Archive | Luty 2014

Naturalne inhibitory cytokin w leczeniu Łuszczycowego zapalenia stawów ŁZS

Łuszczycowe zapalenie stawów jest przewlekłą chorobą zapalną stawów oraz skóry   ŁZS  w której pośredniczy układ immunologiczny oraz mikroflora jelitowa. Progresja choroby jest związana z nieprawidłową ekspresją cytokin prozapalnych . Hamowanie ekspresji cytokiny czynnika martwicy guza TNF-alfa(ang. Tumor Necrosis Factor) było do niedawna jedną z najbardziej skutecznych terapii tej choroby . Jednak nie  wszyscy pacjenci reagują pozytywnie na leczenie syntetycznymi inhibitorami TNF takim jak infliximab, adalimumab czy etanercept. Dziś już wiemy że nie tylko cytokina TNF-alfa ale również interleukiny prozapalne IL-23 oraz IL-17 uczestniczą w nasileniu objawów ŁZS [1],[3]. Lek o nazwie secukinunab jest przeciwciałem monoklonalnym IgG1 które selektywnie wiąże i neutralizuje interleukine IL-17A, której skuteczność w leczeniu przewlekłej łuszczycy wykazano w różnych badaniach klinicznych fazy II [4].Kolejną cytokiną biorącą udział w  ŁZS jest Interleukina IL-36α która uruchamia prozapalne interleukiny IL-6 oraz IL-8 indukujące zapalenie błony maziowej stawów  [2]. Główny nacisk na leczenie ŁZS to wygaszenie  cytokin pozapalnych odpowiedzialnych za ta chorobę .

Mikrobiom (mikroflora jelitowa) jest aktualnie przedmiotem rosnącego zainteresowania etiologii chorób zapalnych o podłożu immunologicznym. Mikroflora jelit jest w stanie wpływać na bardzo odległe miejsca w organizmie człowieka takie jak np stawy oraz skóra poprzez sterowanie naszym układem immunologicznym. Mamy coraz więcej dowodów dotyczących związku między mikrobiomem , układem immunologicznym a łuszczycowym zapaleniem stawów. Bakterie probiotyczne  Bifidobacterium infantis wyciszają cytokiny prozapalne w przebiegu ŁZS.

Leki pochodzenia naturalnego takie jak (zioła ,probiotyki, grzyby ) mogą być skuteczną alternatywą dla syntetyków. Ich zalety to niewątpliwie mniej skutków ubocznych ,łatwa dostępność oraz niska cena w porównaniu z najnowszymi terapiami oferowanymi nam przez koncerny farmaceutyczne.

Roślinne inhibitory cytokin w leczeniu ŁZS:

1) Rośliny hamujące TNF-alfa:

Uczep (Bidens bipinnata , Bidens pilosa) – W tradycyjnej medycynie chińskiej i indyjskiej jest stosowany w leczeniu zapaleniu stawów i łuszczycy. Silnie hamuje cytokiny TNF-alfa ,IL-8 [8] . Ekstrakt z nadziemnych częsci na etanolu 40% 1:3 . Dawkowanie 5ml trzy razy dziennie.

Biodiversity, Plant Inventory Mbizi Forest Reserve and Rukwa Reg

2) Rośliny hamujące interleukiny IL-17 oraz IL-23:

Ku shen (Sophorae flavescentis) – W tradycyjnej medycynie chińskiej (TCM) Ku shen stosowano w formule Xiao Feng Wan w leczeniu swędzenia skóry, czerwonych zmian na skórze, łuszczycy, wyprysków, trądziku, stanów zapalnych skóry. Hamuje interleukiny IL-23 oraz IL-17 [6]. Ekstrakt z korzenia na etanolu 70% 1:3. Dawkowanie 5 ml trzy  razy dziennie  co 8 godzin. Korzeń Ku shen jest dostępny na http://www.ebay.pl oraz http://www.allegro.pl

Ku shen

3) Rośliny hamujące interleukiny Il-6,IL-8 aktywowane przez IL-36 alfa:

Butea monosperma – W tradycyjnej medycynie indyjskiej (Ayurveda) jest stosowana w leczeniu łuszczycy. Hamuje interleukiny Il-1,Il-6,IL-8 [7] . Ekstrakt z kwiatów na etanolu 40%-50% 1:5.Dawkowanie 5 ml trzy razy dziennie co 8 godzin. Można stosować jako wartościowy zamiennik susz z kwiatów Butea superba który można kupić na ww.ebay.pl.

Bueta

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Bibliografia

[1]  
Autoimmun Rev. 2014 Jan 11. pii: S1568-9972(14)00062-7. doi: 10.1016/j.autrev.2014.01.050. [Epub ahead of print]The IL-23/IL-17 axis in psoriatic arthritis.Suzuki E1, Mellins ED2, Gershwin ME1, Nestle FO3, Adamopoulos IE4.
Abstract

Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease, affecting both the skin and joints. Disease progression is associated with aberrant cytokine expression, and TNF blockade is the most successful therapy to date. However, not all patients are responsive to anti- TNF treatment, highlighting the need to better understand the cellular and molecular mechanisms

that govern the disease. PsA associations with single nucleotide polymorphisms in IL23R as well as TRAF3IP2 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to disease pathology. Although both cytokines are implicated in PsA, a full picture of their cellular targets and pathogenic mechanisms has not yet emerged. In this review, we focus on the
IL-23/IL-17 axis-elicited responses mediated by osteoclasts, keratinocytes and neutrophils. Expanding our understanding of the cellular and molecular mechanisms that dictate pathogenicity in PsA will contribute to developing novel treatment strategies to combat disease.


[2]
Ann Rheum Dis. 2013 Sep 1;72(9):1569-74. doi: 10.1136/annrheumdis-2012-202264. Epub 2012 Dec 25.The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium.Frey S, Derer A, Messbacher ME, Baeten DL, Bugatti S, Montecucco C, Schett G, Hueber AJ.
Author information

Abstract
BACKGROUND:

Interleukin (IL)-36α is a recently described member of the IL-1 cytokine family with pro- inflammatory and clearly pathogenic properties in psoriasis.

