Neuroprotective effects of inhaled lavender oil on scopolamine-induced dementia via anti-oxidative activities in rats.
Lavender is used in traditional medicines in Asia, Europe, ancient Greece and Rome, and was mentioned in the Bible and in ancient Jewish texts. Also, lavender is reported to be an effective medical plant in treating inflammation, depression, stress and headache. The present study was undertaken in order to investigate the antioxidant and antiapoptotic activities of the lavender essential oils from Lavandula angustifolia ssp. angustifolia Mill. and Lavandula hybrida Rev, using superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) specific activities, total content of reduced glutathione (GSH), malondialde-hycle (MDA) level (lipid peroxidation) and DNA fragmentation assays in male Wistar rats subjected to scopolamine-induced dementia rat model. In scopolamine-treated rats, lavender essential oils showed potent antioxidant and antiapoptotic activities. Subacute exposures (daily, for 7 continuous days) to lavender oils significantly increased antioxidant enzyme activities (SOD, GPX and CAT), total content of reduced GSH and reduced lipid peroxidation (MDA level) in rat temporal lobe homogenates, suggesting antioxidant potential. Also, DNA cleavage patterns were absent in the lavender groups, suggesting antiapoptotic activity. Taken together, our results suggest that antioxidant and antiapoptotic activities of the lavender essential oils are the major mechanisms for their potent neuroprotective effects against scopolamine-induced oxidative stress in the rat brain.
[c] 2012 Elsevier GmbH. All rights reserved.
Alzheimer's disease (AD) has been estimated to account for 50-60% of dementia cases in persons over 65 years of age worldwide. Characteristic pathological features of the central nervous system (CNS) in AD are senile plaque, neurofibrillary tangle formation, aberrant oxidative and inflammatory processes and neurotransmitter disturbances. Cholinergic deficits are neuropathological occurrences that are consistently associated with memory loss and are correlated with the severity of AD (Kwon et al. 2010).
Despite continued efforts, the development of an effective treatment for AD remains elusive. Current therapeutic strategies are limited to those that attenuate AD symptomology without deterring the progress of the disease itself, and thus only postpone the inevitable deterioration of the affected individual. As the population of AD cases is growing faster than ever (Bonda et al. 2010; Jellinger 2006) the demand for an adequate method of treatment is also on the rise. Moreover, most of the synthetic drugs have severe side effects that limit the dosage and the use by the patients. Notably, as oxidative stress is perhaps the earliest feature of an AD brain (Banda et al. 2010; Zhu et al. 2007) the successful neuronal protection from oxidative damage will potentially prevent the disease altogether. if appropriately administered.
The damaging effect of the oxidative stress is most notable in AD. That is, oxidative damage marked by lipid peroxidation, nitration, reactive carbonyls, and nucleic acid oxidation is increased in vulnerable neurons in AD, relative to unaffected patients, whether or not they contain any other corresponding pathology (i.e., neurofibrillary tangles (NFTs), etc.) (Castellani et al. 2001; Nunomura et al. 2001). Furthermore, reduced metabolic activity, deemed the result of oxidative damage to vital mitochondrial components, has been demonstrated in AD (Hirai et al. 2001). Specifically, cytochrome oxidase, the pyruvate dehydrogenase complex, and the [alpha]-ketoglutarate dehydrogenase complex showed reduced activity as a result of oxidative damage (Aliev et al. 2003; Castegna et al. 2002). Thus, alternative and complementary therapies are needed to develop novel anti-dementia agents (Ren et at. 2004).
Scopolamine, a muscarinic antagonist, interferes with memory in animals and humans, particularly the processes of learning acquisition and short-term memory (Hefco et at. 2003). Scopolamine has been used to induce experimental models of AD (Beatty et at. 1986; Collerton 1986; Kopelman and Corn 1988). Scopolamine significantly increases acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level in the cortex and hippocampus (Ben-Barak and Dudai 1980; Fan et al. 2005; Jeong et al. 2008; Sakurai et al. 1998) and has been used to screen antiamnesic drugs for age-related CNS dysfunction. The elevation of brain oxidative status after administration of amnesic doses of scopolamine further substantiates the value of scopolamine-induced amnesia as an animal model to test for drugs with potential therapeutic benefits in dementia (El-Sherbiny et al. 2003).
