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Sub-Chronic Effects of s-Limonene on Brain Neurotransmitter Levels and Behavior of Rats

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Abstract

The present study was designed to gain insight into the effects of s-limonene on the brain after 1-wk administration. For this purpose, neurotransmitters such as dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamic acid (Glu) and some of their metabolites (DOPAC and 5-HIAA) were determined by HPLC-ECD and amino acid analyzer after 1-wk administration of s-limonene of different concentrations (0, 5, 25, 50 mg/kg). Significant changes, such as GABA, 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT, were confirmed. At the same time, basal hypothalamic-pituitary-adrenal (HPA) activity after 1-wk administration of s-limonene was evaluated by corticosterone. Considering the increment of GABA and the changes of other neurotransmitters, anti-stress effects after 1-wk administration were observed. The experimental results showed that s-limonene could inhibit HPA activity under physical stress and this anti-stress effect of s-limonene may act through the GABA(A) receptor.

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... Limonene showed effects on brain neurotransmitters. A study showed effects of limonene on the γaminobutyric acid A receptor, which is related with the arousal pathway [23]. Citral is a type of monoterpene that was confirmed in inhibitory neurotransmitter modification Figure 11. ...
... Limonene showed effects on brain neurotransmitters. A study showed effects of limonene on the γ-aminobutyric acid A receptor, which is related with the arousal pathway [23]. Citral is a type of monoterpene that was confirmed in inhibitory neurotransmitter modifica-tion [24,25]. ...
... Statistical differences were considered at p-values less than 0.05. EEG brainwave powers were processed by power spectral analysis and frequency domain data of subbands, including slow alpha (8)(9)(10)(11), fast alpha (11)(12)(13), low beta (13-15 Hz), mid beta (15)(16)(17)(18)(19)(20), and high beta (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Mood scores were tested using an unpaired t test. ...
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Article
The functional food market is growing with a compound annual growth rate of 7.9%. Thai food recipes use several kinds of herbs. Lemongrass, garlic, and turmeric are ingredients used in Thai curry paste. Essential oils released in the preparation step create the flavor and fragrance of the famous tom yum and massaman dishes. While the biological activities of these ingredients have been investigated, including the antioxidant, anti-inflammatory, and antimicrobial activities, there is still a lack of understanding regarding the responses to the essential oils of these plants. To investigate the effects of essential oil inhalation on the brain and mood responses, electroencephalography was carried out during the non-task resting state, and self-assessment of the mood state was performed. The essential oils were prepared in several dilutions in the range of the supra-threshold level. The results show that Litsea cubeba oil inhalation showed a sedative effect, observed from alpha and beta wave power reductions. The frontal and temporal regions of the brain were involved in the wave alterations. Garlic oil increased the alpha wave power at lower concentrations; however, a sedative effect was also observed at higher concentrations. Lower dilution oil induced changes in the fast alpha activity in the frontal region. The alpha and beta wave powers were decreased with higher dilution oils, particularly in the temporal, parietal, and occipital regions. Both Litsea cubeba and turmeric oils resulted in better positive moods than garlic oil. Garlic oil caused more negative moods than the others. The psychophysiological activities and the related brain functions require further investigation. The knowledge obtained from this study may be used to design functional food products.
... This monoterpene is widely used as a flavor and fragrance; it has been recognized as safe in food by the Food and Drug Administration [2]. D-limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects [3][4][5][6]. In addition, D-limonene has been reported to show effects on the synthesis/changes of neurotransmitters such as dopamine, serotonin, and GABA [6,7]. ...
... D-limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects [3][4][5][6]. In addition, D-limonene has been reported to show effects on the synthesis/changes of neurotransmitters such as dopamine, serotonin, and GABA [6,7]. Furthermore, the effects of various essential oils on epilepsy and acute seizures were organized [8]. ...
... According to a previous result [6], D-limonene increased GABA level in the whole brain. Therefore, to elucidate the possible mechanism underlying the effect of D-limonene on seizures, we investigated the expression levels of GABA synthesis enzyme (GAD-67) by Western blotting analysis. ...
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Background: Epilepsy is a chronic neurological disorder characterized by the recurrence of seizures. One-third of patients with epilepsy may not respond to antiseizure drugs. Purpose: We aimed to examine whether D-limonene, a cyclic monoterpene, exhibited any antiseizure activity in the pentylenetetrazole (PTZ)-induced kindling mouse model and in vitro. Methods: PTZ kindling mouse model was established by administering PTZ (30 mg/kg) intraperitoneally to mice once every 48 h. We performed immunoblot blots, immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) analysis after the behavioral study. Results: An acute injection of PTZ (60 mg/kg) induced seizure in mice, while pretreatment with D-limonene inhibited PTZ-induced seizure. Repeated administration of PTZ (30 mg/kg) increased the seizure score gradually in mice, which was reduced in D-limonene (10 mg/kg)-pretreated group. In addition, D-limonene treatment increased glutamate decarboxylase-67 (GAD-67) expression in the hippocampus. Axonal sprouting of hippocampal neurons after kindling was inhibited by D-limonene pretreatment. Moreover, D-limonene reduced the expression levels of Neuronal PAS Domain Protein 4 (Npas4)-induced by PTZ. Furthermore, the adenosine A2A antagonist SCH58261 and ZM241385 inhibited anticonvulsant activity and gamma-aminobutyric acid (GABA)ergic neurotransmission-induced by D-limonene. Conclusion: These results suggest that D-limonene exhibits anticonvulsant activity through modulation of adenosine A2A receptors on GABAergic neuronal function.
... In 2000, Viana et al. demonstrated that limonene (200 mg/kg i.p.; 400 mg/kg p.o.) showed anticonvulsant effects against PTZ-induced seizures. This effect can be attributed to the abilities of limonene to decrease glutamate and increase GABA levels in the brain (Zhou et al., 2009). Furthermore, in preclinical studies, it was shown that limonene reduces the levels of iNOS, COX-2, NF-κB and MAPKs (p-38 and p-ERK 1/2) (Rehman et al., 2014;Rufino et al., 2015). ...
... Monoterpenes as citronellal (Melo et al., 2011b), ρ-cymene (de Oliveira, 2014), carvacryl acetate (Pires et al., 2015), citral , isopulegol (Silva et al., 2009b), menthol (Zhang et al., 2008), safranal (Hosseinzadeh and Sadeghnia, 2007) and thymoquinone Hosseinzadeh and Parvardeh, 2004) reduce convulsion through the activation of GABAa inhibitory receptors. Other studies also demonstrated the effect of monoterpenes on the GABA system, such as citronellol (Kessler et al., 2014), carvacrol (Guimarães et al., 2014;Kessler et al., 2014;Melo et al., 2010), carvone (Sánchez-Borzone et al., 2014), limonene (Zhou et al., 2009), thymol (Bianchini et al., 2017;Priestley et al., 2003) and borneol (Granger et al., 2005). In addition, citronellal , decanolactone (Pereira et al., 1997), limonene (Zhou et al., 2009) and linalool (Elisabetsky et al., 1999) also act modulating the glutamatergic pathway and reducing the convulsion. ...
... Other studies also demonstrated the effect of monoterpenes on the GABA system, such as citronellol (Kessler et al., 2014), carvacrol (Guimarães et al., 2014;Kessler et al., 2014;Melo et al., 2010), carvone (Sánchez-Borzone et al., 2014), limonene (Zhou et al., 2009), thymol (Bianchini et al., 2017;Priestley et al., 2003) and borneol (Granger et al., 2005). In addition, citronellal , decanolactone (Pereira et al., 1997), limonene (Zhou et al., 2009) and linalool (Elisabetsky et al., 1999) also act modulating the glutamatergic pathway and reducing the convulsion. ...
Article
Background: Epilepsy affects more than 65 million people worldwide. Treatment for epileptic seizures is ineffective and has many adverse effects. For this reason, the search for new therapeutic options capable of filling these limitations is necessary. Hypothesis/Purpose: In this sense, natural products, such as monoterpenes, have been indicated as a new option to control neurological disorders such as epilepsy. Study Design: Therefore, the objective of this study was to review the monoterpenes that have anticonvulsive activity in animal models. Methods: The searches were performed in the PubMed, Web of Science and Scopus databases in September, 2020 and compiled studies using monoterpenes as an alternative to seizure. Two independent reviewers performed the study selection, data extraction and methodological quality assessment using the Syrcle tool. Results: 51 articles that described the anticonvulsant activity of 35 monoterpenes were selected with action on the main pharmacological target, including GABAa receptors, glutamate, calcium channels, sodium and potassium. In addition, these compounds are capable of reducing neuronal inflammation and oxidative stress caused by seizure. Conclusion: These compounds stand out as a promising alternative for acting through different pharmacological mechanisms, which may not only reduce seizure, but also promote neuroprotective effect by reducing toxicity in brain regions. However, further studies are needed to determine the mechanism of action and safety assessment of these compounds.
... Electroencephalography (EEG) is one of the most popular methods for observing brain oscillations due to its cost efficiency. Brain waves are classified by frequencies ranging from 0.05 to 500 Hz such as delta wave (0-4 Hz), theta wave (4)(5)(6)(7)(8), alpha wave (8)(9)(10)(11)(12)(13), beta wave (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma (above 30 Hz) [10]. In this study, we focused on tangerine (Citrus tangerina) peel essential oil. ...
... Lavandula angustifolia essential oil also decreased sleep onset latency, which is like the threshold level of tangerine oil [23]. In vivo study revealed that limonene significantly increased γ-aminobutyric acid (GABA) and other neurotransmitter changes [24]. GABA is acting though GABA A receptor, which is potentiating chloride current resembling alcohol, barbiturates, and benzodiazepines. ...
... Data analysis for EEG: raw data were processed by power spectral analysis, and frequency domain data are characterized as slow alpha (8)(9)(10)(11), fast alpha (11)(12)(13), low beta (13-15 Hz), mid beta (15)(16)(17)(18)(19)(20), and high beta (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). This describes the distribution of electrical activity across the brain regions and was produced to show overview activities using GraphPad Prism 8. ...
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Article
Tangerine (Citrus tangerina) is one of the most important crops of Thailand with a total harvest that exceeds 100,000 tons. Citrus essential oils are widely used as aromatherapy and medicinal agents. The effect of tangerine essential oil on human brain waves and sleep activity has not been reported. In the present study, we therefore evaluated these effects of tangerine essential oil by measurement of electroencephalography (EEG) activity with 32 channel platforms according to the international 10–20 system in 10 male and 10 female subjects. Then the sleep onset latency was studied to further confirm the effect on sleep activity. The results revealed that different concentrations, subthreshold to suprathreshold, of tangerine oil gave different brain responses. Undiluted tangerine oil inhalation reduced slow and fast alpha wave powers and elevated low and mid beta wave powers. The subthreshold and threshold dilution showed the opposite effect to the brain compared with suprathreshold concentration. Inhalation of threshold concentration showed effectively decreased alpha and beta wave powers and increased theta wave power, which emphasize its sedative effect. The reduction of sleep onset latency was confirmed with the implementation of the observed sedative effect of tangerine oil.
... Limonene a monoterpene from genus Citrus (Zhou et al., 2009) showed anxiolytic-like and antinociceptive properties and regulatory effects on different neurotransmitters (De Almeida et al., 2012;Do Amaral et al., 2007;Zhou et al., 2009). The HTR response was dosedependently inhibited by intracerebroventricular injection of limonene in mice (Yun, 2014b). ...
... Limonene a monoterpene from genus Citrus (Zhou et al., 2009) showed anxiolytic-like and antinociceptive properties and regulatory effects on different neurotransmitters (De Almeida et al., 2012;Do Amaral et al., 2007;Zhou et al., 2009). The HTR response was dosedependently inhibited by intracerebroventricular injection of limonene in mice (Yun, 2014b). ...
... Pretreatment of rats with limonene (200 and 400 mg/kg), also reduced MIH in a dosedependent manner (Yun, 2014b). The protective effect of limonene on MIH may be related to increases in dopamine levels in the nucleus accumbens (Yun, 2014b) and GABA levels in rat brain (Figure 1) (Zhou et al., 2009). ...
Article
Objective: Methamphetamine (METH) increases dopamine, norepinephrine and serotonin concentrations in the synaptic cleft, and induces hyperactivity. The current management of acute METH poisoning relies on supportive care and no specific antidote is available for treatment. The main objective of this review was to present the evidence for effectiveness of the herbal medicine in alleviating the adverse effects of METH abuse. Materials and methods: Literature search was performed using the following electronic databases: MEDLINE, Scopus, PubMed and EMBASE. Results: Plant-derived natural products ginseng and sauchinone reduced METH-induced hyperactivity, conditioned place preference and neurological disorder. Garcinia kola decreased METH-induced hepatotoxicity, raised METH lethal dose, and restored the METH-impaired cognitive function. Repeated administration of baicalein resulted in attenuation of acute binge METH-induced amnesia via dopamine receptors. Activation of extracellular-regulated kinase in the hypothalamus by levo-tetrahydropalmatine facilitated the extinction of METH-induced conditioned place preference and reduced the hyperactivity. Other herbal medicine from various parts of the world were also discussed including hispidulin, silymarin, limonene, resveratrol, chlorogenic acid and barakol. Conclusion: Based on the current study, some natural products such as ginseng and levo-tetrahydropalmatine are promising candidates to treat METH abuse and poisoning. However, clinical trials are needed to confirm these finding.
