The Neuroprotective Role of Origanum syriacum L. and Lavandula dentata L. Essential Oils through Their Effects on AMPA Receptors

Lavandula dentata L. and Origanum syriacum L. essential oils have numerous health benefits and properties, such as possessing common components with a variant degree of depressive actions in the central nervous system. We investigated the depressive property of these oils on AMPA receptors, which are responsible for most of the fast-excitatory neurotransmission in the CNS and play a critical role in synaptic plasticity. Since excessive activation of AMPARs has been linked to neurotoxicity leading to various pathologies, we hypothesize that these oils have a neuroprotective role by acting directly on the kinetics of AMPARs. Using Gas Chromatography-Mass Spectrometry (GC/MS) and patch-clamp electrophysiology, the essential oils of L. dentata flowers and O. syriacum leaves were characterized and the whole cell currents were measured with and without the administration of the oils onto HEK293 cells. The current study results showed that the biophysical properties of AMPA receptor subunits showed a decrease in desensitization rate of GluA1 and GluA2 homomers, using O. syriacum, while administering L. dentata oil decreased the desensitization rate of GluA1 and GluA2 homomers, as well as GluA1/2 heteromers. As for the deactivation rate, both oils slowed the deactivation kinetics of all AMPA receptor subunits. Intriguingly, between the two oils, the effect of desensitization and deactivation was of a greater significance for L. dentata oil than O. syriacum. Our data suggest that the two oils contain components that are essential to identify, as those active components underlie the oils’ neuronal depressive properties reported, and to extract them to synthesize a potent neuroprotective drug to treat neurological diseases potentially.

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Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

eLife ◽

10.7554/elife.28680 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 15

Author(s):

Irene Riva ◽

Clarissa Eibl ◽

Rudolf Volkmer ◽

Anna L Carbone ◽

Andrew JR Plested

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

De Novo ◽

Dominant Role ◽

Mammalian Brain ◽

Binding Assays ◽

Receptor Kinetics ◽

Receptor Complexes ◽

Extracellular Loops ◽

Kinetics Of

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of γ2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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Effect of Geraniol and Citronellol Essential Oils on the Biophysical Gating Properties of AMPA Receptors

Applied Sciences ◽

10.3390/app9214693 ◽

2019 ◽

Vol 9 (21) ◽

pp. 4693 ◽

Cited By ~ 5

Author(s):

Mohammad Qneibi ◽

Nidal Jaradat ◽

Nour Emwas

Keyword(s):

Essential Oils ◽

Ampa Receptors ◽

Neurological Diseases ◽

Whole Cell Patch Clamp ◽

293 Cells ◽

Future Drug ◽

Drug Synthesis ◽

Patch Clamp Electrophysiology ◽

Calming Effect ◽

Natural Template

Essential oils have been advertised endlessly to be very beneficial for the health of humans, and an extensive amount of research examines the validity of such claims. In contribution, the current study evaluates the neuroprotective properties of Citronellol and Geraniol essential oils (EOs). In relationship to the biophysical gating properties of different the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, the EOs were administered to HEK293 (Human embryonic kidney 293) cells and examined for any inhibition and effect on desensitization or deactivation rates, using whole-cell patch-clamp electrophysiology. Our results demonstrated the highest levels of inhibition from Citronellol oil by four-fold on all AMPARs subunits. Likewise, Geraniol oil had a similar inhibiting impact on the receptors, and both oils decreased the desensitization and deactivation rates of the inhibited receptors. Thus, the examined EOs of this study portray neuroprotective qualities by targeting AMPARs activation and reducing desensitization and deactivation rates. Finally, the results of the current study entail a better understanding of AMPARs, provides a natural template for future drug synthesis to treat neurological diseases associated with excessive AMPAR activation, and offers a possible mechanism by which these essential oils deploy their ‘calming’ effect.

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Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons

Journal of Neurophysiology ◽

10.1152/jn.2001.85.5.2030 ◽

2001 ◽

Vol 85 (5) ◽

pp. 2030-2038 ◽

Cited By ~ 25

Author(s):

Saobo Lei ◽

Beverley A. Orser ◽

Gregory R. L. Thatcher ◽

James N. Reynolds ◽

John F. MacDonald

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Organic Nitrate ◽

Receptor Desensitization ◽

Open Probability ◽

Ca1 Neurons ◽

Hippocampal Ca1 ◽

Rate Of Recovery ◽

Kinetics Of

Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC50 of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.

