint or to chronic mild stress (different stressors randomly presented). In this study, we examined the interaction between prolonged exposure to either repeated restraint stress or chronic mild stress with the chronic administration of the antidepressant desipramine on two spontaneous behaviours, in which an involvement of the mesolimbic dopamine system has been suggested: novelty-induced exploratory activity and grooming. Exploratory activity in the open field was reduced by chronic mild stress regardless of the drug treatment, while it was not influenced by restraint stress. Desipramine reduced exploratory activity in rats subjected to restraint stress. Restraint stress increased grooming and desipramine reversed this effect, while increasing grooming in the chronic mild stress group. These findings suggest that antidepressants exert their effect by opposing the modifications induced by stress. The available experimental evidence is consistent with the hypothesis that an important role in the observed behavioural changes is played by the mesolimbic dopamine system.
Article
Changes to the binding properties of cortical N-methyl-D-aspartic acid (NMDA) and beta-adrenergic receptors have both been reported as potential indicators of antidepressant activity. In the present investigation we examined the effects of the noradrenaline reuptake inhibitor, reboxetine, the serotonin reuptake inhibitor, sertraline, alone and in combination on the binding properties of cortical NMDA receptors and cortical beta1-adrenoceptors following 14 days of treatment in the olfactory bulbectomized rat model of depression. A decrease in the potency of glycine to displace the strychnine insensitive glycine antagonist [3H] 5,7 dichlorokynurenic acid (5,7 DCKA) was observed in cortical homogenates of OB rats when compared to sham-operated controls. Similarly, treatment with the combination of reboxetine and sertraline for 14 days produced a decrease in the potency of glycine when compared to vehicle treated controls. By contrast neither olfactory bulbectomy or drug treatment significantly altered basal or glycine enhanced binding of the non-competitive NMDA antagonist [3H] MK-801 in cortical homogenates. Reboxetine alone, and in combination with sertraline, down-regulated [3H]-CGP 12177 (a selective beta-adrenoceptor antagonist) binding in both OB and sham-operated animals. The lack of a bulbectomy effect in the [3H] CGP-12177 binding assay, and the fact that olfactory bulbectomy and antidepressant treatments produce a similar change to the potency of glycine at the NMDA receptor, suggests that these tests do not provide a neurochemical marker for either the behavioral hyperactivity deficit or antidepressant response in the model.
Article
Clonidine is an adrenergic agonist with high affinity for alpha2 adrenoceptors that also has affinity for imidazoline receptors. Clonidine has previously been shown to reduce immobility in the forced swim test (FST) in mice. In the present study, this effect was blocked by idazoxan (0.06 mg/kg s.c.) and by yohimbine (1.0 mg/kg s.c.) suggesting that clonidine's effects in this test are mediated via its action at alpha2 sites. Imidazoline I2 site ligands have been shown to inhibit monoamine oxidase and thus may also have antidepressant activity. Three compounds with selective affinity for I2 receptors (BU224, BU239, BDF 8082) were also tested in the FST. These compounds showed no activity either alone or in combination with a subthreshold dose of imipramine in the FST. These results suggest that I2 receptor ligands do not show antidepressant-like activity in the FST in mice. Furthermore the activity of the mixed alpha2/I1 agonist clonidine is most likely to be due to its action at alpha2 sites.
Article
The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphé (DRN) or median raphé (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology.
Article
The role of serotonin (5-hydroxytryptamine; 5-HT) in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes. The 5-HT1A receptors are particularly relevant to the antidepressant and anxiolytic responses in human beings. They are located presynaptically in the raphe nuclei, where they act as cell body autoreceptors to inhibit the firing rate of 5-HT neurons, and are located postsynaptically in limbic and cortical regions, where they also attenuate firing activity. The azapirones are full agonists at 5-HT1A autoreceptors and are generally, but not exclusively, partial agonists at postsynaptic 5-HT1A receptors. Some of these drugs, including gepirone and other 5-HT1A agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Their delayed therapeutic activity is believed to result from increased activation of postsynaptic 5-HT1A receptors occurring only after 5-HT neurons regain their normal firing activity. The recovery of this parameter, which is attributable to 5-HT1A autoreceptor desensitization, also restores 5-HT release. At this point, the summed effects of a normalized level of synaptic 5-HT and the exogenous 5-HT1A agonist can be exerted on postsynaptic 5-HT1A receptors. The widespread recognition of the clinical efficacy of such agents has largely been hampered by their undesirable pharmacokinetic properties. Most 5-HT1A agonists are indeed readily absorbed but are also rapidly eliminated, thereby often producing either suboptimal therapeutic responses at low doses, or cumbersome adverse effects at higher doses. Extended-release formulations allow once-daily dosing regimens, thus avoiding sharp peak plasma concentrations. This improves compliance and permits the use of higher dosages, which may be associated with enhanced efficacy and better tolerability relative to the immediate-release formulations. In sum, 5-HT1A receptor agonism represents a valuable and efficacious therapeutic approach to major depression.