... This monoterpene is widely used as a flavor and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration (Flamm and Lehman-McKeeman, 1991). Limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects (do Amaral et al., 2007;Zhou et al., 2009;de Almeida et al., 2012;Lima et al., 2013). Recently, we have reported that limonene inhibits an acute single methamphetamine-induced hyperlocomotion in rats by regulating dopamine levels in the nucleus accumbens (Yun, 2014). ...
... However, other neurotransmitter systems, including GABAergic, 5-HTergic, and glutamatergic systems, are also associated with methamphetamine-induced locomotor sensitization and postsynaptic dopamine receptor supersensitivity (Ohmori et al., 1994;Kim and Jang, 1997;Yoo et al., 2010). It has been reported that GABAergic (Zhou et al., 2009) and 5-HTergic (Yun, 2014) neuronal systems may mediate the effects of limonene on the CNS. Therefore, we suggest that limonene may inhibit the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats via regulation of GABAergic and serotonergic modulation of dopaminergic neuronal transmission. ...
... Therefore, we suggest that limonene may inhibit the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats via regulation of GABAergic and serotonergic modulation of dopaminergic neuronal transmission. In another study, Zhou et al. (2009) demonstrated that limonene administration significantly increased brain GABA levels in rats, and our present study also showed that protein expression level of Gad 67 significantly induced through administration of limonene in striatum. Methamphetamine-induced behavioral sensitization down-regulated GAD 67 levels in the nucleus accumbens (Zhang et al., 2006). ...
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Limonene Inhibits Methamphetamine-Induced Sensitizations via the Regulation of Dopamine Receptor Supersensitivity Sun Mi Gu1,†, Sung Yeon Kim2,†, Santosh Lamichhane2 , Jin Tae Hong1,* and Jaesuk Yun1,* 1 College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, 2 College of Pharmacy, Wonkwang University, Iksan 54538, Republic of Korea Abstract Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine-induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated teh effects of limonene on teh psychological dependence induced by drug abuse. Teh development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine-induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonenepretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between teh limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity. Keywords: Dopamine receptor supersensitivity, Methamphetamine, Sensitization, Limonene
... This monoterpene is widely used as a flavor and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration (Flamm and Lehman-McKeeman, 1991). Limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects (do Amaral et al., 2007;Zhou et al., 2009;de Almeida et al., 2012;Lima et al., 2013). Recently, we have reported that limonene inhibits an acute single methamphetamine-induced hyperlocomotion in rats by regulating dopamine levels in the nucleus accumbens (Yun, 2014). ...
... However, other neurotransmitter systems, including GABAergic, 5-HTergic, and glutamatergic systems, are also associated with methamphetamine-induced locomotor sensitization and postsynaptic dopamine receptor supersensitivity (Ohmori et al., 1994;Kim and Jang, 1997;Yoo et al., 2010). It has been reported that GABAergic (Zhou et al., 2009) and 5-HTergic (Yun, 2014) neuronal systems may mediate the effects of limonene on the CNS. Therefore, we suggest that limonene may inhibit the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats via regulation of GABAergic and serotonergic modulation of dopaminergic neuronal transmission. ...
... Therefore, we suggest that limonene may inhibit the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats via regulation of GABAergic and serotonergic modulation of dopaminergic neuronal transmission. In another study, Zhou et al. (2009) demonstrated that limonene administration significantly increased brain GABA levels in rats, and our present study also showed that protein expression level of Gad 67 significantly induced through administration of limonene in striatum. Methamphetamine-induced behavioral sensitization down-regulated GAD 67 levels in the nucleus accumbens (Zhang et al., 2006). ...
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Article
Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine- induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. The development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine- induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonenepretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity.
... It has been suggested that enhanced mesolimbic dopaminergic neuronal transmission is responsible for the enhancement of behavioral changes to a stimulant (Bello et al., 2011;Pak et al., 2006). Limonene is a common terpene from the genus Citrus and has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects (de Almeida et al., 2012;do Amaral et al., 2007;Lima et al., 2013;Zhou et al., 2009). However, the effect of limonene on stimulantinduced behavioral changes is largely unknown. ...
... The mechanism behind limonene-mediated reversal of the increased extracellular dopamine levels of nucleus accumbens is not clear. Zhou et al. (Zhou et al., 2009) demonstrated that limonene administration significantly increased brain ␥-aminobutyric acid (GABA) levels in rats. Pharmacologic increases in brain GABA levels or activation of GABA B receptors, but not activation of GABA A receptors, blocked the increase in dopamine levels elicited by morphine or cocaine injection (Klitenick et al., 1992;Morgan and Dewey, 1998). ...
... It is generally considered that HTR is induced by 5-HT 2A receptor activation (Willins and Meltzer, 1997). To my knowledge, there is no report indicating that limonene can affect 5-HT 2A receptor; however, limonene induces 5-HT release in vitro and in vivo (Fukumoto et al., 2006;Zhou et al., 2009). HTR mediated by 5-HT 2A could be modulated by activation of 5-HT 2C receptor (Canal et al., 2010;Fantegrossi et al., 2010). ...
... 91-92 D-limonene shows effects on the synthesis and changes of neurotransmitters such as dopamine, serotonin and GABA. 93 Mice treated with acute D-limonene showed a decrease in GABA levels in the hippocampus. 94 Administration of limonene results in a significant reduction in the expression of the Il-1 gene, related to inflammatory cytokine; 95 it also exerts anxiolytic effects, regulatory effects on neurotransmitters and anti-contraceptive effects. ...
... 94 Administration of limonene results in a significant reduction in the expression of the Il-1 gene, related to inflammatory cytokine; 95 it also exerts anxiolytic effects, regulatory effects on neurotransmitters and anti-contraceptive effects. 93,96,97 Likewise, consumption of D-limonene in stress-exposed rats improved memory and learning and decreased neuronal loss in the CA1 hippocampus region in these animals. D-limonene also reduced the expression of caspases 3 and 9 and prevented apoptosis by regulating the expression of Bax and Bcl 2 and inhibiting the phosphorylation of p38 MAPK. ...
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Memory and learning is negatively affected by many factors. Alzheimer's disease is a progressive and irreversible neurological disorder that occurs gradually, a sickness that is increasingly common, and multiple scientific articles suggest that essential oils improve memory and learning and are useful in the treatment of various neurodegenerative diseases, including Alzheimer's disease. This review aims to conduct a critical collection of current information on research into both memory and learning impairment, as well as essential oils that are able to avoid this neurodegenerative disease. Currently, different animal models have been useful for the study of neurodegenerative problems that alter memory and learning, experimental pharmacological, genetic and toxicological models that can simulate specific cognitive deficit syndromes. In addition, research in this review show several essential oil compounds that present positive results in animal studies, but still lack human clinical trials. Therefore, the assessment of the safety and efficacy of these phytochemical compounds in diseases that cause memory impairment and learning, remain a promising area for future research.
... Previous studies have demonstrated its ability to produce regression of palpable mammary tumor (Gould, 1997). Moreover, limonene has been reported to suppress the activity of hypothalamic-pituitary-adrenal axis (d'Alessio et al., 2014;Zhou et al., 2009). An earlier report also revealed that limonene suppressed voltage-gated currents in olfactory receptor cells (Kawai et al., 1997), suggesting that limonene tends to be a regulator of membrane ion channels. ...
... Moreover, similar to the ranolazine action, addition of d-limonene could significantly attenuate both amplitude and gating of I Na as well as increase I Na(R) and I Na(P) caused by Tef. Therefore, to some extent, these experimental results could account for d-limonene-induced actions on pituitary function as reported previously (d'Alessio et al., 2014;Zhou et al., 2009). ...
Article
Voltage-gated Na+ currents (INa), known to contain many components (e.g., transient, resurgent and persistent INa) with unique gating properties, are involved in the generation and propagation of action potentials in excitable cells. In this study, how tefluthrin (Tef), a synthetic pyrethoid, and telmisartan (TEL), blocker of angiotensin II receptors can perturb those components of INa was investigated. The presence of either Tef or TEL increased the values of the gating charges of INa involved in the activation (za) and inactivation (za). Tef also increased the amplitude of resurgent INa (INa(R)) or persistent INa (INa(P)) in a pituitary cell line (GH3), while TEL produced minimal effects on them. Subsequent addition of either ranolazine (a blocker of late INa) or d-limonene (a monoterpene), could reverse the changes by TEL or Tef on za or zi. In SCN5A-expressing HEK293T cells, addition of Tef or TEL also increased the peak amplitude and the inactivation time constant of INa which was accompanied by the increased za value of INa. Taken together, the results indicated that Tef- or TEL-mediated changes in the gating kinetics of INa are linked to their actions on functional activity of neurons, neuroendocrine or endocrine cells.
... Administration of limonene (5, 25, and 50 mg/kg for 1 week) also significantly increases GABA, a key hypothalamic neurotransmitter, in the rat brain. This increased activity inhibits the release of corticosterone from the hypothalamic-pituitary-adrenal (HPA) axis under stress conditions, thus playing a vital role as an antistress agent [150]. Molecular docking models have revealed the van der Waals interaction between limonene and active side residues (Ser198, His438, Leu286, Val288, Phe329) of BchE [151]. ...
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Ficus religiosa (Bo tree or sacred fig) and Ficus benghalensis (Indian banyan) are of immense spiritual and therapeutic importance. Various parts of these trees have been investigated for their antioxidant, antimicrobial, anticonvulsant, antidiabetic, anti-inflammatory, analgesic, hepatopro-tective, dermoprotective, and nephroprotective properties. Previous reviews of Ficus mostly discussed traditional usages, photochemistry, and pharmacological activities, though comprehensive reviews of the neuroprotective potential of these Ficus species extracts and/or their important phy-tocompounds are lacking. The interesting phytocompounds from these trees include many ben-galenosides, carotenoids, flavonoids (leucopelargonidin-3-O-β-d-glucopyranoside, leucopelargo-nidin-3-O-α-l-rhamnopyranoside, lupeol, cetyl behenate, and α-amyrin acetate), flavonols
... Limonene is a monoterpene with high oral bioavailability. Previous studies found limonene has antidepressive and antistress effects in mice, with potential GABA A receptor mechanisms or increased serotonin levels (133,134). Another study in hospitalized human patients demonstrated improvements in depression when limonene was diffused into their hospital room (135). ...
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Cannabis and cannabinoids are increasingly being accessed and used by patients with advanced cancer for various symptoms and general quality of life. Specific symptoms of pain, nausea and vomiting, loss of appetite and cachexia, anxiety, sleep disturbance, and medical trauma are among those that have prompted patients with cancer to use cannabis. This conference report from the National Cancer Institute’s “Cannabis, Cannabinoid and Cancer Research Symposium” on the topic of “Cancer Symptom/Treatment Side Effect Management” is an expert perspective of cannabis intervention for cancer and cancer treatment-related symptoms. The purpose of the symposium was to identify research gaps, describe the need for high-quality randomized prospective studies of medical cannabis for palliative care in patients with cancer, and evaluate the impact of medical cannabis on cancer survivors’ quality of life. Further, education of clinicians and affiliated health-care providers in guiding cancer patients in using cannabis for cancer care would benefit patients. Together, these steps will further aid in refining the use of cannabis and cannabinoids for symptom palliation and improve safety and efficacy for patients.
... Regarding the role of limonene as a part of Bergamot EOs, Zhou et al. demonstrated the ability of limonene to increase GABA levels in the brain of rats, which forms a supportive evidence for the GABA-dependent mechanism [83]. Bergamot essential oils (BEOs) were also examined for their anxiolytic effects by using an open field task (OFT), EPM, and a forced swimming task (FST) in rats. ...
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Limonene is a monoterpene confined to the family of Rutaceae, showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its mitigating effect on oxidative stress and inflammation and regulating apoptotic cell death. There are several available studies demonstrating the neuroprotective role of limonene in neurodegenerative diseases, including Alzheimer’s disease, multiple sclerosis, epilepsy, anxiety, and stroke. The high abundance of limonene in nature, its safety profile, and various mechanisms of action make this monoterpene a favorable molecule to be developed as a nutraceutical for preventive purposes and as an alternative agent or adjuvant to modern therapeutic drugs in curbing the onset and progression of neurodegenerative diseases. This manuscript presents a comprehensive review of the available scientific literature discussing the pharmacological activities of limonene or plant products containing limonene which attribute to the protective and therapeutic ability in neurodegenerative disorders. This review has been compiled based on the existing published articles confined to limonene or limonene-containing natural products investigated for their neurotherapeutic or neuroprotective potential. All the articles available in English or the abstract in English were extracted from different databases that offer an access to diverse journals. These databases are PubMed, Scopus, Google Scholar, and Science Direct. Collectively, this review emphasizes the neuroprotective potential of limonene against neurodegenerative and other neuroinflammatory diseases. The available data are indicative of the nutritional use of products containing limonene and the pharmacological actions and mechanisms of limonene and may direct future preclinical and clinical studies for the development of limonene as an alternative or complementary phytomedicine. The pharmacophore can also provide a blueprint for further drug discovery using numerous drug discovery tools.
... Limonene has been reported to exert sedative and anxiolytic effects in mice [30]. Another study showed that the subchronic treatment with BEO's secondary metabolites increased the concentration of GABA in the rats' brain, suggesting an antistress effect [31]. On the other hand, inhalation of linalool induced relaxation and reduced anxiety in mice [32]. ...