OBJECTIVE:
To determine the IL-36α expression in psoriatic arthritis (PsA) compared to rheumatoid arthritis
(RA) and osteoarthritis (OA).

METHODS:
Synovial tissues obtained from arthritis patients were stained for IL-36α, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by immunohistochemistry and immunofluorescence. Lysates were examined for IL-36α by western blot analysis. Synovial fibroblasts (FLS) cultured in the presence of IL-36α were assayed for cytokine expression by quantitative real time PCR and multiplex assay.
IL-36α-induced signal transduction in FLS was analysed by immunoblotting.
RESULTS:
Expression of IL-36R and its ligands IL-36α and IL-36Ra was detected in the synovial lining layer and cellular infiltrates of patients with inflammatory arthritis. IL-36α was expressed significantly higher in PsA and RA than in OA synovium. CD138-positive plasma cells were identified as the main cellular source of IL-36α. No differences were observed for the expression of IL-36R and IL-36Ra between PsA, RA and OA. Functionally, IL-36α induced the expression of IL-6 and IL-8 in FLS through p38/NFkB activation.

CONCLUSIONS:
IL-36α is up-regulated in PsA and RA synovium, expressed by tissue plasma cells and leads to IL-6 and IL-8 production by synovial fibroblasts. Hence, IL-36α links plasma cells to inflammatory cytokine production by FLS and may represent a key link between autoimmunity and the induction of synovitis.


[3]
Clin Rev Allergy Immunol. 2013 Apr;44(2):183-93. doi: 10.1007/s12016-012-8307-1.
Role of IL-17 in psoriasis and psoriatic arthritis.
Raychaudhuri SP.

Author information
Abstract

The role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signature cytokine IL-17. In the last couple of years, many articles are coming out on the role of Th17 and its signature cytokine IL-17 in different autoimmune diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis (PsA), SLE and multiple sclerosis. Psoriasis and PsA are immune- mediated diseases, affecting the skin and joints, respectively. Initially, it was thought that psoriasis and PsA were Th1-mediated diseases; however, studies in knockout animal models (IL-17 knockout mice) as well as human experimental data indicate that Th17 and its signature cytokine IL-17 have a critical role in the pathogenesis of psoriatic disease. Th17 cells have been identified from the dermal extracts of psoriatic lesions. Subsequently, our research group has substantiated this observation that Th17 cells are enriched in the papillary dermis of psoriatic plaques and in freshly isolated effector T lymphocytes from the synovial fluid of PsA patients, and we have reported that the majority of these CD4 + IL-17+ T cells are of memory phenotype (CD4RO(+)CD45RA(-)CD11a(+)). Recent reports also suggest that the synovial tissue in psoriatic arthritis is enriched with IL-17R, and its most well recognized receptor IL-17RA is functionally active in psoriatic arthritis. In this review article, we have discussed the role of IL-17 in psoriatic disease and have narrated about the novel IL17/IL-17R antibodies currently in preparation for its therapeutic uses in autoimmune diseases.

[4] 
Dermatol Ther (Heidelb). 2014 Jan 23. [Epub ahead of print] Efficacy and Safety of Secukinumab in Chronic Plaque Psoriasis and Psoriatic Arthritis Therapy.
Gisondi P, Dalle Vedove C, Girolomoni G.
Author information
Abstract

Psoriasis is a chronic inflammatory skin disease affecting about 1-3% of the general population. Moderate-to-severe psoriasis is commonly associated with various comorbidities, including psoriatic arthritis (PsA) and cardio-metabolic disorders such as obesity, hypertension, diabetes, and metabolic syndrome. There is increasing recognition that systemic inflammation accompanies severe skin disease. Abnormal innate and adaptive immune responses in the skin are involved in pathogenesis. The cytokine interleukin (IL)-17A is produced by T helper 17 (Th17) cells, neutrophils, mast cells, and T cytotoxic 17 cells. IL-17 plays a key role in host defense against extracellular bacteria and fungi. IL-17A acts on keratinocytes to increase expression of chemokines involved in recruiting myeloid dendritic cells, Th17 cells, and neutrophils to the lesion site. IL-17A also induces the production of antimicrobial peptides and pro-inflammatory cytokines that,
in turn, may amplify and sustain immune responses in the skin. Blocking IL-17A improved psoriasis- like pathology in experimental models, and reduction in IL-17 signaling is part of the mechanism of action of tumor necrosis factor-α blockers. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are currently being tested for efficacy and safety in the treatment of plaque psoriasis and PsA. Secukinumab is a fully human IgG1 monoclonal antibody that selectively binds and neutralizes IL-17A whose efficacy in the therapy of chronic plaque psoriasis has been demonstrated in different phase II clinical trial. No new safety signals have emerged so far.


[6] 
Am J Chin Med. 2011;39(5):933-41. doi: 10.1142/S0192415X11009317.
Matrine suppresses production of IL-23/IL-17 and ameliorates experimental autoimmune encephalomyelitis.
Zhao X, Kan Q, Zhu L, Zhang GX.
Author information
Abstract

Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been suggested to possess immunomodulatory characteristics; however, whether it is effective in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is not known. Our aim was to bridge this gap by investigating the possible therapeutic effects of MAT on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have found that, compared to the untreated controls, MAT-treated rats showed a significant decrease in clinical scores, in CNS infiltration of inflammatory cells (including CD4(+), CD8(+) T cells and macrophages) and demyelination. Furthermore, serum levels of IL-23 and IL-17 showed a marked reduction after MAT treatment, particularly in rats treated with higher doses of MAT. This study demonstrates that administration of MAT, as a natural compound, might be a novel therapy for autoimmune disorders
such as MS.