Article
Monoaminergic pathways are highly responsive to aversive stimuli and play a crucial role in the control of affect, cognition, endocrine secretion, chronobiotic rhythms, appetite, and motor function, all of which are profoundly disrupted in depressive states. Accordingly, a perturbation of monoaminergic transmission is implicated in the aetiology of depressive disorders, and all clinically available antidepressants increase corticolimbic availability of monoamines. However, their limited efficacy, delayed onset of action, and undesirable side effects underlie ongoing efforts to identify improved therapeutic agents. Sequencing the human genome has raised the hope not only of better symptomatic control of depression, but even of the prevention or cure of depressive states. In the pursuit of these goals, there is currently a tendency to focus on selective ligands of "novel" nonmonoaminergic targets. However, certain classes of novel agent (such as neurokinin(1) receptor antagonists) indirectly modulate the activity of monoaminergic networks. Others may act "downstream" of them, converging onto common cellular substrates controlling gene expression, synaptic plasticity, and neurogenesis. Further, by analogy to the broad-based actions of currently employed drugs, multitarget agents may be better adapted than selective agents to the management of depression-a complex disorder with hereditary, developmental, and environmental origins. It is, thus, important to continue the creative exploration of clinically validated and innovative monoaminergic strategies within a multitarget framework. In this light, drugs combining monoaminergic and nonmonoaminergic mechanisms of action may be of particular interest. The present article provides a critical overview of monoaminergic strategies for the treatment of depressive states, both established and under development, and discusses interactions of novel "nonmonoaminergic" antidepressants with monoaminergic mechanisms.
Article
Essential oil from a few different population of M. officinalis cultivated in Poland has been investigated. The percentage of essential oil ranged from 0.08 to 0.25 ml/100 g in the leaves and from 0.06 to 0.167 ml/100 g in the herb and was higher in the plant material from experimental patch than that from commercial cultivations. Comparative determinations of the essential oil in fresh and dried material showed slightly higher content of the oil in the fresh one. The analysis of the oil composition has been performed by GC and GC/MS. Great differences in the contents of citral, citronellal, linalool, nerol, geraniol beta-caryophyllene and beta-caryophyllene oxide among the populations has been found. Effect of the harvest time, drying and storage on the composition of lemon balm oil has also been studied.
Article
Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of beta-adrenoreceptors, particularly beta2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective beta-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective beta2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol.
Article
Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) receptors.
Article
Headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography and mass spectrometry using the divinyl/carboxen/polydimethylsiloxane (DVB-CAR-PDMS) fibre was applied for the analysis of aroma profiles of Lavandula angustifolia L. flowers and the corresponding essential oils. The optimal sampling time was determined by studying the equilibrium time profile of the major volatile compounds for the lavender flowers (50 min) and the essential oil (20 min). Comparative analysis of L. Angustifolia L. cultivated in Friuli Venezia Giulia (northeastern Italy) highlighted that the contents of linalool and linalyl acetate were the major differences between the composition of flowers and the hydro-distilled products. Lavender essential oil from Middle-Friuli Venezia Giulia was evaluated as the highest quality for its high level of linalyl acetate (31.7 %) and linalool (45.0 %) and low percentage of camphor (0.5 %). The use of headspace SPME was shown to be a convenient and effective analytical tool for the sampling of volatile compounds and it could be used to test the quality of flowers and essential oils from Lavandula species.
Essential oils in Mexican bays (Litsea spp
  • N D C Jimenez-Perez
  • F G Lorea-Hernandez
  • C K Jankowski
N.D.C. Jimenez-Perez, F.G. Lorea-Hernandez, C.K. Jankowski, R. Reyes-Chilpa, Essential oils in Mexican bays (Litsea spp., Lauraceae): taxonomic assortment and ethnobotanical implications, Econ. Bot. 65 (2011) 178–189.
  • N D C Jimenez-Perez
  • F G Lorea-Hernandez
  • C K Jankowski
  • R Reyes-Chilpa
N.D.C. Jimenez-Perez, F.G. Lorea-Hernandez, C.K. Jankowski, R. Reyes-Chilpa, Essential oils in Mexican bays (Litsea spp., Lauraceae): taxonomic assortment and ethnobotanical implications, Econ. Bot. 65 (2011) 178–189.
The antidepressant effects of curcumin in the forced swimming test involve 5-HT 1 and 5-HT 2 receptors
  • R Wang
  • Y Xu
  • H L Wu
  • Y B Li
  • Y H Li
  • J B Guo
  • X J Li
R. Wang, Y. Xu, H.L. Wu, Y.B. Li, Y.H. Li, J.B. Guo, X.J. Li, The antidepressant effects of curcumin in the forced swimming test involve 5-HT 1 and 5-HT 2 receptors, Eur. J. Pharmacol. 578 (2008) 43-50.