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Article
Background: Neural cells undergo functional or sensory loss due to neurological disorders. In addition to environmental or genetic factors, oxidative stress is a major contributor to neurodegeneration. In this context, there has been a growing interest in investigating the effects of essential oils (EOs) in recent years, especially in the treatment of neuropathologies. The chemical and biological effects of EOs have led to important treatment tools for the management of various neurological disorders. Objective: In the present study we performed a systematic review that sought to comprehend the neuroprotective effects of different EOs. Method: This work is a systematic review where an electronic search was performed on PubMed, Science direct, Cochrane Library and SciELO (Scientific Electronic Library Online) databases, covering the last 10 years, using "Essential oil" and "Neuroprotective effect" as reference terms. Results: A total of 9 articles were identified, in which the efficacy of EOs was described in experimental models of anxiety, dementia, oxidative stress, cerebral ischemia, Alzheimer's disease and oxidative toxicity. Conclusion: EOs from different species of medicinal plants have shown positive responses in neurological disorders such as anxiety, dementia, oxidative stress, cerebral ischemia and oxidative toxicity. Thus, EOs emerges with the potential to be used as alternative agents in the treatment of neurological disorders.
... Limonene and its metabolite perillyl alcohol exhibited significant improvement in memory. [38][39] Currently available treatments for AD focus on increasing ACh availability, it has been suggested that S. lavandulaefolia may provide a novel treatment for Alzheimer's disease. [40][41] A recent parallel-group, placebocontrolled trial reported some protection against declines ...
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Article
Complementary medical therapy has received great interest within the field of dementia treatment and also the use of aromatherapy and essential oils is increasing. Essential oils from plants are used therapeutically for hundreds of years to enhance physical and psychological state, there's very little confirmed scientific proof of their efficacy. Therapeutic uses of essential oils is anticipated to drive the expansion, this is often expected to come up with vast demand for aromatherapy products. This review includes proof from mechanistic, neuropharmacological studies of the results of essential oils in relevant in vitro and in vivo models. It's over that aromatherapy provides a probably effective treatment for Alzheimer's. Clinical trials concluded provide a potentially effective and safe treatment for psychiatrical disorders, including Alzheimer's. Aromatherapy has an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.
... Previous studies have demonstrated that monoterpenes and their synthetic derivatives have various pharmacological (Crowell, 1999;Sousa et al., 2007) and psychological properties (de Sousa et al., 2007;Silva et al., 2009). Limonene, a common terpene found in medicinal plants (Leite et al., 2008), has a great potential for modulating the synthesis or changes in neurotransmitters such as dopamine (DA), serotonin (5-HT), γ-aminobutyric acid (GABA), glutamic acid (Glu), and some of their metabolites (Tujioka et al., 2007;Zhou et al., 2009). ...
Article
Background : Limonene, a common terpene found in citrus fruits, is assumed to reduce stress and mood disorders. Dopamine and γ-aminobutyric acid (GABA) have been reported to play an important role in modulating anxiety in different parts of the brain. Hypothesis/Purpose Herein, we report the anxiolytic activity of limonene. In addition, we identified a possible mechanism underlying the effect of limonene on DAergic and GABAergic neurotransmission. Study Design : In this study, mice were injected with saline in the control group and limonene in the test group before behavioral analysis. We performed immunoblotting and high-performance liquid chromatography (HPLC) analysis after the behavioral study. Results : The limonene treated group showed increased locomotor activity and open-arm preference in the elevated plus maze experiment. Limonene treatment increased the expression of both tyrosine hydroxylase and GAD-67 proteins and significantly upregulated dopamine levels in the striatum. Furthermore, tissue dopamine levels were increased in the striatum of mice following limonene treatment, and depolarization-induced GABA release was enhanced by limonene pre-treatment in PC-12 cells. Interestingly, limonene-induced anxiolytic activity and GABA release augmentation were blocked by an adenosine A2A receptor (A2AR) antagonist. Conclusion : Our results suggest that limonene inhibits anxiety-related behavior through A2A receptor-mediated regulation of DAergic and GABAergic neuronal activity.
... Subsequently, LMN and its metabolites have been shown useful in alleviating depression, anxiety, stress mediating anti-inflammatory, immunomodulatory, and antioxidant properties [48]). Mechanistically, antidepressant activities were shown to mediate Gamma aminobutyric acid (GABAergic), monoaminergic, and neurotrophic mechanisms, as evidenced by the inhibition of hypothalamic-pituitary-adrenal axis hyperactivity and the reduction of monoamine neurotransmitter levels [49,50]). ...
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Coronavirus disease (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing pandemic and presents a public health emergency. It has affected millions of people and continues to affect more, despite the tremendous social preventive measures. The therapeutic strategy relies on suppressing infectivity and inflammation, along with immune modulation. The identification of candidate drugs effective for COVID-19 is crucial, thus many natural products including phytochemicals are also being proposed for repurposing and evaluated for their potential in COVID-19. Among numerous phytochemicals, limonene (LMN), a dietary terpene of natural origin has been recently showed to target viral proteins in the in-silico studies. LMN is one of the main compounds identified in many citrus plants, available and accessible in diets and well-studied for its therapeutic benefits. Due to dietary nature, relative safety and efficacy along with favorable physicochemical properties, LMN has been suggested to be a fascinating candidate for further investigation in COVID-19. LMN showed to modulate numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. We hypothesized that given the pathogenesis of COVID-19 involving infection, inflammation, and immunity, LMN may have potential to limit the severity and progression of the disease owing to its immunomodulatory, anti-inflammatory, and antiviral properties. The present article discusses the possibilities of LMN in SARS-CoV-2 infections based on its immunomodulatory, anti-inflammatory, and antiviral properties. Though, the suggestion on the possible use of LMN in COVID-19 remains inconclusive until the in-silico effects confirmed in the experimental studies and further proof of the concept studies. The candidature of LMN in COVID-19 treatment somewhat appear speculative but cannot be overlooked provided favorable physiochemical and druggable properties. The safety and efficacy of LMN are necessary to be established in preclinical and clinical studies before making suggestions for use in humans.
... s-Limonene is a component of lemon EO. The studies on the anti-stress effect of s-Limonene suggest that the effect may be mediated through the GABAergic system [71]. ...
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Essential oils and the constituents in them exhibit different pharmacological activities, such as antinociceptive, anxiolytic-like, and anticonvulsant effects. They are widely applied as a complementary therapy for people with anxiety, insomnia, convulsion, pain, and cognitive deficit symptoms through inhalation, oral administration, and aromatherapy. Recent studies show that essential oils are emerging as a promising source for modulation of the GABAergic system and sodium ion channels. This review summarizes the recent findings regarding the pharmacological properties of essential oils and compounds from the oils and the mechanisms underlying their effects. Specifically, the review focuses on the essential oils and their constituents targeting the GABAergic system and sodium channels, and their antinociceptive, anxiolytic, and anticonvulsant properties. Some constituents target transient receptor potential (TRP) channels to exert analgesic effects. Some components could interact with multiple therapeutic target proteins, for example, inhibit the function of sodium channels and, at the same time, activate GABAA receptors. The review concentrates on perspective compounds that could be better candidates for new drug development in the control of pain and anxiety syndromes.
... Chronic stress is known to induce increases in serum/plasma glucocorticoid levels (cortisol in humans and CORT in rodents), which are associated with metabolic disturbances [44]. Acute stress by FST was also reported to increase the serum CORT concentrations [45]. Figure 4 shows that HMF did not ameliorate CUMS-induced increases in serum CORT concentrations. ...
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We previously reported that the subcutaneous administration of 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), a citrus polymethoxyflavone, attenuated depressive-like behavior and increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a corticosterone-induced depression-like mouse model. We herein demonstrated that (1) HMF was detectable in the brain 10 and 30 min after its oral administration, (2) orally administered HMF improved chronic unpredictable mild stress (CUMS)-induced pathological conditions, including body weight loss and depressive-like behavior, and CUMS-induced neurochemical changes, such as reduction in BDNF expression, decrease in neurogenesis, and decreased level of phosphorylated calcium-calmodulin-dependent protein kinase II in the hippocampus, and (3) these effects of HMF were inhibited by the pre-administration of U0126, a mitogen-activated protein (MAP) kinase inhibitor. These results suggest that orally administered HMF is beneficial for the upregulation of BDNF in the hippocampus via the extracellular signal-regulated kinase1/2 (ERK1/2)/MAP system, which may account for its antidepression effects.
... especially musculoskeletal pain (Clair and Emir, 2015). Our hypothesis corroborates the previous findings of Zhou et al. (2009) and Rajak et al. (2013) which demonstrated that LIM has pharmacological affinity for the GABA A receptor in CNS, so its effects seem to be related to action on this important neurotransmission system. ...
Article
Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in β-cyclodextrin (LIM-βCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-βCD (50 mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-βCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-βCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with βCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.
... [22] In addition, it was also reported to possess neuroprotective effects, [23] as well as anti-stress activity probably acting on GABA-A receptor. [24] Limonene and linalool are two small hydrophobic molecules capable to cross the blood-brain barrier. As a matter of fact, these two monoterpenes showed maximum transport to the brain after simple inhalation in mice. ...
Article
In the Malagasy traditional practices, smoke from burning leaves of Cinnamosma madagascariensis Danguy is inhaled to treat brain disorders such as dementia, epilepsy and headache. In the present work we have evaluated the in vivo anticonvulsant effects of the essential oil from leaves of C. madagascariensis (CMEO). CMEO was isolated by steam distillation. The anticonvulsant activity of CMEO (0.4 and 0.8 mL/kg bw) administered subcutaneously was evaluated on pentylenetetrazol (PTZ)-induced seizures in Wistar rats; diazepam was used as positive control. Linalool, limonene and myrcene were the major CMEO constituents. At the dose of 0.8 mL/kg, CMEO completely arrested the PTZ-induced convulsions with moderate sedative effects. The traditional anticonvulsant use of C. madagascariensis was confirmed allowing us to candidate molecules from CMEO as potential drugs to treat convulsions associated with strong agitation. This article is protected by copyright. All rights reserved.
... Consequently, lavender aromatherapy could be a useful alternative to psychotropic drugs (Lin et al., 2007). Limonene from the EO of lemon were tested by Zhou et al. (2009) in scopolamine induced dementia model applying passive avoidance test and open field test. Limonene and its metabolite perillyl alcohol exhibited significant improvement in memory. ...
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The use of essential oils (EOs) and their components is known since long in traditional medicine and aromatherapy for the management of various diseases, and is further increased in the recent times. The neuroprotective and anti-aging potentials of EOs and their possible mechanism of actions were evaluated by numerous researchers around the globe. Several clinically important EOs and their components from Nigella sativa, Acorus gramineus, Lavandula angustifolia, Eucalyptus globulus, Mentha piperita, Rosmarinus officinalis, Jasminum sambac, Piper nigrum and so many other plants are reported for neuroprotective effects. This review article was aimed to summarize the current finding on EOs tested against neurodegenerative disorders like Alzheimer disease (AD) and dementia. The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs), cholinergic hypofunction, oxidative stress and glutamatergic abnormalities were focused. Furthermore, effects of EOs on other neurological disorders including anxiety, depression, cognitive hypofunction epilepsy and convulsions were also evaluated in detail. In conclusion, EOs were effective on several pathological targets and have improved cognitive performance in animal models and human subjects. Thus, EOs can be developed as multi-potent agents against neurological disorders with better efficacy, safety and cost effectiveness.
... Limonene has anti-stress effects through its anti-oxidant potential and increases the levels of serotonin, dopamine (DA), gamma-aminobutyric acid (GABA), and neurotransmission conductions in the rat brain suggesting that limonene could inhibit physical stress through GABA receptor. [8] However, no studies have addressed the anti-amnesic effect of T. patula on learning and memory in mice. ...
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Background: Alzheimer′s disease is a progressive neurodegenerative disorder characterized by a gradual decline in memory associated with shrinkage of brain tissue and loss of neurons with a diminished level of the central cholinergic neurotransmitter acetylcholine. Objective: The present study was performed to examine the effect of ethanolic extract of Tagetes patula (EETP) on cognitive impairment induced by scopolamine, a muscarinic antagonist, in mice. Materials and Methods: Rats were treated with EETP and donepezil for 15 successive days followed by treatment with scopolamine (1 mg/kg) for 3 days. The changes in behavioral, biochemical, and neurotransmitters were assessed in rats. Cognitive functions were assessed using step-through latency on a passive avoidance apparatus and Morris water maze test. Antioxidants parametes such as superoxide dismutase (SOD), glutathione reductase (GR), lipid peroxidation (LPO), and nitrates were assessed. Neurotransmitters including acetylcholinesterase (AChE), dopamine (DA), and serotonin were also assessed, and neuronal damage was also analyzed. Results: Scopolamine-treated rats showed impaired learning and memory, increased activity of AChE, LPO and decreased levels of SOD, reduced glutathione, nitrates, serotonin, and DA. The EETP significantly reversed the scopolamine-induced cognitive impairment in mice was measured by the passive avoidance test. In addition, EETP decreased escape latency in the Morris water maze. In probe trail session, EETP increased the latency time in the target quadrant. Ex vivo EETP inhibited AChE activity in the mice brain. EETP treated mice significantly increased the SOD, GR, nitrates, DA, and serotonin levels, and decreased the level of LPO when compared with scopolamine-treated mice. Conclusion: These results indicate that EETP may exert anti-amnesic effect through both by anti-AChE and antioxidant mechanisms.