[7] J Ethnopharmacol. 2013 Jul 9;148(2):537-43. doi: 10.1016/j.jep.2013.05.001. Epub 2013 May 13.Protective effect of a Butea monosperma (Lam.) Taub. flowers extract against skin inflammation: antioxidant, anti-inflammatory and matrix metalloproteinases inhibitory activities.Krolikiewicz-Renimel I, Michel T, Destandau E, Reddy M, André P, Elfakir C, Pichon C.
Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:
Butea monosperma (Lam.) Taubert (Syn. Butea frondosa; family Fabaceae) is a common plant of the Indian continent (Das et al., 2011; Sharma and Deshwal, 2011). The brightly orange flowers of this plant are widely used in traditional medicine and more particularly for inflammatory disease.
AIM OF THE STUDY:
In vitro anti-inflammatory mechanism of a hydroethanolic extract of B. monosperma flowers (BME) and more specifically of an enriched fraction in butrin and isobutrin (BI) was studied using cell culture of Normal Human Keratinocyte, cells involved in the skin inflammatory.
MATERIALS AND METHODS:
Dried and crushed B. monosperma flowers were extracted with Ethanol/H2O (70/30 v/v). The butrin/isobutrin fraction was obtained by centrifugal Partition Chromatography (CPC). Experiments were conducted on UV-B treated normal human epidermis keratinocytes, cells involved in the skin inflammatory response. To evaluate extract anti-inflammatory activity, cytokines IL-1β, IL-6, IL-8, prostaglandin E2 and metalloproteinases MMP-1, -2, -9 and -10 were measured in the cells
supernatant.
RESULTS:
Our data clearly showed that hydroalcoholic B. monosperma flower extract was able to decrease the secretion of IL-1β, IL-6 and IL-8 pro-inflammatory cytokines of -32, -33 and -18% respectively. Interestingly, Prostaglandin E2 production and the secretion of MMP-1, -2, -9 and -10 were also inhibited. Same results were observed in presence of enriched fraction in butrin and isobutrin and confirmed the participation of these molecules in the anti-inflammatory activity.
CONCLUSION:
These results explain the anti-inflammatory activity of B. monosperma and confirm the interest to use it in traditional Indian medicine. Moreover, its metalloproteinases inhibitory activities coupled with its anti-inflammatory action also give anti-aging property to this plant.

[8]
J Pharm Pharmacol. 2012 Jun;64(6):882-7. doi: 10.1111/j.2042-7158.2012.01480.x. Epub 2012 Mar 27.
Total flavonoids of Bidens bipinnata L. a traditional Chinese medicine inhibits the production of inflammatory cytokines of vessel endothelial cells stimulated by sera from Henoch-Schönlein purpura patients.
Bo Y, Yuan LP, Zhang JJ, Meng DD, Jing H, Dai HJ.
Author information

Abstract
OBJECTIVES:
Bidens bipinnata L. is well known as a traditional antipyretic, anti-inflammatory and anti- rheumatic medicine in China. This study was designed to evaluate the role of total extracted flavonoids from B. bipinnata (TFB) in inhibiting the production of inflammatory cytokines.

METHODS:
Human umbilical vein endothelial cells (HUVEC) were used to examine the effect of TFB on the production of inflammatory cytokines. The supernatant interleukin (IL)-8, tumour necrosis factor (TNF)-α and nitric oxide (NO) levels of HUVEC were measured with ELISA methods. Nuclear factor- kappaB (NF-κB) and fractalkine expression was evaluated by RT-PCR and Western blot methods,respectively.

KEY FINDINGS:
We observed that IL-8, TNF-α and NO release of HUVEC incubated with sera from active Henoch- Schönlein purpura (HSP) was significantly increased. TFB intervention may significantly suppressed the supernatant IL-8, TNF-α and NO levels of HUVEC. Similarly, TFB obviously suppressed the NF-κB and fractalkine mRNA and protein expression.

CONCLUSIONS:
These results suggested that TFB may be useful for improving microvascular inflammation in HSP
patients.

Reklamy

Apigenina w regeneracji chrząstki stawowej

Apigenina (4’,5,7-trihydroxyflavone) występuje w wielu roślinach , należy do flawonoidów. Ma formę kryształków o żółtym kolorze.

Apigenina

Źródło apigeniny:

Rośliny mające w składzie najwyższe stężenie apigeniny to: Rdestowiec japoński(Polygonum japonicum), rumianek pospolity (Matricaria chamomilla L.),Przetacznik (Veronica) , Ciemiężyca(Veratrum grandiflorum) , Sosna Lamberta(Pinus Lambertiana) ,Kocanka(Helichrysum),Pietruszka zwyczajna (Petroselinum crispum) świeże ziele zawiera (302.00 mg/100 g ). Warto stosować ekstrakty z rumianku oraz tymianku bowiem wydają się być najlepszym źródłem apigeniny.

Pozostałe rośliny zawierające w swoim składzie apigenine:

Krwawnik pospolity L. – krwawnik pospolity

Apium graveolens L. – seler

Artemisia dracunculus L. – estragon

Camellia sinensis (L.) – herbata, liście

Nobile Chamaemelum (L.) – rumian rzymski

Coriandum sativum L. – kolendra

Digitalis purpurea L. – naparstnica

Echinacea spp. – jeżówka,liście

Gingko biloba L. – miłorząb , liście

Glycyrrhiza glabra L. – lukrecja , korzeń

Linum usitatissimum L. – len

Szanta zwyczajna L. – szanta zwyczajna

Matricaria recutita L. – rumianek

Mentha spicata L. – mięta, w liściach

Ocimum basilicum L. – bazylia

Origanum vulgare L. – oregano

Działanie farmakologiczne:

Apigenina jest silnym aktywatorem kanału jonowego TRPV4 który pobudza wzrost nowej chrząstki w stawach, naśladując efekt działania fizycznego ruchu który  również w umiarkowanym zakresie aktywuje jej wzrost. Kanał jonowy zwany TRPV4 jest potencjalnym celem dla nowych terapii do leczenia choroby zwyrodnieniowej stawów w tym regeneracji chrząstki [1,2]. Badania wykazały że zablokowanie kanału TRPV4 aktywuje zmiany zwyrodnieniowe w osteoartretyzmie [3].Apigenina również stymuluje neurogeneze i tworzenie nowych neronów (pamięć ,koncentracja)[4]. Apigenina ma działanie przeciwnowotworowe.