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Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

10.1101/140053 ◽

2017 ◽

Author(s):

Irene Riva ◽

Clarissa Eibl ◽

Rudolf Volkmer ◽

Anna L. Carbone ◽

Andrew J. R. Plested

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

De Novo ◽

Dominant Role ◽

Mammalian Brain ◽

Binding Assays ◽

Receptor Kinetics ◽

Receptor Complexes ◽

Extracellular Loops ◽

Kinetics Of

AbstractAt synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of Y2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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Architecture of fully occupied Glua2 Ampa receptor – TARP complex elucidated by single particle cryo-electron microscopy

10.1101/060046 ◽

2016 ◽

Cited By ~ 2

Author(s):

Yan Zhao ◽

Shanshuang Chen ◽

Craig Yoshioka ◽

Isabelle Baconguis ◽

Eric Gouaux

Keyword(s):

Ion Channel ◽

Ampa Receptor ◽

Ampa Receptors ◽

Receptor Activation ◽

Regulatory Proteins ◽

Dimer Interface ◽

Cryo Electron Microscopy ◽

Excitatory Neurotransmission ◽

Conformational Rearrangements ◽

Kinetics Of

SummaryFast excitatory neurotransmission in the mammalian central nervous system is largely carried out by AMPA-sensitive ionotropic glutamate receptors. Localized within the postsynaptic density of glutamatergic spines, AMPA receptors are composed of heterotetrameric receptor assemblies associated with auxiliary subunits, the most common of which are transmembrane AMPA-receptor regulatory proteins (TARPs). The association of TARPs with AMPA receptors modulates the kinetics of receptor gating and pharmacology, as well as trafficking. Here we report the cryo-EM structure of the homomeric GluA2 AMPA receptor saturated with TARP γ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TM helices. Poised like partially opened ‘hands’ underneath the two-fold symmetric ligand binding domain (LBD) ‘clamshells’, one pair of TARPs are juxtaposed near the LBD dimer interface, while the other pair are near the LBD dimer-dimer interface. The extracellular ‘domains’ of TARP are positioned to not only modulate LBD ‘clamshell’ closure, but also to affect conformational rearrangements of the LBD layer associated with receptor activation and desensitization, while the TARP transmembrane (TM) domains buttress the ion channel pore.

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Essential Oils of Alpinia nantoensis Retard Forskolin-Induced Melanogenesis via ERK1/2-Mediated Proteasomal Degradation of MITF

Plants ◽

10.3390/plants9121672 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1672

Author(s):

K. J. Senthil Kumar ◽

M. Gokila Vani ◽

Pei-Chen Wu ◽

Hui-Ju Lee ◽

Yen-Hsueh Tseng ◽

...

Keyword(s):

Essential Oils ◽

Nuclear Translocation ◽

Proteasomal Degradation ◽

Gas Chromatography Mass Spectrometry ◽

Active Components ◽

Down Regulation ◽

Bioactive Ingredients ◽

In Vitro Treatment ◽

Tyrosinase Related Protein

The anti-melanogenic activity of essential oils of Alpinia nantoensis and their bioactive ingredients were investigated in vitro. Treatment with leaf (LEO) and rhizome (REO) essential oils of A. nantoensis, significantly reduced forskolin-induced melanin production followed by down-regulation of tyrosinase (TYR) and tyrosinase related protein-1 (TRP-1) expression at both transcriptional and translational levels. Further studies revealed that down-regulation TYR and TRP-1 were caused by LEO/REO-mediated suppression of Microphthalmia-associated transcription factor (MITF), as evidenced by reduced nuclear translocation of MITF. Also, we found that LEO/REO induce the sustained activation of ERK1/2, which facilitate subsequent proteasomal degradation of MITF, as confirmed by that LEO/REO failed to inhibits MITF activity in ERK1/2 inhibitor treated cells. In addition, a significant increase of ubiquitinated MITF was observed after treatment with LEO and REO. Furthermore, the chemical composition of LEO and REO were characterized by gas chromatography-mass spectrometry (GC-MS) resulted that camphor, camphene, α-pinene, β-pinene, isoborneol and D-limonene were the major compounds in both LEO and REO. Further studies revealed that α-pinene and D-limonene were the active components responsible for the anti-melanogenic properties of LEO and REO. Based on the results, this study provided a strong evidence that LEO and REO could be promising natural sources for the development of novel skin-whitening agents for the cosmetic purposes.

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Regulation of synaptic stability by AMPA receptor reverse signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1015163108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 367-372 ◽

Cited By ~ 31

Author(s):

Beth Ripley ◽

Stefanie Otto ◽

Katie Tiglio ◽

Megan E. Williams ◽

Anirvan Ghosh

Keyword(s):

Glutamate Receptor ◽

Ampa Receptor ◽

Ampa Receptors ◽

Cortical Neurons ◽

Critical Role ◽

Extracellular Domain ◽

Glutamatergic Synapses ◽

Reverse Signaling ◽

Structural Interactions ◽

The Stability

The establishment of neuronal circuits relies on the stabilization of functionally appropriate connections and the elimination of inappropriate ones. Here we report that postsynaptic AMPA receptors play a critical role in regulating the stability of glutamatergic synapses. Removal of surface AMPA receptors leads to a decrease in the number and stability of excitatory presynaptic inputs, whereas overexpression increases synapse number and stability. Furthermore, overexpression of AMPA receptors along with Neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs from cortical neurons onto heterologous cells. The stabilization of presynaptic inputs by AMPA receptors is not dependent on receptor-mediated current and instead relies on structural interactions mediated by the N-terminal domain of the glutamate receptor 2 (GluR2) subunit. These observations indicate that transsynaptic signaling mediated by the extracellular domain of GluR2 regulates the stability of presynaptic terminals.