Lavender essential oil is popular as a complementary medicine in its own right and as an additive to many over the counter complementary medicine and cosmetic products (Muyima et al. 2002). The essential oil is traditionally believed to have sedative (Buchbauer et at. 1991), carminative (Catherine and Kathi 2001), anti-depressive (Delaveau et at. 1989) and anti-inflammatory properties (Valiollah et at. 2003) in addition to its recognized antimicrobial effect (Moon et al. 2004). The lavender oil is commonly used in aromatherapy and massage therapy (Welsh 1995). Its major clinical benefits are on the central nervous system (Delaveau et al. 1989).
Silexan (1) is an essential oil produced from fresh Lavandula angustifolia flowers by steam distillation that has been licensed in Germany as herbal medicinal product for the treatment of states of restlessness during anxious mood (Uehleke et at. 2012). Silexan acts via the GABA receptors (Aoshima and Hamamoto 1999), and pre-clinical data have suggested that it may have anxiolytic and antidepressant potential (Kasper et al. 2010; Woelk and Schlafke 2010).
Lavender extracts display antioxidant (Atsumi and Tonosaki 2007) and AChE inhibitory activities (Adsersen et al. 2006). Inhibitory effects of lavender on glutamate-induced neurotoxicity have also been reported (Adsersen et al. 2006). Based on these findings, it is assumed that lavender may alleviate dementia in some neurodegenerative disorders such as AD. Furthermore, recently, we demonstrated that the lavender essential oils possess a wide spectrum of biological activities, including anxiolytic and antidepressant actions, as well as positive effects on spatial memory formation (Hritcu et al. 2012). Moreover, we suggested that the effects of the lavender essential oils could be attributed to the presence of various constituents, such as linalool and linalyl acetate.
Therefore, the aim of the present study was to investigate the relationship between the antioxidant and antiapoptotic action of the lavender essential oils and their neuroprotective proprieties in scopolamine-induced a dementia rat model.
Materials and methods
Essential oil and chemical analysis
Lavandula angustifolia ssp. angustifolia Mill. and Lavandula hybrida Rev, were harvested from the Botanical Garden Galati (South-East of Romania) in July 2010 and identified. Vouchers specimens are preserved at the Department of Pharmacognosy. Faculty of Pharmacy (University of Medicine and Pharmacy "Cr. T. Popa", Iasi, Romania), for ready reference. Organic volatile fractions of Lavandula angustifolia (LO1) and Lavandula hybrida (LO2) were obtained by hydro-distillation of dried flower heads.
The chemical composition was determined by GC-MS, injection volume 1 [micro]l (Column: HP, 5MS bonded phase 5% phenylmethyl-siloxane; 0.25 mm i.d.; 30m length; 0.25 p.m film thickness; splitteron, ratio 1:100. Carrier gas: helium. Injector 250 [degrees]C, detector 280 [degrees]C. Column 50 [degrees]C, 2 min; 10 [degrees]C/min to 250 [degrees]C for 10 min. GC/MS: Agilent Technologies 6890N/5975 insert XL Mass Selective detector).
The identification of the volatile compounds was based on comparison of their retention indices (RIs), and mass spectra with those obtained from authentic samples and/or NIST/NBS, Wiley libraries and literature. The main components in both analyzed samples, LO1 and L02, were linalool (28.0% and 21.5%, respectively) and linalyl acetate (17% and 22.5%, respectively) followed by terpinen-4-ol (3.3% and 16.7%), lavandulyl acetate (8.3% and 8.4%, respectively). Interesting is that the presence of camphor and borneol was in trace amounts, which is inconsistent with literature data (Lis-Balchin 2002).
50 male Wistar rats weighing 250 [+ or -] 50 g at the start of the experiment were used. The animals were housed in a temperature and light-controlled room (22 [degrees]C, a 12h cycle starting at 08:00 h) and were fed and allowed to drink water ad libitum. The rats were divided into 5 groups (10 animals per group): (1) control group received saline treatment (0.9% NaCl); (2) scopolamine (Sco)-treated group received silexan, as positive control. Although silexan is currently the only pharmaceutical quality lavender oil preparation for oral use (Kasper et al. 2010), we administered silexan by inhalation as a reference compound for our lavender oils activities; (3) scopolamine (Sco) alone-treated group; (4) scopolamine-treated group received Lavandula angustifolia essential oil (L01 + Sco); and (5) scopolamine-treated group received Lavandula hybrida essential oil (L02 +Sco). Control and scopolamine alone-treated groups were caged in the same conditions but in the absence of the tested oils. Rats were treated in accordance with the guidelines of animal bioethics from the Act on Animal Experimentation and Animal Health and Welfare from Romania and all procedures were in compliance with the European Council Directive of 24 November 1986 (86/609/EEC). This study was approved by the local Ethic Committee (registration number 2032) and also, efforts were made to minimize animal suffering and to reduce the number of animal used.