Wskazania: Choroby zwyrodnieniowe stawów, artretyzm , osteoartretyzm ,RZS, borelioza z Lyme z objawami stawowymi.

Farmakokinetyka:

Apigenine cechuje powolny metabolizm oraz powolna faza eliminacji z ustroju.
Maksymalne stężenie w organizmie apigenina osiąga od 1 do 4 godziny po podaniu doustnym . Okres półtrwania dla apigeniny to 12 godzin. Procent wydalonej dawki po spożyciu to 45,2 % (16,6 % w moczu , 28,6 % w kale ). Apigenina wchłania się z jelit o 50% słabiej u osób będących po kuracji antybiotykowej bądź z wyjałowioną florą bakteryjną.

Preparaty i dawkowanie:

Apigenina najskuteczniej rozpuszcza się w Dimetylosulfotleneku (CH3)2SO.

Intrakt z kwiatów rumianku na etanolu 50%-70% 1:3 . Dawkowanie 5-10 ml x 3/4 razy dziennie.

Ekstrakt z czystej apigeniny 100mg x 3 dziennie .

Świeże ziele pietruszki 3 razy dziennie po 20 gramów.

Synergizm:

Kozieradka (Trigonella foenum-graecum L.) oraz  resveratrol wzmacniają regeneracje chrząstki stawowej. Lukrecja oraz piperyna zwiększają przyswajalność apigeniny.

Źródła kupna apigeniny:

Swanson-ultra-apigenin-50-mg-90-caps    na stronie  www.swansonvitamins.com

Chamomile-20-1-Powder-500g  na www.ebay.pl

Nature’s Way Chamomile Standardized Digestive Soothing 60 Capsules 1.2% Apigenin na www.ebay.pl

apigenin

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Bibliografia


[1] 
Chemical Signaling Simulates Exercise in Cartilage Cells
Jan. 13, 2014 — Cartilage is notoriously difficult to repair or grow, but researchers at Duke Medicine have taken a step toward understanding how to regenerate the connective tissue. By adding a chemical to cartilage cells, the chemical signals spurred new cartilage growth, mimicking the
effects of physical activity.
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The findings, published online in the Proceedings of the National Academy of Sciences the week of Jan. 13, 2014, point to an ion channel called TRPV4 as a potential target for new therapies to treat osteoarthritis or even regrow cartilage. Articular cartilage is the tissue that lines joints such as hips, knees and shoulders, providing cushioning and smooth movement. Similar to bones and muscles, cartilage only stays healthy and
strong through loading, or applying force, through physical activity.
Abnormal forces on the joints can cause a variety of problems leading to pain and loss of mobility. Overloading joints through overuse or injury can lead to the cartilage breaking down, while lack of use can result in cartilage wasting through atrophy. Both kinds of cartilage
deterioration leave joints prone to osteoarthritis, a degenerative and debilitating disease. Until recently, researchers did not know how cartilage converts mechanical loading into the ion channel signals that promote growth. Understanding how cartilage senses mechanical loading could
equip researchers with the knowledge needed to prevent or better treat joint diseases. „Mechanical loading plays a critical role in the overall health of the cartilage,” said Farshid Guilak, Ph.D., Laszlo Ormandy Professor of Orthopaedic Surgery at Duke and the study’s senior
author. „If we can figure out how cartilage cells sense mechanical loads, we can trick them into thinking they are being exercised or stop them from responding to abnormal loading. Think of it as
artificial exercise for your cartilage.” In the study, led by MD/PhD student Christopher O’Conor, the researchers looked at articular cartilage cells from pigs and focused on TRPV4, an ion channel abundant in cartilage cells that can be turned on during mechanical loading. When the researchers „exercised” the cartilage cells using mechanical loading, the cells sensed the loading and grew cartilage tissue. When they added
a compound that blocked TRPV4, essentially turning off signals from the ion channel, the cartilage did not grow and the effects of the mechanical loading were lost.Next, the researchers substituted mechanical loading for a chemical that activated TRPV4. Without having to exercise the cartilage, they observed the growth of cartilage even more so than with the mechanical loading. The findings suggest that TRPV4 is responsible for sensing mechanical loading in the cartilage. Now that they know that turning on TRPV4 can simulate the effects of mechanical loading in cartilage cells, the researchers are looking at ways to harness this potential. „Our next step is to see if this synthetic ‚exercising’ technology works on human cells that could be used to regrow new human cartilage,” said O’Conor, who is completing his MD/PhD degree at the
University of North Carolina at Chapel Hill and is performing his dissertation work with Guilak in the Duke Orthopaedic Bioengineering Laboratories. Beyond growing new cartilage, the researchers will investigate whether the compounds that activate or block TRPV4 could act as new therapies to prevent cartilage degeneration and joint disease.

[2] 
Br J Pharmacol. 2012 May;166(1):349-58. doi: 10.1111/j.1476-5381.2011.01767.x.
Apigenin, a plant-derived flavone, activates transient receptor potential vanilloid 4 cation
channel.
Ma X, He D, Ru X, Chen Y, Cai Y, Bruce IC, Xia Q, Yao X, Jin J.
Author information
Abstract
BACKGROUND AND PURPOSE:
Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+) -permeable channel with multiple modes of activation. Apigenin is a plant-derived flavone, which has potential preventive effects on the development of cardiovascular disease. We set out to explore the effects of apigenin on
TRPV4 channel activity and its role in vasodilatation.
EXPERIMENTAL APPROACH:
The effects of apigenin (0.01-30 µM) on TPRV4 channels were investigated in HEK293 cells over- expressing TRPV4, rat primary cultured mesenteric artery endothelial cells (MAECs) and isolated small mesenteric arterial segments using whole-cell patch clamp, fluorescent Ca(2+) imaging,
intracellular recording and pressure myography.
KEY RESULTS:
Whole-cell patch clamp and fluorescent Ca(2+) imaging in HEK cells over-expressing TRPV4 showed that apigenin concentration-dependently stimulated the TRPV4-mediated cation current and Ca(2+) influx. In MAECs, apigenin stimulated Ca(2+) influx in a concentration-dependent manner. These
increases in cation current and Ca(2+) influx were markedly inhibited by TRPV4-specific blockers and siRNAs. Furthermore, pressure myography and intracellular recording in small third-order mesenteric arteries showed that apigenin dose-dependently evoked smooth muscle cell membrane
hyperpolarization and subsequent vascular dilatation, which were significantly inhibited by TRPV4 -specific blockers. TRPV4 blocker or charybdotoxin (200 nM) plus apamin (100 nM) diminished the
apigenin-induced dilatation.
CONCLUSION AND IMPLICATIONS:
This is the first study to demonstrate the selective stimulation of TRPV4 by apigenin. Apigenin was found to activate TRPV4 channels in a dose-dependent manner in HEK cells over-expressing TRPV4
and in native endothelial cells. In rat small mesenteric arteries, apigenin acts on TRPV4 in endothelial cells to induce EDHF-mediated vascular dilatation.