... [21] Moreover, potential medical applications are ascribed to the monoterpenes S-(À)limonene, S-(+)-carvone, R-(À)-carvone and (À)-fenchone. [9,[22][23][24] Furthermore, all the tested monoterpenoids are main constituents of many common aromatic plants, such as Anethum graveolens L. (Apiaceae), [10,13,25] Carum carvi L. (Apiaceae), [10,13] Foeniculum vulgare Mill (Apiaceae), [26] Lavandula angustifolia Mill (Lamiaceae), [27] Lavandula stoechas L. (Lamiaceae), [27] Mentha spicata L. [8,28] and other Mentha species, [21] Ocimum basilicum L., [29] etc. ...
Article
The genotoxicity of 10 essential oil constituents was evaluated using the Drosophila melanogaster (Meigen) somatic mutation and recombination test, also known as the wing spot test, in the frame of a screening project aiming at evaluating the mutagenic activity of widely used substances, natural or not. Of the compounds that we tested here, l-carveol, dihydrocarveol, (+)-dihydrocarvone, (−)-fenchone and (−)-carvyl acetate did not exhibit any mutagenic or recombinogenic activity, whereas (±)-linalool, S-(+)-carvone and S-(−)-limonene gave inconclusive results. In contrast, α-phellandrene and R-(−)-carvone significantly increased the frequency of mutant spots when compared with the negative control, suggesting mutagenic activity even at the lowest concentration used (1.5 µl/ml). Moreover, these data clearly demonstrate differences in activity between stereoisomers such as S-(+)- and R-(−)-carvone. Given that α-phellandrene and R-(−)-carvone are widely used compounds, further research is needed in order to have a better understanding of their activity and a clearer picture of their genotoxicity in order to decide whether they should remain or not in the lists of compounds that are safe to use. Copyright © 2011 John Wiley & Sons, Ltd.
... alpha-Pinene, an antiinflammatory (Bae et al., 2012), and 1.2-1.9% limonene, which has anti-stress (Park et al., 2011) and sedative (Zhou et al., 2009) properties. Finally, leaf extract form Sphagneticola trilobata has antibacterial, antioxidant and fibroblast stimulatory compounds that contribute to wound healing (Balekar et al., 2012), and may be protective for menorrhagia. ...
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Ethnopharmacological relevance: In Dominica, women offer dysmenorrhea, delayed menses, and menorrhagia as prevalent menstrual troubles. Dominican humoral theory considers menstruation to be "hot" such that menstrual problems are caused by the introduction of too much "cold" in the body. These conditions can be painful and may require herbal medicine. Our method finds the most culturally salient plants for these conditions-those which are of common knowledge across the population. We hypothesize that cultural agreement on ethnobotanical treatments (1) reflects their perceived ethnophysiological efficacy, and that (2) salient plants contain bioactive compounds appropriate for the menstrual conditions for which Dominicans employ the plants. Materials and methods: Qualitative data on local explanatory models and treatment of menstrual conditions were collected using participant-observation, focus groups, and informal key informant interviews. Quantitative ethnobotanical data come from freelist (or "free-list") tasks, conducted with 54 adults. Results: Mean salience values calculated from freelisted data reveal that the same four plants, Cinnamomum verum (synonym Cinnamomum zeylanicum) (Lauraceae), Mentha suaveolens (Lamiaceae), Pimenta racemosa (Myrtaceae) and Sphagneticola trilobata (synonym Wedelia trilobata) (Asteraceae) are used to treat dysmenorrhea and delayed menses. The only remedy reported for menorrhagia, Sphagneticola trilobata (Asteraceae), is also a treatment for dysmenorrhea and delayed menses. The Dominican humoral system views menstruation as a "hot" condition, yet these "bush medicines" are also "hot." Dominicans do not view menstruation as a problem, rather, they reckon that excess "cold" in a woman׳s menstruating body impedes menstrual function to cause problems thus requiring "hot" plants to alleviate their symptoms. A literature review revealed that all four plants contain analgesic, anti-nociceptive, and anti-inflammatory properties. Additionally, Mentha suaveolens is muscle-relaxing and anti-spasmodic, Cinnamomum verum has a mild anti-coagulant, and Sphagneticola trilobata has wound healing, anti-stress, and sedative properties. Conclusions: In Dominican menstrual problems there is correspondence between cultural consensus, bioactivity, and humoral theory. Examining the ethnophysiology of menstruation and its complications provides evidence for the expectations of actions and effectiveness of locally culturally salient medicinal plants.
... Recently, several studied have reported that monoterpenoids present within the essential oils of such herbal medicines have modulatory activity with GABA at several GABA A receptor subtypes. Zhou et al. [22] demonstrated the effect of limonene on brain neurotransmitter levels and behavior on rat. According to their results, limonene was applied for 1 week, significant changes concerning, for example GABA, 5-HIAA and 5-HT, were observed. ...
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Litsea cubeba (Lauraceae) is woody plant endemic to Taiwan that is traditionally used as a spice. In the current study, several behavioral analyses were performed to evaluate the neuropharmacological activity of the essential fruit oil of L. cubeba in ICR mice. Oral administration of 100, 300 and 500 mg/kg of L. cubeba fruit oil significantly prolonged pentobarbitone-induced mouse sleeping time by 20.0, 110.8, and 159.6 %, respectively. In addition, after administration of L. cubeba oil, mice significantly increased the time spent in the open arms and number of entries into the open arms of an elevated plus maze compared to saline-treated mice suggesting that L. cubeba oil has anxiolytic activity. A tail-flick test conducted after treatment of mice with 500 mg/kg L. cubeba fruit oil also suggested that this oil has potent analgetic activity. According to GC/MS analyses, the essential fruit oil of L. cubeba oil consists of 23 compounds. The main components are geranial (37.16 %), neral (28.29 %), and d-limonene (22.90 %). We conclude that L. cubeba oil has a potent effect on the central nervous system of mice.
Chapter
Limonene is one of the most common terpenes found in nature and a primary bioactive compound of essential oils obtained from citrus fruit peels. Limonene is considered as generally recognized as safe (GRAS) in the Code of Federal Regulations. Owing to its lemon-like odor and rich flavor profile, it has been widely used as a flavoring and/or preserving agent in numerous food products. It can be applied in many types of beauty and household products, such as fresheners, soaps, perfumes, shampoos, hair conditioners, shower gels, cleaning products, detergents, and eco-friendly pesticides. In this chapter, biogenesis, physicochemical properties, distribution, extraction/purification, metabolism/bioavailability, and medicinal/pharmaceutical and food applications of limonene are described.
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Introduction Essential oils from plants are recognized as one of the most promising secondary metabolites for the development of cheap and safer drugs. While Erythrina caffra has been prominently used in folk medicine for the treatment of microbial infections, there is dearth of information on the pharmacological effectiveness and chemical composition of its essential oil. The study, therefore, aimed at identifying the chemical composition and biological activities of the essential oil of Erythrina caffra. Methods In this study, the essential oil was extracted with all-glass Clevenger. The antioxidant activities of the essential oil and antibacterial susceptibility assay by agar well diffusion techniques were assessed while GC-MS analysis was performed to identify the chemical constituents of the essential oil. Results The study showed that the radical scavenging activity of the essential oil increases as the concentration of the essential oil increases. All bacterial isolates were susceptible to essential oil with the exception of Salmonella typhimurium and Pseudomonas aeruginosa producing inhibition zones ranging between 22±1.3 and 35±2.1 mm in the susceptible isolates. The GC-MS chromatogram indicated there are 35 bioactive compounds in the essential oil and Caryophyllene oxide (53.54%), [1S-(1α,7α,8aβ)]-1,2,3,5,6,7,8,8a-octa-1 - hydro-1,8a-dimethyl-7-(1-methylethenyl)-Naphthalene (7.81%), Kauran-18-al (6.49%), 10,10-Dimethyl-2,6-dimethylenebicy clo[7.2.0]undecan-5.beta.-ol (5.83%), 10s,11s-Himachala-3(12),4-diene (4.51%), Caryophyllene (3.65%) and 1- Hexanol (3.31%) were the most prominent compounds. Conclusion Excessive production of free radicals or reactive oxygen species (ROS) causes oxidative stress and disease. Oxidative stress resulting from imbalance between excessive generation of free radicals and inadequate antioxidant defense system has been linked to pathogenesis of many diseases. The essential oil of E. caffra stem bark extract possess antimicrobial and good antioxidant activities and its rich level of phytochemicals can be used as either dietary or complementary agents.
Article
Depression is a common global mental disorder that seriously harms human physical and mental health. With the development of society, the increase of pressure and the role of various other factors make the incidence of depression increase year by year. However, there is a lack of drugs that have a fast onset, significant effects, and few side effects. Some volatile oils from traditional natural herbal medicines are usually used to relieve depression and calm emotions, such as Lavender essential oil and Acorus tatarinowii essential oil. It was reported that these volatile oils, are easy to enter the brain through the blood-brain barrier and have good antidepressant effects with little toxicity and side effects. In this review, we summarized the classification of depression, and listed the history of using volatile oils to fight depression in some countries. Importantly, we summarized the anti-depressant natural volatile oils and their monomers from herbal medicine, discussed the anti-depressive mechanisms of the volatile oils from natural medicine. The volatile oils of natural medicine and antidepressant drugs were compared and analyzed, and the application of volatile oils was explained from the clinical use and administration routes. This review would be helpful for the development of potential anti-depressant medicine and provide new alternative treatments for depressive disorders.
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Citrus sinensis (orange) by-products represent one of the most abundant citric residues from orange juice industrial production, and are a promising source of health-promoting compounds like terpenes. In this work, different extraction solvents have been employed to increase terpene extraction yield and selectivity from this orange juice by-product. A set of bioactivity assays including enzymatic (acetylcholinesterase (AChE), butylcholinesterase (BChE) and lipoxygenase (LOX)) as well as antioxidant (ABTS, reactive oxygen species (ROS) and reactive nitrogen species (RNS)) activity tests have been applied to investigate the neuroprotective potential of these compounds. New fluorescence-based methodologies were developed for AChE and BChE assays to overcome the drawbacks of these tests when used in vitro to determine the anticholinergic activity of colored extracts. Comprehensive phytochemical profiling based on gas chromatography coupled to quadrupole time of flight mass spectrometry (GC-qTOF-MS) analysis showed ahigh content of mono- and sesquiterpenes in the extracts obtained with ethyl acetate, whereas n-heptane extracts exhibited a large amount of triterpenes and carotenoids. From a neuroprotective activity point of view, ethyl acetate extract is the most promising due to its anticholinergic activity and antioxidant capacity. Finally, a multivariate data analysis revealed a good correlation between some monoterpenes (e.g. nerol or limonene) and the antioxidant capacity of the natural extract, while a group of sesquiterpenes (e.g. δ-Cadinene or nootkatone) showed correlation with the observed AChE, BChE and LOX inhibition capacity. Hydrocarbons mono- and sesquiterpenoids reveal high capacity in vitro to cross the blood–brain barrier (BBB).
Article
In this study, a secondary electrospray ionization-high resolution mass spectrometer (SESI-HRMS) system was employed to profile the real-time exhaled metabolome of ten subjects who had ingested a peppermint oil capsule. In total, six time points were sampled during the experiment. Using an untargeted way of profiling breath metabolome, 2333 m/z unique metabolite features were determined in positive mode, and 1322 in negative mode. To benchmark the performance of the SESI-HRMS setup, several additional checks were done, including determination of the technical variation, the biological variation of one subject within three days, the variation within a time point, and the variation across all samples, taking all m/z features into account. Reproducibility was good, with the median technical variation being 18% and the median variation within biological replicates being 34%. Both variations were lower than the variation across individuals. Washout profiles of compounds from the peppermint oil, including menthone, limonene, pulegone, menthol and menthofuran were determined in all subjects. Metabolites of the peppermint oil were also determined in breath, for example, cis/trans-carveol, perillic acid and menthol glucuronide. Butyric acid was found to be the major metabolite that reduce the uptake rate of limonene. Pathways related to limonene metabolism were examined, and meaningful pathways were identified from breath metabolomics data acquired by SESI using an untargeted analysis.
Article
Limonene is a natural monoterpene having antioxidant, anti-inflammatory, and neuro-protective properties. We investigated the effects of limonene on memory impairment, hippocampal damage, and high anxiety induced by chronic immobilization stress in male rats. Fourty male Wistar rats were divided into the control (C), limonene (L), stress (S), and stress+limonene (S+L) groups. Animals of the S and S+L groups were put in a restrainer daily for 6 h for 21 consecutive days. Within the same period, the L and S+L groups were treated with limonene (10 mg/kg, gavaging). The Morris water maze (MWM) and elevated plus-maze (EPM) tests were used to evaluate spatial learning, formation of memory, and the anxiety level. At the end of the course, structural hippocampal damage was evaluated by Nissl’s staining. Chronic immobilization reduced memory, caused the emergence of anxiety, and induced neuronal loss in the CA1 area of the hippocampus. The duration and distance traveled to reach the hidden platform in the MWM test in the S+L group were significantly smaller compared with those in the S group (P < 0.05), while time spent in the target quadrant was significantly greater compared with the latter group (P < 0.01). Also, limonene provided a significant increase in the percentage of open-arm entries and stay in these arms of the EPM, as compared with the S group (respectively, P < 0.01 and P < 0.05), and reduced stress-induced damage in CA1 pyramidal neurons in these animals. It is concluded that limonene provides spatial memory improvement and reduces anxiety in rats exposed to immobilization stress; it may appear efficient in treating neurodegenerative diseases.