The inhalation apparatus consisted of a Plexiglas chamber (50 cm x 40 cm x 28 cm). Two chambers were used, one to the control and scopolamine alone-treated animals, which were not exposed to any substance, and the other one to the experimental animals, which were exposed to silexan and lavender oils. Silexan and lavender oils were diluted with 1% Tween 80 (v/v). Silexan and lavender exposure (200 [micro]l) was via an electronic vaporizer placed at the bottom of chamber, but out of reach of the animals. Rats in the silexan and lavender groups were exposed to oil vapors for controlled 60 min period, daily, for 7 continuous days. 60 min is a suitable inhalation period for the expected effects (Linck et al. 2010). Chambers were always cleaned up (10% ethanol solution).
Scopolamine hydrobromide (Sigma, Germany) was dissolved in an isotonic solution (0.9% NaCl) and 0.7 mg/kg scopolamine was injected intraperitoneally (i.p.), daily, for 7 continuous days, 30 min after silexan and lavender exposition procedure.
Biochemical parameter assay
One week after the silexan and lavender exposure, all rats were anesthetized rapidly decapitated and whole brains were removed. The temporal lobes were collected. Each of brain tissue samples were weight and homogenized (1:10) with Potter Homogenizer coupled with Cole-Parmer Servodyne Mixer in ice-cold 0.1M potassium phosphate buffer (pH 7.4), 1.15% KCI. The homogenate was centrifuged (15 min at 3000 rpm) and the supernatant was used for assays of SOD, GPX, CAT activities, total content of reduced GSH and MDA level.
Determination of SOD
The activity of superoxide dismutase (SOD, EC 22.214.171.124) was assayed by monitoring its ability to inhibit the photochemical reduction of nitroblue tetrazolium (NBT). Each 1.5 ml reaction mixture contained 100 mM Tris/HCI (pH 7.8), 75 mM NBT, 2 [micro]M riboflavin, 6mM EDTA, and 200[micro]l of supernatant. Monitoring the increase in absorbance at 560 nm followed the production of blue formazan. One unit of SOD is defined as the quantity required to inhibit the rate of NBT reduction by 50% as described by Winterbourn et al. (1975). The enzyme activity is expressed as units/mg protein.
Determination of GPX
Glutathione peroxidase (GPX, E.C. 126.96.36.199) activity was analyzed by a spectrophotometric assay. A reaction mixture consisting oil ml of 0.4 M phosphate buffer (pH 7.0) containing 0.4 mM EDTA, 1 ml of 5 mM Na[N.sub.3], 1 ml of 4 mM GSH, and 0.2 ml of supernatant was pre-incubated at 37 [degrees]C for 5 min. Then 1 ml of 4 mM [H.sub.2][0.sub.2] was added and incubated at 37 [degrees]C for further 5 min. The excess amount of GSH was quantified by the DTNB method as described by Sharma and Gupta (2002). One unit of GPX is defined as the amount of enzyme required to oxidize 1 nmol GSH/min. The enzyme activity is expressed as units/mg protein.
Determination of CAT
Catalase (CAT, EC 188.8.131.52) activity was assayed following the method of Sinha (1972). The reaction mixture consisted of 150111 phosphate buffer (0.01 M, pH 7.0), 100 [micro]l supernatant. Reaction was started by adding 250 [micro]1 [H.sub.2][0.sub.2] 0.16 M. incubated at 37 [degrees]C for 1 min and reaction was stopped by addition of 1.0 ml of dichro-mate:acetic acid reagent. The tubes were immediately kept in a boiling water bath for 15 min and the green color developed during the reaction was read at 570 nm on a spectrophotometer. Control tubes, devoid of enzyme, were also processed in parallel. The enzyme activity is expressed as [micro]mol of [H.sub.2][O.sub.2] consumed/min/mg protein.
Total content of reduced GSH
Glutathione (GSH) was measured following the method of Fukuzawa and Tokumura (1976). 200 [micro]l of supernatant was added to 1.1 ml of 0.25 M sodium phosphate buffer (pH 7.4) followed by the addition of 130[micro] DTNB 0.04%. Finally, the mixture was brought to a Final volume of 1.5 nil with distilled water and absorbance was read in a spectrophotometer at 412 nm and results were expressed as lig GSH/[micro]g protein.