[3] 
Experimental Arthritis
You have full text access to this OnlineOpen article
Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: Age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice Andrea L. Clark1, Bartholomew J. Votta2,†, Sanjay Kumar2,†, Wolfgang Liedtke1, Farshid Guilak1,*
Article first published online: 25 JUN 2010

[4]  Expert Opin Ther Pat. 2009 Apr;19(4):523-7. doi: 10.1517/13543770902721279.
Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483.
Taupin P.
Author information
Abstract
The application is in the field of adult neurogenesis and its therapeutic potential. It aims to characterize the activity of apigenin and related compounds on adult neurogenesis in vivo and in vitro. Apigenin and related compounds are derivatives used in food products. They were
administered intraperitoneally and orally in adult rodents and assessed for their activity in promoting the generation of neuronal cells and learning and memory performance. They were also tested on adult rat hippocampal-derived neural progenitor and stem cells to assess their neurogenic property. Apigenin and related compounds stimulate adult neurogenesis in vivo and in vitro, by promoting neuronal differentiation. Apigenin promotes learning and memory performance in the Morris water task. The application claims the use of apigenin and related compounds for stimulating adult neurogenesis and for the treatment of neurological diseases, disorders and injuries, by stimulating the generation of neuronal cells in the adult brain.

Leczenie depresji naturalną terapią biologiczną (Psychobiotyki) cz.4

PsychobiotykiPsychobiotyk jest to żywy organizm który po spożyciu w odpowiedniej ilości daje korzyści dla zdrowia pacjentów cierpiących na choroby  takie jak np. depresja.Do psychobiotyków zaliczamy tzw. probiotyki (podawane doustnie wyselekcjonowane kultury bakterii lub drożdży) , jak również inne bakterie zdolne do wytwarzania i dostarczania substancji neuroaktywnych które działają na oś mózg-jelito, takich jak kwas gamma-aminomasłowy czy serotonina. Wiele chorób psychicznych o charakterze immunologicznym charakteryzuje się przewlekłymi stanami zapalanymi. Depresja i stany lękowe są powszechne u pacjentów z zespołem jelita drażliwego (IBS) która to choroba ma źródło w wadliwie funkcjonującym układzie immunologicznym powodującym stany zapalne jelita. Istnieje mnóstwo dowodów wskazujących na związek między florą bakteryjną jelita a stanem zapalnym. Badania dotyczące szczepów probiotycznych wykazały  zdolność bakterii do modulowania stanu zapalnego i przywracania zdrowych funkcji układowi immunologicznemu. Aplikowanie psychobiotyków powoduje zmniejszenie stanu zapalnego w organizmie a tym samym eliminowanie źródła depresji. Psychobiotyki pełnią jeszcze jedną bardzo istotna funkcje a mianowicie modyfikują funkcję kory nadnerczy która jest odpowiedzialna za kontrolę nad stresem oraz lękiem. Szczepy bakterii probiotycznych takich jak Lactobacillus helveticus oraz Bifdobacterium longum mają zdolność do zmniejszania poziomu hormonów stresu i utrzymania zdrowego spokojnego snu. Ostatnią bardzo istotną funkcją jaką spełniają psychobiotyki w naszym organizmie to bezpośrednio wpływa na poprawę nastroju poprze stymulowanie wytwarzania receptorów kannabinoidowych i opiatów (Lactobacillus acidophilus)[1],[2].

Lista psychobiotyków:

a) Bifidobacterium infantis – tłumi prozapalną odpowiedz immunologiczną odpowiedzialną za depresje. Hamuje cytokiny prozapalne (IFN -gamma , TNF -alfa i IL – 6 ) [3].

b) Lactobacillus Helvetius – zmniejsza objawy depresji oraz lęku [4].

c)  Bifdobacterium longum – zmniejsza objawy depresji oraz lęku [4].

d) Lactobacillus rhamnosus – zmniejsza poziom stresu, lęku i objawów związanych z depresją. Ponadto obniżają poziom hormonu wywołanego stresem, kortykosteronu [5].

_____

Probiotyk „Primadophilus® Optima „ firmy Nature’s Way zawiera wszystkie wyżej wymienione psychobiotyki . Można go nabyć na http://www.ebay.pl , http://www.allegro.pl. Skład Optima: L. casei-108; B. longum-135;-122 L. acidophilus, L. plantarum-119, L. rhamnosus-111, L. rhamnosus-114, B. breve-129, B. bifidum-132; L. lactis-136; S. thermophilus-110; B. infantis-116, L. bulgaricus-137; L. salivarius-118, L-128 helveticus .