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This brief report explores the adjunctive use of therapeutic essential oils in clinical practice to reduce overall patient anxiety and stress. The use of therapeutic essential oils is becoming increasingly popular among the general population. Studies have validated that these oils have the potential to affect patient health and wellness positively, if used properly in the clinical setting. This report discusses how to incorporate essential aromatic oils safely and efficiently in clinical practice and advocates for more research on the efficacy of aromatic oils to reduce patient anxiety in human populations.
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Natural killer (NK) cells play an important role in the innate immune system by eliminating cancer cells and virally infected cells. Aging and stress attenuate the activity of NK cells, thereby increasing the risk of various diseases. In this study, we demonstrated that the consumption of a small number of kumquats in an in vivo model could suppress elevated plasma corticosterone levels and reverse the decline in splenocytes cytotoxicity caused by restraint-stress. Our results identified β-cryptoxanthin (BCX) as an active kumquat component with NK cell-activating effect, and R-limonene as an active component that mediates not only the anti-stress effect but also NK cell activation by oral administration. In addition, BCX, R-limonene, and R-limonene metabolites were found to enhance IFN-γ production in KHYG-1 cells, a human NK cell line. Collectively, our findings suggest that the ingestion of a few kumquats on daily basis can help combat stress and enhance NK cells activity.
Article
R-(+)-limonene (d-limonene) is a commonly used flavor additive in food, beverages and fragrances for its pleasant lemon-like odor. Considering its increasing applications, it's necessary to understand toxicological effects and risk associated with its use. R-(+)-limonene is rapidly absorbed in experimental animals and human beings following oral administration. In humans, it gets distributed to liver, kidney, and blood resulting in the formation of metabolites like perillic acid, dihydroperillic acid, limonene-1,8-diol and limonene-1,2 diol. Important toxic effects primarily reported in rodents are severe hyaline droplet nephrotoxicity (only in male rats due to specific protein α2u-globulin; however, this effect isn't valid for humans), hepatotoxicity and neurotoxicity. R-(+)-limonene does not show genotoxic, immunotoxic and carcinogenic effects. Substantial data is available about limonene's stability after treatment with thermal and non-thermal food processing techniques; however, information about toxicity of metabolites formed and their safe scientific limits is not available. In addition, toxicity of limonene degradation products formed during storage of citrus juices isn't known. Based on all available toxicological considerations, R-(+)-limonene can be categorized as low toxic additive. More detailed studies are required to better understand interaction of limonene with modern food processing techniques as well as degradation products generated and toxicity arising from such products.
Article
Background: Ginsenoside Rg1 is regarded as one of main bioactive compounds responsible for pharmaceutical actions of ginseng with little toxicity and has been shown to have possibly neuroprotective effects. However, the mechanism of its neuroprotection for acute ischemic stroke is still elusive. The purpose of present study is thus to assess the neuroprotective effects of the ginsenoside Rg1 against neurological injury in a mice model of cerebral ischemia/reperfusion (I/R), and then to explore the mechanisms for these neuroprotective effects. Methods: Mices were pretreated with ginsenoside Rg1 20,40 mg kg−1 d−1, ig, for 7d, respectively, then subjected to cerebral ischenmia (middle cerebral artery occlusion) for 2 h and reperfusion for 22 h. The infarct volume and the neurological deficit were determined by TTC staining and Longa′s scoring, respectively. The protein expression of brain-derived neurotrophic factor (BDNF) was analyzed by Immunohistochemistry and Western blot, respectively. Interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) expression in serum was measured by ELISA kit. High-performance liquid chromatography (HPLC) was used to explore the contents of Glu and Asp. Results: Compared with the ischemia/reperfusion group, ginsenoside Rg1 40 mg/kg group has significantly reduced infarct volume, neurological deficit scores (P
Background: Initial evidences have shown that diabetes mellitus occurs concomitantly with obsessive-compulsive disorder (OCD) symptomatology. Serotonergic psychiatric therapy posits that serotonin is a central character in the management of OCD. Hence, it is worth investigating novel chemical entities affecting the serotonergic system for targeting OCD. An isoflavonoid phytoestrogen, genistein, has been recognized as of great pharmacological value especially for protecting neurodegeneration, depression (serotonin regulation), and diabetes. The effectiveness of genistein pretreatment on the symptoms of OCD in streptozotocin-induced diabetic mice is investigated in this study. We also evaluate the probable involvement of the serotonergic system. Methods: Groups of diabetic mice were treated with genistein at the dose of 5.0 and 10.0 mg/kg (intraperitoneal, twice daily, 14 days), and symptoms of OCD were assessed by the marble-burying behavior, in comparison with the standard drug fluoxetine. Neurochemical assessment of the serotonergic ratio 5-hydroxyindole-3-methoxyphenylacetic acid/5-hydroxytryptamine (5-HIAA/5-HT) in the cortical region of the brain was performed using HPLC (high-pressure liquid chromatography). Results: Chronic treatment with genistein significantly recovered [F(6, 35)=53.00, p<0.0001, R2=0.9008] the symptoms of OCD as assessed by marble burying behavior in normal and diabetic mice. Locomotor performance was not influenced by the diabetic condition or any associated treatment. The turnover of serotonin neurotransmission (5-HIAA/5-HT) was significantly boosted in the diabetic condition; genistein treatment dragged it [F(6, 35)=35.75, p<0.0001, R2=0.8597] toward the respective control. Conclusions: Genistein supplementation might be a potential therapeutic line for the management and/or prevention of diabetes-associated OCD symptomatology.
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Fragrance compounds are chemicals belonging to one of several families, which are used frequently and globally in cosmetics, household products, foods and beverages. A complete list of such compounds is rarely found on the ingredients-list of such products, as “fragrance mixtures” are defined as “trade secrets” and thus protected by law. While some information regarding the general toxicity of some of these compounds is available, their neurotoxicity is known to a lesser extent. Here, we discuss the prevalence and neurotoxicity of fragrance compounds belonging to the three most common groups: phthalates, synthetic musks and chemical sensitizers.
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γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter reducing neural excitability in the mammalian central nervous system (CNS) with three subclasses of receptors. Several conventional drugs and compounds modulate the GABAergic system, demonstrating different pharmacological effects. In this review, interactions of natural terpenoids with the GABAergic system are highlighted with relation to disorders like anxiety, insomnia, convulsion, pain, and cognitive deficits. Terpenoids with various structures affect the function of the GABAergic system via dissimilar mechanisms. Most of the discussed compounds interact with GABA receptors, but especially with the GABAA subtype. This may be due to the fact that researchers tend to assess the interaction of compounds using GABAA receptors. However, bilobalide, a sesquiterpene, showed anticonvulsant properties through the activation of glutamic acid decarboxylase (GAD) enzyme, which is a key enzyme in biosynthesis of GABA. Therefore, further studies evaluating and comparing terpenoids of different classes and their interaction with the GABA system, along with their pharmacokinetic properties, could be worthwhile in future studies.
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Penehyclidine hydrochloride can promote microcirculation and reduce vascular permeability. However, the role of penehyclidine hydrochloride in cerebral ischemia-reperfusion injury remains unclear. In this study, in vivo middle cerebral artery occlusion models were established in experimental rats, and penehyclidine hydrochloride pretreatment was given via intravenous injection prior to model establishment. Tetrazolium chloride, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and immunohistochemical staining showed that, penehyclidine hydrochloride pretreatment markedly attenuated neuronal histopathological changes in the cortex, hippocampus and striatum, reduced infarction size, increased the expression level of Bcl-2, decreased the expression level of caspase-3, and inhibited neuronal apoptosis in rats with cerebral ischemia-reperfusion injury. Xanthine oxidase and thiobarbituric acid chromogenic results showed that penehyclidine hydrochloride upregulated the activity of superoxide dismutase and downregulated the concentration of malondialdehyde in the ischemic cerebral cortex and hippocampus, as well as reduced the concentration of extracellular excitatory amino acids in rats with cerebral ischemia-reperfusion injury. In addition, penehyclidine hydrochloride inhibited the expression level of the NR1 subunit in hippocampal nerve cells in vitro following oxygen-glucose deprivation, as detected by PCR. Experimental findings indicate that penehyclidine hydrochloride attenuates neuronal apoptosis and oxidative stress injury after focal cerebral ischemia-reperfusion, thus exerting a neuroprotective effect.
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Citrus junos (Yuzu, CJ) is a traditional fruit in Japan and its essential oil (EO) has been used in food, cosmetics, and traditional medicine. The present study examined the influence of essential oil from Citrus junos (EOCJ) on emotional behavior in mice, and how its action differed in comparison to (+)-limonene (LI), its major component. The influence of inhaled administration (i.h.) of EOCJ for 90 minutes on mouse emotional behavior was examined using the light/dark box (LDB) test, open field (OF) test, and elevated plus-maze (EPM) test. In addition, gas chromatography (GC) was used in clarifying the amount of LI absorbed in the internal organs. Inhalation of EOCJ at 3.4 and 6.7 mg/L air indicated the tendency for an anxiolytic-like effect in LDB and EPM tests. In addition, an increase in locomotor activity was observed at 6.7 mg/L air EOCJ (i.h.) in the OF test. Inhalation of (+)-LI at 3.4 and 6.7 mg/L air indicated the same anxiolytic-like effect in EPM test as with EOCJ. In contrast, the anxiolytic-like effect of (+)-LI was smaller than that of EOCJ in the LDB test. Furthermore, an increase in locomotor activity was not observed at 6.7 mg/L air (+)-LI (i.h.).
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d-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor. d-Limonene has been designated as a chemical with low toxicity based upon lethal dose (LD50) and repeated-dose toxicity studies when administered orally to animals. However, skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products. In experimental animals and humans, oxidation products or metabolites of d-limonene were shown to act as skin irritants. Carcinogenic effects have also been observed in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein α2u-globulin responsible for this effect in rodents is absent in humans. Thus, the liver was identified as a critical target organ following oral administration of d-limonene. Other than the adverse dermal effects noted in humans, other notable toxic effects of d-limonene have not been reported. The reference dose (RfD), the no-observed-adverse-effect level (NOAEL), and the systemic exposure dose (SED) were determined and found to be 2.5 mg/kg/d, 250 mg/kg//d, and 1.48 mg/kg/d, respectively. Consequently, the margin of exposure (MOE = NOAEL/SED) of 169 was derived based upon the data, and the hazard index (HI = SED/RfD) for d-limonene is 0.592. Taking into consideration conservative estimation, d-limonene appears to exert no serious risk for human exposure. Based on adverse effects and risk assessments, d-limonene may be regarded as a safe ingredient. However, the potential occurrence of skin irritation necessitates regulation of this chemical as an ingredient in cosmetics. In conclusion, the use of d-limonene in cosmetics is safe under the current regulatory guidelines for cosmetics.
Article
This study was conducted to investigate physiological and behavioral effects of the exposure to plant-derived odorants in Holstein steers (8 month of age) under the acute stress of social isolation in a novel environment. Each steer was tethered in a new room alone and exposed to one of three odorants: a mixture of equal amounts of trans-2-hexenal and cis-3-hexenol (green odor, GO; n = 5), essential oil of grapefruits (EOG; n = 5) and solvent (SOL; n = 6). Behaviors were recorded and blood samples were taken at intervals of 10-15 min for 6 h. Compared with SOL, exposure to GO or EOG decreased the frequency of vocalization (P < 0.05), shortened the latency period before the onset of rumination (P < 0.05) and increased the duration of rumination (P < 0.05). Plasma cortisol concentrations in steers exposed to plant-derived odorants (GO and EOG) during 90-130 min from commencement of sampling were significantly lower (P < 0.05) compared with SOL. These results suggest that appeasing effects of plant-derived odorants on behavioral and physiological stress responses previously reported in laboratory rodents could be also be expected in steers.
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The administration of essential oils or their constituents in aromatherapy, complementary medicine, and folk medicine has been known for a long time, and its relevance is steadily growing. In the last few years, many scientific studies were conducted to investigate the effect and the mechanisms of action of these compounds on the central nervous system. The aim of this article is to summarize the literature on this topic published in the period 2008–2010, upgrading a comprehensive review. The major actions discussed are pain, anxiety, learning, memory, attention, arousal, relaxation, sedation and sleep. Furthermore, the effects on mood, behaviour and perception as well as the application of essential oils in the treatment of epilepsy, stress, dementia and Alzheimer's disease are discussed. Copyright © 2011 John Wiley & Sons, Ltd.
Article
Bergamot essential oil (BEO), Citrus aurantium subsp. bergamia (Risso) Wright & Arn. (Rutaceae), is used widely in aromatherapy to reduce stress and anxiety despite limited scientific evidence. A previous study showed that BEO significantly increased gamma-aminobutyric acid levels in rat hippocampus, suggesting potential anxiolytic properties. The aim of this study was to investigate the effect of BEO (1.0%, 2.5% and 5.0% w/w) administered to rats on both anxiety-related behaviours (the elevated plus-maze (EPM) and hole-board tests) and stress-induced levels of plasma corticosterone in comparison with the effects of diazepam. Inhalation of BEO (1% and 2.5%) and injection of diazepam (1 mg/kg, i.p.) significantly increased the percentage of open arm entries on the EPM. The percentage time spent in the open arms was also significantly enhanced following administration of either BEO (2.5% and 5%) or diazepam. Total arm entries were significantly increased with the highest dose (5%), suggesting an increase in locomotor activity. In the hole-board test, 2.5% BEO and diazepam significantly increased the number of head dips. 2.5% BEO and diazepam attenuated the corticosterone response to acute stress caused by exposure to the EPM. In conclusion, both BEO and diazepam exhibited anxiolytic-like behaviours and attenuated HPA axis activity by reducing the corticosterone response to stress.