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The influence of the chemical composition of essential oils of Clausena lansium seeds on the growth of Candida strains

Scientific Reports ◽

10.1038/s41598-021-99188-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yinzheng Ma ◽

Yuanxiao Wang ◽

Xia Zhou ◽

Heng Yang ◽

Huixin Zhang ◽

...

Keyword(s):

Chemical Composition ◽

Antifungal Activity ◽

Essential Oils ◽

Synergistic Effects ◽

Scientific Evidence ◽

Inhibition Zone ◽

Gas Chromatography Mass Spectrometry ◽

Active Components ◽

Traditional Use ◽

The Difference

AbstractClausena lansium (Lour.) Skeels seeds have been shown to have diverse beneficial medical value due to their unique active components. This study analysed the composition of essential oils (EOs) of C. lansium seeds and investigated their potential antifungal effects against Candida strains. A total of forty-six components were identified in all samples by gas chromatography-mass spectrometry (GC–MS). The main components were sabinene, β-phellandrene and 4-terpineol. Thirteen EOs of C. lansium seeds were classified into three clusters based on their components. Cluster analysis showed that the difference between the tropics and subtropics was the greatest. These EOs and the three main chemicals showed different antifungal activities against five Candida species (C. albicans, C. tropicalis, C. glabrata, C. krusei and C. parapsilosis). The antifungal activity against C. glabrata and C. krusei was higher than that against other Candida strains. EOs of C. lansium seeds displayed noteworthy antifungal activity against both sensitive and fluconazole-resistant strains, with inhibition zone diameters in the range of 9.4–23.4 mm. Comprehensive analysis illustrated the importance of sabinene, β-phellandrene and 4-terpineol to antifungal activity, and there may be some synergistic effects with other components. These results represent the first report about the correlation between the chemical composition of EOs of C. lansium seeds and antifungal activity. Taken together, the results obtained provide scientific evidence for the traditional use of C. lansium seeds waste.

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AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide

Journal of Neurophysiology ◽

10.1152/jn.1996.75.6.2322 ◽

1996 ◽

Vol 75 (6) ◽

pp. 2322-2333 ◽

Cited By ~ 52

Author(s):

M. W. Fleck ◽

R. Bahring ◽

D. K. Patneau ◽

M. L. Mayer

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Splice Variants ◽

Differential Sensitivity ◽

Stratum Radiatum ◽

Receptor Subtypes ◽

Receptor Desensitization ◽

B Subunits ◽

Kinetics Of

1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by cyclothiazide, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by cyclothiazide than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by cyclothiazide. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to cyclothiazide seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by cyclothiazide was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to cyclothiazide, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by cyclothiazide was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to cyclothiazide. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission.

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Insecticidal Activity of 28 Essential Oils and a Commercial Product Containing Cinnamomum cassia Bark Essential Oil against Sitophilus zeamais Motschulsky

Insects ◽

10.3390/insects11080474 ◽

2020 ◽

Vol 11 (8) ◽

pp. 474 ◽

Cited By ~ 2

Author(s):

Yunho Yang ◽

Murray B. Isman ◽

Jun-Hyung Tak

Keyword(s):

Essential Oils ◽

Insecticidal Activity ◽

Inhibitory Activity ◽

Sitophilus Zeamais ◽

Gas Chromatography Mass Spectrometry ◽

Active Components ◽

Cinnamon Oil ◽

Tea Tree ◽

Rice Grains ◽

Stored Product Pests

Maize weevils, Sitophilus zeamais, are stored product pests mostly found in warm and humid regions around the globe. In the present study, acute toxicity via contact and residual bioassay and fumigant bioassay of 28 essential oils as well as their attraction–inhibitory activity against the adults of S. zeamais were evaluated. Chemical composition of the essential oils was analyzed by gas chromatography-mass spectrometry, and a compound elimination assay was conducted on the four most active oils (cinnamon, tea tree, ylang ylang, and marjoram oils) to identify major active constituents. Amongst the oils examined, cinnamon oil was the most active in both contact/residual and fumigant bioassays, and exhibited strong behavioral inhibitory activity. Based on the compound elimination assay and chemical analyses, trans-cinnamaldehyde in cinnamon oil, and terpinen-4-ol in tea tree and marjoram oils were identified as the major active components. Although cinnamon oil seemed promising in the lab-scale bioassay without rice grains, it failed to exhibit strong insecticidal activity when the container was filled with rice. When a cinnamon oil-based product was applied both in an empty glass jar and a rice-filled container, all weevils in the empty jar were killed, whereas fewer than 15% died in the rice-filled container.

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