Dawkowanie to jedna tabletka raz dziennie w trakcie posiłku. Probiotyk _______________________________________________________

Bibliografia


[1] 
Biol Psychiatry. 2013 Nov 15;74(10):720-6. doi: 10.1016/j.biopsych.2013.05.001. Epub 2013 Jun 10. Psychobiotics: a novel class of psychotropic. Dinan TG, Stanton C, Cryan JF. Author information Abstract Here, we define a psychobiotic as a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. As a class of probiotic, these bacteria are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the brain-gut axis. Preclinical evaluation in rodents suggests that certain psychobiotics possess antidepressant or anxiolytic activity. Effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems. So far, psychobiotics have been most extensively studied in a liaison psychiatric setting in patients with irritable bowel syndrome, where positive benefits have been reported for a number of organisms including Bifidobacterium infantis. Evidence is emerging of benefits in alleviating symptoms of depression and in chronic fatigue syndrome. Such benefits may be related to the anti-inflammatory actions of certain psychobiotics and a capacity to reduce hypothalamic-pituitary-adrenal axis activity. Results from large scale placebo-controlled studies are awaited.


[2] 
Neurogastroenterol Motil. 2013 Sep;25(9):713-9. doi: 10.1111/nmo.12198. Melancholic microbes: a link between gut microbiota and depression? Dinan TG, Cryan JF. Author information Abstract There is a growing awareness of the potential for microbiota to influence gut-brain communication in health and disease. A variety of strategies have been used to study the impact of the microbiota on brain function and these include antibiotic use, probiotic treatments, fecal microbiota transplantation, gastrointestinal infection studies, and germ-free studies. All of these approaches provide evidence to support the view that the microbiota can influence brain chemistry and consequently behavior. Efforts are now turning to investigate the role of microbiota in animal models of psychopathology. Animal models of depression are thus essential in studying the complex interplay between the microbiota and brain. Recent studies published in this Journal and elsewhere demonstrate that there is a distinct perturbation of the composition of gut microbiota in animal models of depression and chronic stress. This has direct implications for the development of psychobiotic-based therapeutic strategies for psychiatric disorders. Moreover, given that affective co-morbidities, such as major depression and anxiety states, are common in patients presenting with irritable bowel syndrome (IBS), it may have implications for functional bowel disorders also. Further studies require appropriately phenotyped patients with depression and/or IBS using a judicious use of techniques including functional imaging and in depth microbial pyrosequencing. 


[3] 
J Psychiatr Res. 2008 Dec;43(2):164-74. doi: 10.1016/j.jpsychires.2008.03.009. Epub 2008 May 5. The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. Author information Abstract It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-gamma, TNF-alpha and IL-6 cytokines following mitogen stimulation (p<0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p<0.005) and kynurenic acid (p<0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted. 


[4] 
Br J Nutr. 2011 Mar;105(5):755-64. doi: 10.1017/S0007114510004319. Epub 2010 Oct 26. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel JM. Author information Abstract In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0•05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0•05; somatisation, P < 0•05; depression, P < 0•05; and anger-hostility, P < 0•05), the HADS (HADS global score, P < 0•05; and HADS-anxiety, P < 0•06), and by the CCL (problem solving, P < 0•05) and the UFC level (P < 0•05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.


[5] 
Javier A. Bravo, Paul Forsythe, Marianne V. Chew, Emily Escaravage, Hélène M. Savignac, Timothy G. Dinan, John Bienenstock, John F. Cryan. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptorexpression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences, 2011; DOI:10.1073/pnas.1102999108

Leczenie depresji ziołową terapią biologiczną (Inhibitory MAO,Agoniści receptora 5-HT1A) cz.3

Inhibitory ( MAO ) są to substancje chemiczneDepresja które hamują czynność  enzymów oksydazy monoaminowej . Są one szczególnie skuteczne w leczeniu tzw. depresji atypowej charakteryzującej się obecnością w obrazie chorobowym nadmiernej senności, zwiększonego apetytu i pogarszania się nastroju w godzinach wieczornych.

1) Inhibitory monoaminooksydazy MAO-A  i MAO-B

a) Krzyżownica (Polygala tenuifolia) – inhibitor MAO-A oraz MAO-B ,blokuje podwyższony poziom kortyzolu w osoczu który jest wskaźnikiem aktywności osi podwzgórze-przysadka-nadnercza (HPA) [1].  Ekstrakt z nadziemnych części na etanolu 50% 1:5 . Dawkowanie 5ml 3 razy dziennie co 8 godzin.

Krzyżownica

 

 

 

 

 

b) Kozieradka pospolita (Trigonella foenum-graecum L.) – inhibitor MAO-A [2]. Ekstrakt etanolowy 50% 1:5   z nasion. Dawkowanie 5 ml trzy razy dziennie.

kozieradka

 

 

 

 

 

 

 

 

c) Seler (Apium L.) – inhibitor MAO-A [2]. Ekstrakt etanolowy 40% 1:5 z liści . Dawkowanie 5ml trzy razy dziennie.

Seler

 

 

 

 

 

 

 

d) Wrzos pospolity (Calluna vulgaris) –  inhibitor MAO-A [2]. Wodny ekstrakt z nadziemnych części rośliny .  Jedną kopiastą łyżeczkę zalać 250 ml wrzącej wody .    Pić trzy razy dziennie po jednej szklance.

Wrzos

 

 

 

 

 

 

 

____________

Dysfunkcja receptora 5-HT1A może być przyczyną zaburzeń depresyjnych . Receptory 5-HT mogą odgrywać rolę w łagodzeniu depresji  przez tzw. odczulanie autoreceptorów 5-HT1A. Leki przeciwdepresyjne, takie jak inhibitory MAO i TLPD, SSRI, lit, wszystkie zwiększają postsynaptyczną sygnalizacji 5-HT 1A. Zioła stanowią skuteczną oraz bezpieczną alternatywę dla tego typu leków syntetycznych.

2) Agoniści receptora 5-HT1A:

a) Nelumbinis  – agonista receptora 5-HT1A  [3]. Wodny ekstrakt z nasion.  Jedną  łyżeczkę nasion zalać 250 ml wrzącej wody . Pić trzy razy dziennie po jednej szklance.

Semen

 

 

 

 

 

 

 

b) Kurkumina (Curcuma longa) – agonista receptorów 5-HT (1a/1b) i 5-HT (2C) [4]. Rozdrobnione kłącze  zażywamy w ilości 3 gramy trzy razy dziennie popijając wodą .