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The mortality of individuals suffering from depression has been increasing, especially post-menopausal women; therefore, their care and treatment are important to maintain a high quality of life. In the present study, we evaluated the antidepressant-like effects of a major isoflavonoid, genistein (4',5,7-trihydroxyisoflavone), using a behavioral model of depression, the forced swimming test (FST), in ovariectomized rats. Daily administration of genistein to ovariectomized rats at a dosage of 10 mg/kg of body weight/d for 14 d significantly reduced the immobility time during the FST without changing motor dysfunction. On the other hand, a higher dosage, 100 mg/kg/d, did not have any effects on the immobility time compared with the vehicle control. Repeated administration of genistein at 10 mg/kg of body weight did not affect serotonergic activities in the hippocampus compared to the vehicle control in ovariectomized rats. A 5-min FST trial stimulated these activities. On the other hand, repeated pretreatment with genistein protected against changes in activity during the FST trial. These results suggest that daily consumption of genistein 10 mg/kg/d might have antidepressant-like effect on ovariectomized rats by regulating changes in serotonergic metabolism in the hippocampus under stressful conditions.
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The effects of application of five different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the striatum and hippocampus were compared using in vivo microdialysis. Forced swimming for 30 min elevated extracellular 5-hydroxytryptamine to 90% above basal levels and reduced 5-hydroxyindoleacetic acid to 45% of basal levels in the striatum during the swim session. In contrast, hippocampal 5-hydroxytryptamine was not altered significantly by forced swimming but 5-hydroxyindoleacetic acid levels were reduced to 60% of basal levels. Tail pinch for 5 min elevated 5-hydroxytryptamine to 55% above basal levels in striatum and to 35% above basal levels in hippocampus. Tail pinch had no effect on 5-hydroxyindoleacetic acid in either brain region. In contrast to forced swimming and the tail pinch, the other three stressors, immobilization stress for 100 min, exposure to a cold environment (4°C) for 2 h, and forced motor activity on a rotarod for 30 min, failed to alter extracellular 5-hydroxytryptamine in either the striatum or the hippocampus. All five stressors increased plasma corticosterone levels: tail pinch, 246%; cold stress, 432%; immobilization, 870%; forced motor activity, 1030%; and forced swimming, 1530%. These results suggest that individual stressors produce different effects on extracellular 5-hydroxytryptamine in different brain regions. In addition, there does not appear to be a relationship between the effects of stressors on the 5-hydroxytryptamine system and the magnitude of their ability to activate the hypothalamic-pituitary-adrenal axis.
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Chronic stress is known to result in impairment of learning and memory and precipitate several affective disorders including depression and anxiety. Drugs of natural origin are known to possess several effects on the central nervous system and are emerging as promising alternative therapies. In this context, the hydroalcoholic extract of Euphorbia hirta (Eh) was evaluated for anxiolytic property in chronically stressed rats subjected to elevated plus maze (EPM) and open field test (OFT). Eh treatment (200 mg/kg, p.o.; seven days) showed marked anti-anxiety activity in chronic immobilization stress. In contrast, the forced swim stress-induced anxiety was only partially decreased by Eh. Co-treatment of rats with flumazenil (0.5 mg/kg, i.p.), bicuculline (1 mg/kg, i.p.) or picrotoxin (1 mg/kg, i.p.) resulted in a significant reduction of anxiolytic effect of Eh indicating that its actions are mediated through GABA(A) receptor-benzodiazepine receptor-Cl(-) channel complex. Thus, our studies indicate that Eh is a potential anxiolytic drug, which might be beneficial in the treatment of stress-induced anxiety disorders.
Article
The dorsal raphe nucleus (DR)-serotonin (5-HT) system has been implicated in depression and is dramatically affected by swim stress, an animal model with predictive value for antidepressants. Accumulating evidence implicates the stress-related neuropeptide corticotropin-releasing factor (CRF) in the effect of swim stress on this system. This study investigated neural circuits within the DR that are activated by swim stress as revealed by neuronal expression of the immediate early gene, c-fos. Swim stress increased c-fos expression in the dorsolateral subregion of the DR. The majority of c-fos-expressing neurons were doubly labeled for GABA (85 +/- 5%), whereas relatively few were immunolabeled for 5-HT (4 +/- 1%), glutamate (0.5 +/- 0.3%) or calbindin (1.5 +/- 0.3%). Dual immunohistochemical labeling revealed that c-fos-expressing neurons in the dorsolateral DR were enveloped by dense clusters of CRF-immunoreactive fibers and also contained immunolabeling for CRF receptor, suggesting that c-fos-expressing neurons in the DR were specifically targeted by CRF. Consistent with this, the CRF receptor 1 antagonist, antalarmin, prevented swim-stress-elicited c-fos expression in the dorsolateral DR. Together with previous findings that both swim stress and CRF decrease 5-HT release in certain forebrain regions, these results suggest that swim stress engages CRF inputs to GABA neurons in the dorsolateral DR that function to inhibit 5-HT neurons and 5-HT release in the forebrain. This circuitry may underlie some of the acute behavioral responses to swim stress as well as the neuronal plasticity involved in long-term behavioral changes produced by this stress.
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Citrus essential oils, including lemon essential oil, have long been used widely in aromatherapy and alternative medicine. This study was designed to assess the effects of flavour components in lemon essential oil on physical and psychological stress. In this evaluation, acute cold stress and communication box techniques were used to apply stress after intraperitoneal administration of essential oil components such as limonene, γ-terpinene and citral. Serum corticosterone and monoamines in brain tissues were then determined. In the present study, it found the presence of perillic acid, a limonene metabolite, at concentrations of 1.5–2.5 μg/mL in serum and 0.4–0.6 μg/g in brain tissue collected 3 h after administration. The research also showed that the lemon components R-limonene, citral and γ-terpinene inhibited elevation of serum corticosterone levels and cerebral monoamine levels. S-limonene, a stereoisomer of R-limonene, seemed to have stronger effect than other monoterpenes and inhibited brain monoamines elevation on psychological stress. These findings suggest that limonenes, and particularly S-limonene, have a potent stress-alleviating effect, and the possibility that different stereoisomers of limonene have different levels of activity in their effect on stress responses. These results suggest a possibility that ingestion of lemon essential oil containing components such as limonene and citral alleviates both physical and psychological stress. Copyright © 2007 John Wiley & Sons, Ltd.
Article
Behavioral studies have suggested an involvement of the glutamate pathway in the mechanism of action of anxiolytic drugs, including the NMDA receptor complex. It was shown that magnesium, an NMDA receptor inhibitor, exhibited anxiolytic-like activity in the elevated plus-maze test in mice. The purpose of the present study was to examine interaction between magnesium and benzodiazepine/GABA(A) receptors in producing anxiolytic-like activity. We examined behavior of mice treated with magnesium and benzodiazepine/GABA(A) receptor ligands, in the elevated plus maze. The anxiolytic-like effect of magnesium (20 mg/kg) was antagonized by flumazenil (10 mg/kg) (benzodiazepine receptor antagonist) while combined treatment with the non-effective doses of magnesium (10 mg/kg) and benzodiazepines (diazepam (0.5 mg/kg) or chlordiazepoxide (2 mg/kg)) produced synergistic interaction (increased time in open arms and number of open arm entries) in this test. The obtained data indicate that benzodiazepine receptors are involved in the anxiolytic-like effects of magnesium.
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To study the neurochemical identity of axons in synaptic contact with identified hypothalamic neurosecretory neurons in rats, we combined retrograde axonal transport of a marker molecule with postembedding immunogold staining for amino acid neurotransmitters. After intravenous injections of horseradish peroxidase, neurosecretory neurons with axons in the median eminence or neurohypophysis transported the peroxidase retrogradely back to the cell body of origin. Serial ultrathin sections from the paraventricular and arcuate nuclei were immunostained with glutamate or GABA antisera. Peroxidase-labeled neurons and their dendrites received synaptic contact from colloidal gold-labeled axons immunoreactive for GABA or for glutamate. Axons which were highly immunoreactive for GABA and other axons immunoreactive for glutamate but not for GABA consistently made converging synaptic contact with the same peroxidase-labeled cell. Some of the peroxidase-labeled neurons from the arcuate nucleus which were postsynaptic to both GABA and glutamate axons were themselves identified as being GABA immunoreactive. Serial ultrathin sections revealed that multiple presynaptic axons immunoreactive for glutamate or GABA made repeated contacts with single neurons. These results suggest a widespread convergence of the major inhibitory and excitatory amino acid transmitter on the neurons which control both the anterior and posterior pituitary hormones.
Article
The concentrations of catecholamine and indoleamine metabolites were measured in intact and adrenalectomized mice to determine whether adrenal hormones mediate or modulate the stress-induced responses. Thirty minutes of footshock resulted in significant increases of the ratios of the dopamine (DA) catabolite, dihydroxyphenylacetic acid (DOPAC), to DA in prefrontal cortex, nucleus accumbens, striatum, hypothalamus, and brainstem, and of homovanillic (HVA)/DA ratios in nucleus accumbens, striatum, amygdala, and hypothalamus. Ratios of 3-methoxy-4-hydroxyphenylethyleneglycol to norepinephrine (NE) were also increased in prefrontal cortex, nucleus accumbens, septum, amygdala, hypothalamus, hippocampus, and brainstem. The concentration of NE was decreased in amygdala. 5-Hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT, serotonin) ratios and free tryptophan were also increased in every brain region. Very similar data were obtained from mice restrained for 30 min. Adrenalectomy resulted in increased HVA/DA ratios in prefrontal cortex and striatum, and 5-HIAA/5-HT in septum. The stress-related changes were largely similar in adrenalectomized mice. Significant interactions between adrenalectomy and footshock treatment occurred in prefrontal cortical DOPAC/DA and hypothalamic NE which was depleted only in adrenalectomized mice, suggesting tendencies for these measures to be more responsive in adrenalectomized mice. Corticosterone administration (0.5-2.0 mg/kg s.c.) which resulted in plasma concentrations in the physiological range did not alter the concentrations of the cerebral metabolites measured in any region. We conclude that adrenal hormones do not mediate cerebral catecholamine or indoleamine metabolism in stress, although adrenalectomy may affect HVA and 5-HIAA metabolism, and there was a tendency for catecholamines to be more sensitive to stress in adrenalectomized animals.
Article
1. Synaptic potentials were recorded with intracellular electrodes from rat dorsal raphe neurons in a slice preparation. 2. Synaptic potentials were evoked by applying electrical pulses to bipolar stimulating electrodes positioned immediately dorsal to the raphe nucleus; these arose after a latency of 0.5-5 ms and had a duration of 20-200 ms. 3. The synaptic potential was biphasic (at the resting potential) when the recording electrodes contained potassium citrate; a depolarization was followed by a hyperpolarization. The hyperpolarization reversed in polarity at -70 mV and was blocked by bicuculline. 4. The depolarizing synaptic potential was reduced to 50-90% of control by kynurenate (1-2 mM) or 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX) (10 microM) and increased in amplitude and duration by magnesium-free solution. 5. In magnesium-free solutions (with CNQX), the depolarizing synaptic potential was blocked by DL-2-amino-5-phosphonovaleric acid (APV, 50 microM). APV also blocked depolarization caused by adding N-methyl-D-aspartate (NMDA) to the superfusion solution. 6. The results indicate that raphe neurons display two synaptic potentials having a duration of 150-200 ms: one that is mediated by GABA and a second that is due to an excitatory amino acid. The component mediated by an excitatory amino acid involves, in part, a receptor of the NMDA type.
Article
The effects of intracerebroventricular administration of the 5-hydroxytryptamine (5-HT)1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 pmol) on adrenocortical and neurochemical responses to stress were examined in conscious male rats. The following stress paradigms were used: acoustic stimulation (105 dB for 2 min); footshock (0.2 mA, five shocks over 5 min); conditioned fear (animals placed in a footshock chamber for 5 min, 24 h after footshock); restraint (5 min); intraperitoneal (i.p.) injection of recombinant human interleukin-1 alpha (rHu-IL-1 alpha, 20 micrograms/kg); and injection of cocaine hydrochloride (20 mg/kg, i.p.). As previously shown, 8-OH-DPAT was able to attenuate the adrenocortical response to acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration. Cocaine decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios and norepinephrine (NE) concentration in the prefrontal cortex, hypothalamus, and brainstem in all experiments, and 8-OH-DPAT reversed the changes in DOPAC/DA ratio without affecting 5-HIAA/5-HT ratios or NE content. 8-OH-DPAT alone had no effect on these parameters, although it decreased NE content in the prefrontal cortex in several experiments, and in the brainstem in one experiment. Significant decreases in NE content were observed in some brain regions following some of the stressors, but these changes were not generally affected by 8-OH-DPAT. Increases in the 5-HIAA/5-HT and DOPAC/DA ratios were also observed in some brain sites following some stressors, but these changes were not affected by 8-OH-DPAT except in the case of the increased 5-HIAA/5-HT ratio in the prefrontal cortex following the conditioned fear response. These results indicate that although 8-OH-DPAT is able to decrease plasma corticosterone responses following acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration, these effects do not appear to be related to an action of the 5-HT1A agonist on biogenic amine metabolism. This observation indicates that the predominant effect of 8-OH-DPAT on adrenocortical responses is mediated at postsynaptic sites not involved in the regulation of cerebral biogenic amine metabolism.