Determination of MDA
Malondialdehyde (MDA), which is an indicator of lipid peroxidation, was spectrophotometrically measured by using the thiobarbituric acid assay as described by Ohkawa et al. (1979). 200[micro]l of supernatant was added and briefly mixed with 1 ml of 50% thichloracetic acid in 0.1 M HCI and 1 ml of 26 mM thiobarbituric acid. After vortex mixing, samples were maintained at 95 [degrees]C for 20 min. Afterwards, samples were centrifuged at 3000 rpm for 10 min and supernatants were read at 532 nm. A calibration curve was constructed using MDA as standard and the results were expressed as nmol/mg protein.
Estimation of protein concentration
Estimation of protein was done using a BCA protein assay kit (Sigma, Germany).The BCA protein assay is a detergent-compatible formulation based on bicinchoninic acid (BCA) for the colorimetric detection and quantification of total protein, as described by Smith et al. (1985).
Total DNA was isolated from the temporal cortex samples using the phenol/chloroform method described by Ausubel et al. (2002). 50 mg brain tissue sample was digested overnight at 37 [degrees]C in 0.6 ml digestion buffer (100 mM NaCl, 10 mM Tris/HCl, 25 mM EDTA pH 8.00, 0.5% SDS) containing 0.1 mg/m1 proteinase K (Boehringer Mannheim, Germany). The digest was extracted with equal volumes of Tris-saturated phenol (pH 8.0) (Roti-phenol, Roth, Germany) by shaking gently to completely mix the two phases. The phases were then separated by centrifugation and the aqueous phase (approx. 0.6 ml) was transferred to another tube avoiding interphase. The DNA was then precipitated by adding 300 [micro]l of 7.5M ammonium acetate (i.e., 1/2 of volume) and equal volume of 100% ethanol at room temperature and shaken gently to mix thoroughly. DNA seen as stringy precipitate was pelleted by centrifugation and washed with 70% ethanol to remove traces of sodium dodecyl sulfate and phenol. After removing ethanol, DNA was air-dried for 10 min at room temperature and suspended with 50 [micro]l of 10 mM Tris (pH 8.0), 1 mM EDTA. DNA content was determined spectrophotometrically by absorbance at 260 nm and the purity of the DNA was confirmed by a ratio > 1.8 at 260/280 nm. Approx. 0.5 mg genomic DNA was dissolved in a mixture of 10 [micro]l of Tris-EDTA and 5 [micro]l of gel loading buffer (0.25% bromophenol blue, 0.25% xylene cyanol FF. 30% (v/v)glycerol ) and then loaded on a 1.5% agarose gel in Tris-boric acid-EDTA (TBE) buffer (89 mM Tris boric acid, 2 mM EDTA, pH 8.0). Electrophoresis was performed in TBE at 120V until sufficient resolution was obtained. A I kb DNA tackler (New England Biolabs, Ipswich, MA) was used as a standard size marker. The bands were visualized by ethidium bromide staining under UV light.
All results are expressed as mean [+ or -] standard error (S.E.M.). Statistical analyses were performed using one-way analysis of variance (ANOVA). Significant differences were determined by Tukey's post hoc test. F values for which p <0.05 were regarded as statistically significant. Pearson's correlation coefficient and regression analysis were used to evaluate the connection between the antioxidant defence and lipid peroxidation.
Effect of lavender essential oils on SOD, GPX and CAT activities
Biochemical analyses showed a significant increase of the main enzymatic antioxidant defences (SOD, GPX and CAT) estimated in the temporal lobe homogenates of scopolamine-treated groups exposed to LO1 and L02. suggesting that these essential oils possess strong antioxidant proprieties.
Fig. 1A shows a significant increase of the SOD specific activity (F(4,45)= 54.75, p < 0.0001) in scopolamine-treated groups received LO1 and L02 compared to that of the scopolamine-treated group. Additionally, post hoc analyses revealed statistically significant differences between Sco and silexan + Sco groups (p = 0.0001), Sco and LO1 + Sco groups (p = 0.0001). Sco and L02 + Sco groups (p = 0.0001) and silexan + Sco and LO1 + Sco groups (p = 0.04) and no statistically significant differences between silexan + Sco and L02 +Sco groups (p = 0.095) and LO1 + Sco and L02 + Sco groups (p= 0.979) for SOD activity (Fig. 1A).