Curcuma

 

 

 

 

 

 

 

 

 

c) Lawenda (Lavandula angustifolia) – agonista receptora 5-HT1A  [6].  Stosujemy w formie inhalacji olejkiem  3 razy dziennie po 10-15 minut.

lawenda

 

 

 

 

 

 

 

d) Mięta meksykańska (Agastache mexicana)   – agonista receptora 5-HT1A  [7].  Nadziemnie części rośliny zalewamy etanolem 40% 1:5 . Dawkowanie 5 ml  trzy razy  dziennie.

mieta mexykańska

___________________________________________________________________

Bibliografia


[1]    

J Pharm Pharmacol. 2011 Jun;63(6):869-74. doi: 10.1111/j.2042-7158.2011.01281.x. Epub 2011 May 3.
Possible mechanism of the antidepressant effect of 3,6′-disinapoyl sucrose from Polygala tenuifolia Willd.
Hu Y, Liu M, Liu P, Guo DH, Wei RB, Rahman K.
SourceDepartment of Clinical Pharmacology and Pharmacy, Center of Pharmacy, Chinese PLA General Hospital, Beijing, China.

Abstract
OBJECTIVE: The present study was designed to observe the effects of 3,6′-disinapoyl sucrose (DISS), an active oligosaccharide ester component obtained from the roots of Polygala tenuifolia Willd., on behavioral and biochemical aspects of depression induced by chronic mild stress (CMS) in rats. It is the first exploration of the possible association between DISS’s antidepressant-like effects and biochemical markers of depression, and involved measuring monoamine oxidase (MAO) activity, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels.

METHODS: Rats were exposed to stressor once daily for consecutive 5 weeks. DISS and a positive control drug, fluoxetine, were administered via gastric intubation to once daily for consecutive 3 weeks from the third week.
KEY FINDINGS: The results showed that rats subjected to CMS exhibit a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activity, plasma cortisol levels, and MDA levels were increased, while SOD activity was decreased following CMS exposures. DISS significantly inhibited MAO-A and MAO-B activity and blocked plasma elevated cortisol level, an indicator of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, DISS increases SOD activity, inhibits lipid peroxidation, and lessens production of MDA.
CONCLUSION: These results suggest that DISS may possess potent and rapid antidepressant properties, which are mediated via MAO, the HPA axis and oxidative systems. These antidepressant actions make DISS a potentially valuable drug for the treatment of depression.

[2]
J Ethnopharmacol. 2013 Feb 13;145(3):822-5. doi: 10.1016/j.jep.2012.12.021. Epub 2012 Dec 21.
Screening of plants used in Danish folk medicine to treat depression and anxiety for affinity to the serotonin transporter and inhibition of MAO-A.
Jäger AK, Gauguin B, Andersen J, Adsersen A, Gudiksen L.
SourceDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen O, Denmark. Electronic address: anna.jager@sund.ku.dk

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: A number of plant species are used in Danish folk medicine for treatment of depression and anxiety.

MATERIALS AND METHODS: Aqueous and ethanolic extracts of 17 plant species were tested for affinity to the serotonin transporter and for inhibition of MAO-A-both targets for antidepressive treatment.
RESULTS: An ethanolic extract of aerial parts of Borago officinalis had affinity to the serotonin transporter. Ten extracts, from eight plants, had IC(50) values below 25µg/ml extract in the MAO-A assay. The most active extracts in the MAO-A assay were the ethanol extract of seeds of Trigonella foenum-graecum (IC(50) 4µg/ml); ethanol extract of leaves of Apium graveolens (IC(50) 5µg/ml) and the water extract of aerial parts of Calluna vulgaris (IC(50) 8µg/ml).
CONCLUSIONS: Besides Borago officinalis, which toxicity profile excludes it from further development as an herbal drug, none of the plants had potential as serotonin reuptake inhibitors. Several plants had MAO-A inhibitory activity.

[3]

Arch Pharm Res. 2004 Oct;27(10):1065-72.
Nelumbinis Semen reverses a decrease in 5-HT1A receptor binding induced by chronic mild stress, a depression-like symptom.
Jang CG, Kang M, Cho JH, Lee SB, Kim H, Park S, Lee J, Park SK, Hong M, Shin MK, Shim IS, Bae H.
SourceDepartment of Pharmacology, College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea.

Abstract
Depression is associated with a dysfunctional serotonin (5-hydroxytryptamine; 5-HT) system. More recently, several lines of evidence suggest that an important factor in the development of depression may be a deficit in the function and expression of 5-HT1A receptors. The present study assessed if Nelumbinis Semen (N.s.) had an anti-depression effect through reversing a decrease in 5-HT1A receptor binding in rats with depression-like symptoms induced by chronic mild stress. Using a 5-HT1A receptor binding assay, with a specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin), the mechanism of the anti-depression effect of N.s. on rats was investigated, and the effects compared with two well-known antidepressants, Hyperium Perforatum (St. Johns Wort) and fluoxetine (Prozac). Animals were divided into five groups: the normal (N) group without chronic mild stress (CMS), the control (C) group under CMS for 8 weeks, the Nelumbinis Semen (N.s.) treatment group under CMS for 8 weeks, the Hyperium Perforatum (H.p.) treatment group under CMS for 8 weeks and finally, the fluoxetine (F) treatment group under CMS for 8 weeks. Each treatment was administered to rats during the last 4 weeks of the 8-week CMS. A sucrose intake test was performed to test the anti-depression effect of N.s. The N.s. treatment significantly reversed the decreased sucrose intake under CMS (P < 0.05 compared to control group under CMS). In the CA2 and CA3 regions of the hippocampus, both N.s. and H.p. reversed the CMS-induced decrease in 5-HT1A receptor binding. In the I to II regions of the frontal cortex, N.s. and H.p. also reversed the CMS-induced decrease in 5-HT1A receptor binding, and even showed a significant increase in 5-HT1A receptor binding compared to the F treatment group (N.s. vs. P, p < 0.05, H.p. vs. P, p < 0.05). However, in the hypothalamus, all treatments reversed the CMS-induced decrease in 5-HT1A receptor binding. This reversal effect of N.s. on the decrease in 5-HT1A receptor binding in the frontal cortex, hippocampus and hypothalamus of rat brains was very similar to that of H.p, but different from that of F. It is concluded that N.s. presents an anti-depression effect through enhancing 5-HT1A receptor binding.