Article
The present study examined whether regional patterns of brain dopamine (DA) and serotonin (5-HT) activation after physical and psychological stress depend on the intensity of that stress. Monoamine concentrations (DA, 5-HT, and their metabolites) were measured using high-performance liquid chromatography with electrochemical detection in eight brain regions of rats exposed to two different intensities of foot shock stress for 30 min (1.5 mA or 2.5 mA) or conditioned fear stress (CFS, after single or repeated foot shock). A low level of foot shock selectively increased the DA metabolism in the medial prefrontal cortex (mPFC), whereas a high level of foot shock increased it in most of the brain regions examined in the present study. A low level of foot shock did not increase the 5-HT metabolism in any regions, but a high-intensity shock increased the 5-HT metabolism in the mPFC, nucleus accumbens, and lateral hypothalamus. Rats that received high-intensity shock displayed more freezing than those that received low-intensity shock in a conditioned fear paradigm (24 h after receiving foot shock, the animals were placed in a shock chamber without being given shock), indicating an augmentation of conditioned fear. The increased DA and 5-HT metabolism were especially marked in the mPFC after CFS following a single foot shock session (2.5 mA). Rats that were repeatedly exposed to 2.5 mA foot shock for a period of 10 days displayed a greater degree of freezing induced by CFS than those given only one foot shock session, indicating an augmentation of fear and stress intensity. CFS after repeated foot shock, like foot shock per se, increased the DA metabolism in most of the brain regions except for the striatum and increased the 5-HT metabolism in the mPFC, nucleus accumbens, and amygdala. These results suggest that regional patterns of brain DA and 5-HT activation after physical and psychological stress depend on the intensity of that stress, although there are some differences between these stress; and that the more widespread activation of DA and 5-HT after more severe stress might relate to behavioral changes that reflect the augmentation of fear.
Article
That serotonin (5HT) is involved in regulating hypothalamic-pituitary- adrenal axis (HPA) function has long been recognized. A variety of drugs including precursors of 5HT such as 5HTP, drugs which release 5HT such as fenfluramine and drugs which act directly on 5HT receptors such as ipsapirone increase cortisol and ACTH concentrations. There is a general assumption that such stimulation occurs at a hypothalamic level. However, our increasing understanding of the complex interplay between 5HT and the HPA raises questions as to the validity of this simple model. An increasing volume of experimental research indicates that 5HT can act directly on the adrenal gland and possibly on the anterior pituitary as well. These findings have major implications for the interpretation of neuroendocrine studies of 5HT conducted in psychiatric conditions, such as depression.
Article
Neuroactive steroidal modulation of immobilization-stress and possible involvement of GABA-A and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) has been investigated in mice. Immobilization of mice for 2 h induced intense antinociception, anxiety state, and associated with a fall in adrenal ascorbic acid levels. Pretreatment with high dose of progesterone (10 mg/kg), a precursor of neurosteroids, significantly decreased the stress-induced antinociception, anxiety and fall in adrenal ascorbic acid, while low doses (1 and 5 mg/kg) or hydrocortisone (10 and 100 mg/kg) were ineffective. In contrast, progesterone (1 mg/kg, for 9 days) produced a significant antistress effect, which was blocked by GABA-A antagonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg), but not by flumazenil (2 mg/kg), a specific benzodiazepine (BZD) antagonist. 4'-chlordiazepam (0.1 and 0.25 mg/kg), a specific high affinity MDR agonist, produced significant anti-stress effect in a flumazenil-insensitive manner, but was blocked by pretreatment with PK11195 (1.5 mg/kg), a selective partial agonist of MDR, and with bicuculline (1 mg/kg), a potent GABA-A receptor antagonist. At higher doses, progesterone and 4'-chlordiazepam which are effective in immobilization stress also reduced locomotion. However, lower doses of progesterone (6.5 mg/kg) neither affected locomotion, nor produced any motor toxicity on rota-rod test. At the lower doses, the MDR ligand 4'-chlordiazepam (50 micrograms/kg) decreased locomotor activity, without altering motor toxicity on rota-rod test. Further, the per se effects of these treatments on unstressed mice were not significantly different from those of untreated controls, except for plus-maze test. The antistress profile of progesterone may be attributed to the in vivo production of neurosteroid allopregnanolone, thus resembled that of BZDs. Furthermore, the antistress actions are flumazenil-resistant, reaffirming that there may be an increase in the levels of pregnane neurosteroids in vivo, which may act on a specific allosteric site on GABA-A receptors distinct from BZD site. Because 4'-chlordiazepam binds to MDRs and stimulate mitochondrial neurosteroidogenesis, the anti-stress effects of 4'-chlordiazepam may be imputed to its MDR-induced neurosteroids, which then act on GABA-A receptors. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the antistress actions of neurosteroids and reinforces their ameliorative effect in physiological stress.
Article
Recently, local injection of morphine in the dorsal raphe nucleus (DRN) has been shown to increase serotonin release in the forebrain of unanesthetized rats. This study investigated the site of action of opioids in rat brain slices containing the DRN. Postsynaptic currents (PSCs), measured intracellularly under voltage clamp, were induced in serotonergic neurons with bath and microiontophoretic applications of NMDA to activate local neurons. Met-enkephalin (ENK) suppressed spontaneous and NMDA-induced GABAergic inhibitory PSCs. This effect, which was mimicked by the mu agonist DAMGO but not the kappa-agonist U50488 or the delta-agonist DPDPE, was reversed by the mu antagonist CTOP. ENK also suppressed spontaneous and NMDA-induced glutamatergic excitatory PSCs. By searching with focal microiontophoretic NMDA applications, GABAergic and glutamatergic cells projecting on serotonergic neurons were found in the DRN and the adjacent periaqueductal gray. Consistent with the reduction in PSCs, ENK inhibited/hyperpolarized the great majority (81%) of non-serotonergic neurons recorded extra- and intracellularly in the DRN; the ENK effect reversed polarity at -99 +/- 9 mV, close to the potassium reversal potential. In contrast, ENK inhibited/hyperpolarized only 28% of serotonergic neurons; in the affected cells, the ENK effect, blocked by CTOP, had its reversal potential shifted with change of extracellular potassium in agreement with the value predicted by the Nernst equation for a potassium conductance; serotonin occluded the ENK inhibition. Taken together, these results indicate that opioids inhibit both local GABAergic and glutamatergic cells projecting onto DRN serotonergic neurons.
Article
Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis stimulates the release of both facilitatory and inhibitory components. We proposed that the transient removal of the inhibitory component, corticosterone, during a stressor would leave the HPA axis in a state of hyper-responsiveness (facilitated state). Consistent with this expectation, we have previously observed that aminoglutethimide (AG)-induced removal of corticosterone during an immobilization stressor resulted in the hypersecretion of both ACTH and corticosterone to a subsequent stressor. In the present study we determined the effect of stressor duration on the magnitude of facilitation. AG plus a 10-min immobilization (IMM(10)) stress on day 1 resulted in facilitation of the HPA axis. This was reflected in higher ACTH and corticosterone responses to an injection stress on day 2 as compared to appropriate control rats. AG plus a 60-min immobilization (IMM(60)) stress on day 1 resulted in significantly greater facilitation as compared to the AG+IMM(10) pretreatment. It is apparent that facilitation of the HPA axis is dependent on the duration of stress. Stress can alter plasma corticosterone-binding globulin levels and AG administration can cause accumulation of the corticosterone biosynthetic precursor, adrenal cholesterol. In order to rule out these peripheral reasons for the hypersecretion of ACTH and corticosterone in our paradigm, we measured the plasma free fraction of corticosterone and adrenal mitochondrial cholesterol levels on day 2 after different pretreatments on day 1. AG+IMM(60) pretreatment caused a significant increase in the plasma free fraction of corticosterone. Hypersecretion of ACTH and corticosterone in this group, despite an enhanced feedback signal, suggests central loci for the origin of facilitation. Also, AG treatment on day 1 did not result in accumulation of free or esterified adrenal cholesterol levels on day 2, and therefore cannot account for the hypersecretion of corticosterone. In our final study we attempted to determine if serotonin released during the first stressor is partially responsible for stress-induced facilitation of the HPA axis. We administered 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5HT(1A) agonist, either alone or in conjunction with stress and examined the effects of these pretreatments on the magnitude of facilitation. Interestingly, DPAT administered in lieu of stress produced facilitation similar in magnitude to that produced by IMM(10). DPAT administered in conjunction with IMM(10) augmented stress-induced facilitation. Our results suggest that stress-induced facilitation of the HPA axis is associated with the release of serotonin during stress.
Article
GABA has been identified as an important neurotransmitter in stress-related circuitry mediating inhibitory effects on neurosecretory neurons that comprise the central limb of the hypothalamo-pituitary-adrenocortical axis. Using combinations of pre-embedding immunostaining and postembedding immunogold methods at the ultrastructural level, direct synaptic contacts were revealed between GABA-containing terminals and neurosecretory cells that were immunoreactive for corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN). The vast majority of axo-dendritic GABA synapses was symmetric (inhibitory) type, and 46% of all synaptic boutons in the medial parvocellular subdivision of the PVN were immunoreactive to GABA. Using the disector method, an unbiased stereological method on serial ultrathin sections, the total calculated number of synaptic contacts within the medial parvocellular subdivision of the PVN was 55.4 x 10(6)/mm(3). On CRH-positive profiles 20.1 x 10(6) GABAergic synaptic boutons were detected per mm(3) in control, colchicine-treated rats. In the medial parvocellular subdivision, 79% of GABAergic boutons terminated on CRH neurons. Following adrenalectomy, which increases the synthetic and secretory activities of CRH neurons, the number of GABAergic synapses that terminate on CRH-positive profiles was increased by 55%. GABA-containing boutons appeared to be swollen, while the contact surfaces of cellular membranes between GABAergic boutons and CRH-positive profiles were shorter in adrenalectomized animals than in controls. Our data provide ultrastructural evidence for direct inhibitory GABAergic control of stress-related CRH neurons and suggest a pivotal role of GABA-containing inputs in the functional plasticity of parvocellular neurosecretory neurons seen in response to adrenalectomy.
Article
The microdialysis technique was used to study the ability of essential oil from citrus lemon to modulate hippocampal acetylcholine (ACh) release in male and female rats. Animals were allowed to inhale this odor while experiencing a persistent nociceptive input (50 microl formalin, 5%) or under control conditions (sham-injection). In males, exposure to the essential oil did not change the time course and magnitude of the ACh increase induced by pain. In females, the pain-induced increase of ACh was delayed and increased by exposure to lemon essential oil. The present results indicate that lemon essential oil affects the ACh release differently in male and female rats during a painful condition.
Article
The effects of edible mushroom Mycoleptodonoides aitchisonii on the synthesis of nerve growth factor (NGF) and neurotransmitter metabolism in rat brain were examined in Wistar strain rats fed a controlled diet for 14 days. Then each brain was dissected to detect the levels of neurotransmitters and NGF in various regions. Dopamine concentration in the cerebral cortex was 1.5-fold significantly increased in the M. aitchisonii feeding group than the control group. However, NGF concentration of the M. aitchisonii feeding was significantly low. NGF concentration in this remaining area of brain from where the cerebral cortex, striatum, hippocampus, cerebellum, hypothalamus and amygdala were removed was significantly higher in the M. aitchisonii feeding. At the same time, in the striatum, the dopamine metabolite DOPAC was significantly increased in the M. aitchisonii feeding. Thereafter, we measured dopamine release from striatal slices using aqueous extract of M. aitchisonii, there was an enhancing effect on dopamine release. These results suggested that M. aitchisonii has enhancing effect on the synthesis of NGF and catecholamine metabolites in the rat brain.
Article
Corticotropin-releasing factor (CRF), the major adrenocorticotropic hormone (ACTH) secretagogue, acts within the brain to integrate the stress responses of the central nervous, endocrine and immune systems. The involvement of this peptide in the origin and pathophysiology of various endocrine, neurologic, inflammatory and psychiatric diseases, particularly affective disorders, has also been suggested. The antiepileptic drug valproic acid is frequently used as a mood-stabilizing agent in patients with bipolar disorders; however, its mechanism of action for the latter indication is still poorly characterized. We investigated whether valproic acid can directly modulate CRF production by using the incubation of rat hypothalamic explants as an in-vitro model. We then studied the involvement of the gamma-aminobutyric acid (GABA) system as a putative mediator of the effects of valproic acid on CRF production. Rat hypothalamic explants were incubated in a 24-well plate (2 hypothalami per well) at 37 degrees C in a humidified atmosphere (5; CO(2) and 95% O(2)) in incubation medium, 700 muL, then were treated with medium alone (control) or test substances, namely, valproic acid, KCI, bicuculline methiodide and muscimol. Released CRF was measured by radioimmunoassay. CRF mRNA was measured by RNase protection analysis. Incubation of the hypothalamic fragments with valproic acid, 100 mumol/L, resulted in a reduction of basal CRF secretion after 3 hours' treatment. The drug was also able to inhibit KCl-stimulated CRF release. Moreover, valproic acid, 100 mumol/L, significantly decreased CRF mRNA levels after 3 hours. A specific GABA(A) receptor antagonist, bicuculline methiodide, completely reversed the inhibition of CRF gene expression and peptide release induced by valproic acid; in this paradigm, the GABA(A)-specific agonist muscimol inhibited both CRF gene expression and peptide release in a concentration-dependent manner. These results suggest that valproic acid may exert part of its therapeutic effect as a mood-stabilizing drug via the modulation of CRF secretion from the hypothalamus. This action may be mediated in part by the activation of GABAergic neurotransmission.