[FIGURE 1 OMITTED]
We also observed a significant increase of the GPX specific activity (F(4,45) = 66.12, p <0.0001) (Fig. 1B) in scopolamine-treated groups received LO1 and L02 compared to that of the scopolamine-treated group. Also, post hoc analyses revealed statistically significant differences between Sco and silexan + Sco groups (p = 0.0001), Sco and LO1 + Sco groups (p = 0.0001), Sco and L02 + Sco groups (p= 0.0001), silexan + Sco and LO1 + Sco groups (p= 0.0001) and LO1 + Sco and L02 + Sco groups (p = 0.01) and no statistically significant differences between silexan + Sco and L02 + Sco groups (p = 0.07) for GPX activity (Fig. 1B).
In addition, a significant increase of the CAT specific activity (F(4,45)= 24.67, p < 0.0001) (Fig. 1C) in scopolamine-treated groups received LO1 and L02 compared to that of the scopolamine-treated group. Also, post hoc analyses revealed statistically significant differences between Sco and silexan + Sco groups (p= 0.0001), Sco and LO1 + Sco groups (p 0.0001), Sco and L02 + Sco groups (p = 0.0001), silexan +Sco and LO1 +Sco groups (p=0.004), silexan + Sco and L02 + Sco groups (p = 0.0001) and LO1 +Sco and L02 + Sco groups (p = 0.0001) for CAT activity (Fig. 1C).
Effect of lavender essential oils on MDA level and total content of reduced GSH
Rats in the lavender groups exhibited attenuation in lipid peroxidation, indicated by a significant decrease of MDA level (F(4,45)=35.93, p < 0.00001) (Fig. 2A) estimated in temporal lobe homogenates compared to that in the scopolamine-treated group. Also, post hoc analyses revealed statistically significant differences between Sco and silexan + Sco groups (p = 0.0001), Sco and LO1 + Sco groups (p = 0.0001), Sco and L02 + Sco groups (p = 0.0001), silexan + Sco and LO1 + Sco groups (p = 0.002) and no statistically significant differences between silexan + Sco and L02 + Sco groups (p = 0.067) and LO1 + Sco and LO2 + Sco groups (p = 0.175) for MDA level (Fig. 2A). Furthermore, a significant increase of total content of reduced GSH (F(4,45) = 47.25, p <0.00001) (Fig. 2B) estimated in temporal lobe homogenates of the lavender groups compared to that in the scopolamine-treated group, was observed. Additionally, post hoc analyses revealed statistically significant differences between Sco and silexan + Sco groups (p= 0.0001), Sco and LO1 + Sco groups (p = 0.0001), Sco and L02 + Sco groups (p= 0.0001), silexan + Sco and L02 + Sco groups (p = 0.01) and LO1 + Sco and L02 + Sco groups (p = 0.02) and no statistically significant differences between silexan + Sco and L01 + Sco groups (p = 0.932) for the total content of reduced GSH (Fig. 2B).
[FIGURE 2 OMITTED]
These results support the hypothesis that the lavender essential oils may have induce a decrease in neuronal oxidative stress.
More importantly, a significant positive correlation was evidenced by determination of the linear regression between SOD vs. MDA (n = 50, r = 0.819, p = 0.0001) (Fig. 3A), GPX vs. MDA (n = 50, r = 0.726, p = 0.0001) (Fig. 3B) and CAT vs. MDA (n = 50, r = 0.716, p = 0.0001) (Fig. 3C) in LO1 + Sco and L02 + Sco groups.
[FIGURE 3 OMITTED]
Effect of lavender essential oils on DNA fragmentation
In our study, DNA cleavage patterns were absent in the lavender groups (Fig. 4), suggesting that the lavender essential oils protect against neurotoxicity and this effect could be related to their antioxidant activities.
[FIGURE 4 OMITTED]
Many clinical studies have reported strong evidence that oxidative stress is involved in the pathogenesis of AD (Jeong et al. 2008; Marcus et al. 1998; Sano et al. 1997). The oxygen-free radicals are implicated in the process of age related decline in the cognitive performance may be responsible for the development of AD in elderly persons (Nade et al. 2011). It has been reported that memory impairment in the scopolamine-induced animal model of dementia is associated with the increased oxidative stress within rat brain (El-Sherbiny et al. 2003). Recently, we reported that inhalation of lavender essential oils improved spatial memory deficits in the scopolamine-induced animal model of dementia (Hritcu et al. 2012). Moreover, these in vivo observations suggested that lavender oils could exert protective effects against oxidative and free radical injuries occurring in dementia conditions induced by scopolamine administration (Hritcu et al. 2012).
Antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) are involved in the reduction of oxidative stress. Antioxidant enzymes display the reduced activities in the affected brain region of patients of AD. Furthermore, reduction in the level of intracellular oxidized protein under these conditions has been associated with the improvement of cognitive and/or psychomotor functions (El-Sherbiny etal. 2003).
The current hypothesis about the mechanisms by which neurons come into necrotic or apoptotic processes has led to believe that the therapeutic use of antioxidants may be beneficial in aging and neurodegenerative disorders (Di Matteo and Esposito 2003; McGhie et al. 2007; Zhou et al. 2008). These agents reduce the oxidative damage and promote a functional recovery in degenerative disorders.
The GC-MS analysis determined the main volatile component of our LO1 and L02 samples to be linalool (28.0% and 21.5%, respectively), so this is probably the responsible constituent for the observed antioxidant effects.
Scopolamine-treated rats exhibited a decrease of total (reduced) GSH level, SOD, GPX and CAT specific activities and elevated MDA level. Increased MDA level have been shown to be an important marker for in vivo lipid peroxidation. Oxidative stress results from a marked imbalance between free radical production and elimination by antioxidant system. Furthermore, both lavender oils (L01 and L02) restored the activity of SOD with the same efficiency in scopolamine-treated rats. Moreover, both lavender oils, but especially L02, significantly increased GPX and CAT specific activities in the temporal lobe homogenates. As expected for antioxidant agents, LO1 and L02, but especially L02. decreased MDA level and increased the content of reduced GSH in the temporal lobe homogenates. Such regulation of oxidative stress markers by the lavender oil may be well correlated with previous reports, where lavender oils have antioxidant and neuroprotective properties which may probably be due to their free radical scavenging ability (Atsumi and Tonosaki 2007; Miguel 2010).
The present findings support the hypothesis that increased SOD activity can lead to decreased production of intracellular of 1-1202 with a simultaneous increase of GPX, CAT activities and GSH level. This could decrease the stimulation of lipid peroxidation and protein oxidation, implying that lavender oil possesses strong antioxidant property. Furthermore, the present study demonstrates that increased activity of the antioxidant enzymes in scopolamine groups exposed to lavender oils is significantly correlated to a decrease of lipid peroxidation (MDA), in the temporal cortex, the most vulnerable cortical area to oxidative stress effects (Karelson et al. 2001). Moreover, we found a significant positive correlation between SOD vs. MDA, GPX vs. MDA and CAT vs. MDA, when linear regression was determined. This could suggest that the increase of the antioxidant defence and decrease of lipid peroxidation could be correlated with the involvement of lavender oils in neuroprotection against scopolamine-induced neuronal oxidative stress generation.
Finally, we reported that DNA cleavage patterns is absent in the scopolamine treated-rats exposed to lavender oils (LW and L02), suggesting that lavender oils possess antiapoptotic and neuroprotective activity.
In summary, the present study indicated that multiple exposures to lavender oils could effectively restore antioxidant brain status and may confer neuroprotection due to alleviation of oxidative damage induced by scopolamine. Moreover, lavender oil inhalation might offer a useful therapeutic choice in either the prevention or the treatment of dementia conditions.
Lucian Hritcu was supported by CNCSIS-UEFISCSU, project number 1073/2009, PNII-IDEI code 85/2008, Romania. The authors declare that they have no potential conflicts of interest to disclose.
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" Corresponding author. Tel.: +40 232201666; fax: +40 232201472. E-mail address: email@example.com (L. Hritcu).
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(1.) Silexan is the active substance of LASEA[R] (W.Spitzner Arzneimittelfabrik GmbH, Ettlingen, Germany).
Monica Hancianu (b), Oana Cioanca (b), Marius Mihasan (a), Lucian Hritcu (a)
(a.) Department of Biology. Alexandra loan Caw University, Bd. Carol I. No. 11, Iasi 700506, Romania
(b.) Faculty of Pharmacy. University of Medicine and Pharmacy "Cr. T. Popa", 16 University Str., Iasi 700117, Romania
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|Author:||Hancianu, Monica; Cioanca, Oana; Mihasan, Marius; Hritcu, Lucian|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||May 15, 2013|
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