[4]

Eur J Pharmacol. 2008 Jan 6;578(1):43-50. Epub 2007 Sep 19.
The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors.
Wang R, Xu Y, Wu HL, Li YB, Li YH, Guo JB, Li XJ.
SourceDepartment of Pharmacology, School of Basic Medical Sciences and State Key Laboratory of Natural & Biomimetic Drugs, Peking University, Beijing 100083, China.

Abstract
Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2′-methoxy-phenyl)-1-[2′-(n-2”-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) receptors.


[6]
J Ethnopharmacol. 2013 May 20;147(2):412-8. doi: 10.1016/j.jep.2013.03.028. Epub 2013 Mar 22.
Anxiolytic-like effect of lavender essential oil inhalation in mice: participation of serotonergic but not GABAA/benzodiazepine neurotransmission.
Chioca LR, Ferro MM, Baretta IP, Oliveira SM, Silva CR, Ferreira J, Losso EM, Andreatini R.
SourceDepartamento de Farmacologia, Setor de Ciencias Biológicas, Universidade Federal do Paraná, Centro Politécnico, PO Box 19031, Curitiba, PR 81540-990, Brazil. leachioca@yahoo.com.br
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Lavandula angustifolia (lavender) inhalation has been used in folk medicine for the treatment of anxiety, and clinical and animal studies have corroborated its anxiolytic effect, although its mechanism of action is still not fully understood.
AIMS OF THE STUDY: The objective of the present study was to determine whether the GABAA/benzodiazepine complex or serotonin neurotransmission mediates the anxiolytic-like effect of lavender essential oil.
MATERIALS AND METHODS: Male Swiss mice were subjected to the marble-burying test after being exposed to the aroma of lavender essential oil (1-5%), amyl acetate (5%; used as a behaviorally neutral odor), or distilled water for 15 min via inhalation. Additionally, the effect of 5% lavender essential oil was also evaluated in mice subjected to the elevated plus maze. GABAA/benzodiazepine mediation was evaluated by pretreating the mice with the GABAA receptor antagonist picrotoxin before the marble burying test and [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Serotonergic mediation was studied by pretreating the mice with O-methyl-[3H]-N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635), a serotonin 5-HT1A receptor antagonist before the marble burying test. We also evaluated changes in the pharmacologically induced serotonin syndrome and the effects of combined administration of subeffective doses of lavender essential oil and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
RESULTS: Lavender essential oil (1-5%) decreased the number of marbles buried compared with the control and amyl acetate groups. In the elevated plus maze, 5% lavender essential oil inhalation increased the percentage of time spent on and number of entries into the open arms compared with controls. No effect was seen in the number of closed arm entries or number of beam interruptions in the automated activity chamber. Pretreatment with the GABAA receptor antagonist picrotoxin (0.5mg/kg) did not modify the behavioral effect of 5% lavender essential oil in the marble-burying test. Lavender essential oil also did not alter [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Pretreatment with the serotonin 5-HT1A receptor antagonist WAY100635 (3mg/kg) blocked the anxiolytic-like effect of lavender essential oil and the 5-HT1A receptor agonist 8-OH-DPAT (3mg/kg). A combination of ineffective doses of 8-OH-DPAT (0.5mg/kg) and lavender essential oil (0.1%) reduced the number of marbles buried. Finally, 5% lavender essential oil attenuated the serotonin syndrome induced by 40 mg/kg fluoxetine plus 80 mg/kg 5-hydroxytryptophan.
CONCLUSIONS: These results indicate an important role for the serotonergic system in the anxiolytic-like effect of lavender essential oil.

[7]

Pharmacol Biochem Behav. 2013 Sep;110:255-64. doi: 10.1016/j.pbb.2013.07.020. Epub 2013 Aug 7.
Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism.
Verano J, González-Trujano ME, Déciga-Campos M, Ventura-Martínez R, Pellicer F.
SourceLaboratorio de Neurofarmacología de Productos Naturales, Dirección de Investigaciones en Neurociencias del Instituto Nacional de Psiquiatría Ramón de la Fuente Muniz, Calz. México-Xochimilco 101, Col. Sn Lorenzo Huipulco, 14370 México, D.F., Mexico; Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Col. Santo Tomás, 11340 México, D.F., Mexico.

Abstract
Agastache mexicana is a plant that has long been used in large demands in Mexican folk medicine to treat anxiety, insomnia and pain, among others affections. Chromatographic technique was used to identify ursolic acid (UA), 130.7mg/g and 20.3mg/g, as an antinociceptive active compound identified in ethyl acetate and methanol extracts of A. mexicana aerial parts, respectively. Temporal course curves of the antinociceptive response demonstrated a dose-dependent and significant activity of UA (1 to 100mg/kg, i.p.) with an ED50=2mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100mg/kg, i.p.), a non-steroidal anti-inflammatory drug, with an ED50=11.56mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium-flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor. Finally, an ED50=44mg/kg was calculated in the neurogenic and inflammatory nociception induced in the formalin test in rats. The antinociceptive response of UA in the formalin test was not modified in presence of naloxone, flumazenil or l-arginine. Nevertheless, it was reverted in presence of 1-H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, an inhibitor of soluble guanylyl cyclase) and increased in presence of N(G)-l-nitro-arginine methyl ester (l-NAME, inhibitor of nitric oxide synthase), theophylline (inhibitor of phosphodiesterase) and WAY100635 (an antagonist of 5-HT1A receptors). Current results provide evidence that the antinociceptive response of A. mexicana depends in part on the presence of UA. Moreover, this triterpene may exerts its antinociceptive effect mediated by the presence of cGMP and an additive synergism with 5HT1A receptors, but also an antagonistic activity towards TRPV1 receptors may be involved.