Article
Fourteen days pregnant Wistar strain rats were fed powder or aqueous extract of the edible fungus MycoleptFodonoides aitchisonii. Nerve growth factor (NGF) concentrations were measured in the brain of newborn rats during the lactation period at 0, 7 and 14 days after the birth. Two M. aitchisonii-fed groups showed a significant increase in NGF concentrations in brain halves compared to those who were fed control feed at days 7 and 14. At day 21, NGF concentrations in the cerebral cortex and hippocampus were not significantly different among the three groups. After weaning, the young rats were fed the same test diet as their mothers. Ten days later, Morris water maze test was started. After the test, the rats were sacrificed and NGF concentrations in the cerebral cortex and hippocampus were measured. Significant NGF concentration increases were detected in the cerebral cortex for two M. aitchisonii-fed groups and in the hippocampus in the aqueous extract group. These results suggest that NGF in the brain reached the same levels by day 21, but that M. aitchisonii affected the growth rate in the lactation period. The learning test stimulated the brain and some compounds of M. aitchisonii enhanced NGF synthesis in rat cerebral cortex and hippocampus.
Article
In a previous study, we found that olfactory stimulation with scent of grapefruit oil (SGFO) excites the sympathetic nerve innervating the white adipose tissue in rats. Here we further examined the effects of SGFO in rats and observed that olfactory stimulation with SGFO excited the sympathetic nerves innervating the brown adipose tissue and adrenal gland and inhibited the parasympathetic gastric nerve. Local anesthesia of the nasal mucosa with xylocaine or anosmic treatment using ZnSO4 eliminated the autonomic changes caused by SGFO. Moreover, stimulation with SGFO elevated the plasma glycerol level, and treatment with either ZnSO4 or an intraperitoneal injection of diphenhydramine, a histamine H1 receptor-antagonist, abolished the glycerol elevation by SGFO. Furthermore, a 15-min exposure to SGFO three times a week reduced food intake and body weight. Finally, limonene, a component of grapefruit oil, induced responses similar to those caused by SGFO, and diphenhydramine eliminated the glycerol response to limonene. Thus, the scent of grapefruit oil, and particularly its primary component limonene, affects autonomic nerves, enhances lipolysis through a histaminergic response, and reduces appetite and body weight.
Article
Previously, we observed that olfactory stimulation with scent of lavender oil (SLVO) suppressed sympathetic nerve activities and elevated gastric vagal (parasympathetic) nerve activity (GVNA), decreased plasma glycerol concentration and body temperature, and enhanced appetite in rats. Here, we further showed that olfactory stimulation with SLVO lowered renal sympathetic nerve activity (RSNA) and blood pressure (BP) and elevated GVNA in urethane-anesthetized rats. Olfactory stimulation with linalool, a component of lavender oil, also elicited decreases in RSNA and BP and an increase in GVNA in urethane-anesthetized rats. Anosmia induced by pretreatment of the nasal cavity by application of ZnSO4 eliminated the effects of both SLVO and scent of linalool on RSNA, GVNA and BP. Furthermore, intracerebroventricular administration of thioperamide, a histaminergic H3-antagonist, abolished the suppression of RSNA and BP as well as the elevation of GVNA mediated by both SLVO and scent of linalool. Finally, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) eliminated RSNA and BP suppression and the elevation of GVNA due to SLVO or linalool. Thus, it was concluded that scent of lavender oil and its active component, linalool, affects autonomic neurotransmission and reduces blood pressure through the central histaminergic nervous system and the SCN.
Article
(-)-Epigallocatechin gallate (EGCG), a flavonoid, is the principal catechin found in green tea and is distributed in the brain after tea consumption. The aim of the present study was to investigate the effects of EGCG in the chick brain under an acute stressful condition and to clarify the mechanism by which EGCG attenuates stress behavior with special reference to gamma-aminobutyric acid (GABA). Intracerebroventricular (i.c.v.) injection of EGCG (50, 100 and 200 microg) suppressed the vocalization which normally occurs during social separation stress. EGCG decreased the time spent in active wakefulness and induced sleep-like behavior in a dose-dependent manner. Additionally, i.c.v. injection of EGCG attenuated plasma corticosterone release under social separation stress. These effects of EGCG on distress-induced vocalization were significantly attenuated by the GABAA receptor antagonist picrotoxin but not by the GABAB receptor antagonist CGP 54626 (3-N-(1-(3,4-dichlorophenyl)ethylamino)-2-hydroxypropyl cyclohexylmethyl phosphinic acid hydrochloride). These results indicate that EGCG has sedative and hypnotic effects in the brain, partially through GABAA receptors, and consequently moderates an acute stress response.
Article
Ethanolic and water extracts, together with volatile oils from the rhizomes of six selected Zingiberaceous plants, including Curcuma mangga, Kaempferia galanga, Kaempferia parviflora, Zingiber cassumunar, Zingiber officinale and Zingiber zerumbet were investigated for their anti-allergic activities using a RBL-2H3 cell line. The ethanolic (EtOH) extract of Kaempferia parviflora exhibited the most potent anti-allergic effect against antigen-induced beta-hexosaminidase release as a marker of degranulation in RBL-2H3 cells, with an IC(50) value of 10.9 microg/ml, followed by Zingiber cassumunar (EtOH, IC(50)=12.9 microg/ml) and Curcuma mangga (water, IC(50)=36.1 microg/ml). The volatile oils of these six plants were apparently inactive (IC(50)>100 microg/ml). The crude extracts were also tested on beta-hexosaminidase activity to clarify whether their effects were due to the inhibition of enzyme activity or of degranulation. As a result, the plant extracts were inactive against the enzyme activity of beta-hexosaminidase. These findings support the use in Thai traditional medicine of these selected Zingiberaceous plants, especially Kaempferia parviflora and Zingiber cassumunar, for treatment of allergy and allergic-related diseases.
Article
Lavender is a popular treatment for stress and mild anxiety in Europe and the USA. The present study investigated the effects of (Lavandula angustifolia Mill. (Lamiaceae)) lavender odour inhalation over 2 weeks or 24 h periods, on gerbil behaviour in the elevated plus maze in mature male and female gerbils, and compared results with the effects of diazepam (1 mg/kg) i.p. after 30 min and 2-week administration. Traditional measures of open entries showed an increasing trend over the 2 weeks exposure, whereas ethological measures indicative of anxiety; stretch-attend frequency and percentage protected head-dips, were significantly lower. Exploratory behaviour, total head-dip frequency, increased after 24 h lavender and 2 weeks exposure. These results are comparable with diazepam administration. There were sex differences in protected head-dip an ethological indicator of anxiety: females showed a significant decrease in protected head-dips compared to both males and to female controls. In conclusion exposure to lavender odour may have an anxiolytic profile in gerbils similar to that of the anxiolytic diazepam. In addition, prolonged, 2-week lavender odour exposure increased exploratory behaviour in females indicating a further decrease in anxiety in this sex.
Article
Paraventricular corticotropin-releasing factor (CRF) neurons play a pivotal role in regulating neuroendocrine responses to stress. The mechanisms by which synaptic inputs control the activity of these neurons are not well understood. The present study was undertaken to determine the role of the intrinsic gamma-aminobutyric acid (GABA)- and glutamatergic neural circuits of the hypothalamic paraventricular nucleus (PVN) in the control of CRF neural activity. We show that in organotypic cultures of the PVN, blockade of the intrinsic GABAergic neurotransmission by the GABAA receptor antagonist bicuculline resulted in a significant increase in CRF secretion. The bicuculline-induced CRF secretory activity was abolished by the coadministration of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Electrical stimulation of the CRF cell division elicited glutamatergic extracellular field potentials that were dramatically enhanced by bicuculline and were suppressed by CNQX. These results show that the functional activity of CRF neurons in organotypic cultures of the PVN is under a tonic inhibitory influence of an intrinsic GABAergic circuit. Suppression of GABAergic transmission appears to have a permissive role for inducing an increased secretory activity of CRF neurons that is driven by an excitatory glutamatergic network via AMPA/kainate receptors.
Article
There is a growing body of data to support the notion that GABA(B) receptors may be a therapeutic target for anxiety disorders. However, the application of GABA(B) receptor agonists in anxiety research and psychiatry is hampered by side effects that include motor in-coordination and hypothermia. Recently the GABA(B) receptor positive modulator GS39783 was shown to be anxiolytic in rodent models, but was devoid of accompanying side effects characteristic of full agonists. However, it is important to test whether such anxiolytic effects generalise to another chemical class of GABA(B) receptor positive modulators. We therefore aimed to investigate the anxiolytic and side-effect profile of CGP7930, the first-reported GABA(B) receptor positive modulator, in rodent models of anxiety, motor coordination and hypothermia. CGP7930 (3-300 mg/kg) showed a modest, compared to the benzodiazepine chlordiazepoxide (10mg/kg), dose-dependent anxiolytic profile in the mouse stress-induced hyperthermia (100mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3-100mg/kg), but did not have any anxiolytic effects in the rat elevated plus maze. Similar to GS39783, CGP7930 also demonstrated a greatly reduced side-effect profile in comparison to the GABA(B) receptor full agonist baclofen in the mouse rotarod and traction wire tests and did not induce hypothermia. Although the effects of CGP7930 were modest, these results represent a second, structurally distinct, class of GABA(B) positive modulators showing anxiolytic activity. As such, these data support the premise that GABA(B) receptor positive modulation represents a novel therapeutic strategy for the development of anxiolytic drugs with a superior side-effect profile. The generation of more potent compounds is now warranted.
Article
Atypical antipsychotics, such as olanzapine, have been reported to display anxiolytic properties as shown in several preclinical and clinical studies. Furthermore, several experimental evidences have shown that olanzapine reduces fear and anxiety in activated anxiety-like behavior test such as Geller-Seifter test, ultrasonic vocalization test and stress-induced EtOH consumption. Here, we hypothesized that the anxiolytic action of olanzapine might be due to via an indirect activation of the gamma-amino butyric acid (GABA)-ergic system through 3alpha-hydroxy-5alpha-pregnan-20-one [allopregnanolone (ALLO)], a potent neuroactive steroid that positively modulates the benzodiazepine-gamma-aminobutyric acid type A (GABA(A))/benzodiazepine receptors complex. To address this question, we used a preclinical animal test to screen for novel anxiolytic compounds - the elevated plus-maze (EPM) - in basal condition and after 45 min restrain stress after acute or repeated (21 days) administration of olanzapine (0.5mg/kg, i.p.). In this condition, we therefore study the effect of the 5-alpha-reductase inhibitor finasteride (FIN) (50mg/kg) after co-administration with olanzapine. FIN is an inhibitor of steroidogenic enzymes which acts by inhibiting type II 5-alpha reductase, the enzyme that converts into 5-alpha-reduced metabolites like the GABA(A) positive neuroactive steroid ALLO. Results showed an anxiolytic effect of the acute, but not of the chronic, treatment with olanzapine only in stressed rats. This anxiolytic effect was counteracted by the co-administration with FIN. These evidences suggest that the anxiolytic effects of olanzapine might be due to possible action of olanzapine on steroid function via activation of GABA system.
Article
We identified an effect of gamma-glutamylethylamide (theanine) on feeding in a rat study. Oral theanine suppressed the food intake of rats. The serum glucose level did not differ from the control, but the insulin concentration was reduced and the corticosterone concentration was increased by theanine. We suggest that the effect of theanine on feeding involved hormones.
Article
Glutamate exerts its effects through binding and activation of two classes of specific receptors: ionotropic (iGluRs) and metabotropic (mGluRs). Group I mGluR includes mGluR1 and mGluR5 subtypes, group II includes mGluR2 and mGluR3 subtypes and group III includes the subtypes mGluR 4, 6, 7 and 8. Glutamate and its receptors are found in all key hypothalamic areas critically involved in reproduction and neuroendocrine function. To date, considerable data support an important role for iGluRs in the control of neuroendocrine function; however, the role of mGluRs as regulators of hypothalamic-pituitary function has not been clearly elucidated.
Evidence for a PVN site of action for gamma aminobutyric acid in the regulatory control of the rat stress axis
  • W E Cullinan
Cullinan WE. 1998. Evidence for a PVN site of action for gamma aminobutyric acid in the regulatory control of the rat stress axis. Physiologist 41: 379.
Effect of lemon odor on brain neurotransmitters in rat and electroencephalogram in human subjects
  • S Ishikawa
  • Y Miyake
  • H Yokogoshi
Ishikawa S, Miyake Y, Yokogoshi H. 2002. Effect of lemon odor on brain neurotransmitters in rat and electroencephalogram in human subjects. Aroma Research 3: 126-130.