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Background: Plants of the genus Markhamia have been traditionally used by different tribes in various parts of West African countries, including Cameroun. Markhamia tomentosa (Benth.) K. Schum. (Bignoniaceae) is used as an antimalarial, anti-inflammatory, analgesic, antioxidant and anti-Alzheimer agent. The current study was undertaken in order to investigate its anti-amnesic and antioxidant potential on scopolamine-induced cognitive impairment and to determine its possible mechanism of action. Methods: Rats were pretreated with the aqueous extract (50 and 200 mg/kg, p.o.), for 10 days, and received a single injection of scopolamine (0.7 mg/kg, i.p.) before training in Y-maze and radial arm-maze tests. The biochemical param- eters in the rat hippocampus were also assessed to explore oxidative status. Statistical analyses were performed using two-way ANOVA followed by Tukey’s post hoc test. F values for which p < 0.05 were regarded as statistically significant. Results: In the scopolamine-treated rats, the aqueous extract improved memory in behavioral tests and decreased the oxidative stress in the rat hippocampus. Also, the aqueous extract exhibited anti-acetylcholinesterase activity. Conclusions: These results suggest that the aqueous extract ameliorates scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus. Keywords: Markhamia tomentosa stem bark extract, Scopolamine, Spatial memory, Oxidative stress, Acetylcholinesterase, Alzheimer’s disease Background The biochemical hallmarks of AD include the accu- Alzheimer’s disease (AD) is considered to be the most mulation of the amyloid-beta (Aβ) peptide oligom- common form of dementia relating to memory and cog- ers and soluble hyperphosphorylated tau proteins . nitive decline. AD is a progressive neurodegenerative AD is also accompanied by the loss of the choliner- disorder in which dementia symptoms gradually worsen gic markers in vulnerable neurons and the degenera- over a number of years . tion of basal forebrain cortical cholinergic neurons in end–stage AD patients . The memory loss and cog- nitive impairments are strongly related to changes in *Correspondence: email@example.com; firstname.lastname@example.org; email@example.com the acetylcholinesterase (AChE) activity . Moreover, Department of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol AChE can increase the rate of fibrillation by binding I, No. 11, 700506 Iasi, Romania 3 amyloid-β-associated proteins as potent amyloid-pro- Department of Biological Sciences, Faculty of Science, University of Maroua, PO Box, 814, Maroua, Cameroon moting factors . Thus, the cholinergic hypothesis Department of Chemistry, Alexandru Ioan Cuza University of Iasi, Bd. led to the development of clinically effective therapeu- Carol I, No. 11, 700506 Iasi, Romania tics for AD . Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ionita et al. Behav Brain Funct (2017) 13:5 Page 2 of 13 Scopolamine, a muscarinic acetylcholine receptor terpenoids, phytosterols, lignans, and flavonoids. Ver - (MAChR) antagonist, can block the cholinergic function bascoside, one of the main active phenylpropanoid of the central nervous system by targeting M1AChR and glycoside from M. tomentosa leaves, was reported to M2AChR. It has been reported that scopolamine can reverse memory impairment induced by a combination induce anterograde memory impairment, particularly of D-gal and AlCl in a senescent mouse model . short-term memory and learning acquisition . More- Isoverbascoside, another phenylpropanoid glycoside over, scopolamine can significantly increase the activity from M. tomentosa leaves, ameliorated cognitive deficits of AChE and malondialdehyde (MDA) levels in the cor- in AD-like rat model induced by administration of Aβ1– tex and hippocampus, and oxidative stress in the brain 42 through blocking of amyloid deposition, reversing [8, 9]. cholinergic and hippocampal dopaminergic neuronal Oxidative stress is an important factor in the patho- function . Oleanolic acid, a triterpene identified in physiology of neurodegenerative disorders, including the stem bark of M. tomentosa, exhibited neuroprotec- AD . Oxidative damage triggers the pathogenesis and tive effects and improved Aβ-induced memory deficits cognitive disturbances in AD . AD is highly related to in mice [21, 22]. Palmitone, a lignin isolated from the cholinergic deficits and intracellular oxidative stress. Sco - stem heartwood of M. tomentosa, exhibited neuropro- polamine-induced AD model is a valuable animal model tective effects and prevents pentylenetetrazole-induced for screening anti-AD drugs . neuronal damage in the CA3 hippocampal region Markhamia tomentosa (Benth.) K. Schum. commonly of the prepuberal Wistar rats . Lapachol and its known in west Cameroon as “bobedu, abbe or mawelu” furano derivatives, a quinone isolated from the stem is a shrub or tree that belongs to the family Bignoniaceae bark of M. tomentosa, displayed significant anxiolytic . Previously, we demonstrated that the methanolic and antidepressant effects in mice . Finally, luteo - extract of M. tomentosa leaves (50, 100 and 200 mg/kg) lin, a flavonoid identified from the M. tomentosa leaves, possess in vivo analgesic and anti-inflammatory effects in ameliorated memory impairment in streptozotocin- healthy rats and mice as claimed by the traditional prac- induced AD rat model . Although the identified titioners . In addition, we suggested that anti-inflam - compounds from M. tomentosa had significant activity matory and analgesic effects of the methanolic extract are in AD, there is no study clarifying the possible cogni- attributed to the inhibition of serotonin, histamine, pros- tive-enhancing and antioxidant potentials of the aque- taglandin and morphinomimetic action. ous extract from M. tomentosa stem bark in a rat model The root bark of M. tomentosa has been in vitro of scopolamine. Therefore, we investigated the possible screened for AChE and butyrylcholinesterase inhibitory memory-enhancing effects of the aqueous extract from activity [14, 15]. The authors suggested that this plant M. tomentosa stem bark in memory-impaired rats and could be considered for further studies in the manage- its possible mechanism on the levels of biochemical ment of early stages of AD. Moreover, ethanolic extract parameters in the rat hippocampus of the scopolamine of M. tomentosa leaves (50, 100 and 150 mg/kg) was model. reported to prevent gastric mucosal ulceration in stom- achs of the Wistar rats supported a scientific base for Methods the traditional use of this plant . Ibrahim et al.  Plant collection and extraction demonstrated that the leaf extract of M. tomentosa has Markhamia tomentosa (Benth.) K. Schum. (Bigno- shown antiproliferative and apoptosis profile on the niaceae) stem bark was collected from Yaoundé, Cam- HeLa cells, but not in the MCF-7 breast cancer cell line eroon in June 2010. Identification and authentication of and normal Vero cell line. Furthermore, the methanolic the plant material were done at the National Herbarium, extract of M. tomentosa possesses in vitro high antioxi- Yaoundé, Cameroon where a voucher specimen (Nº1974/ dant activity as evidenced by DPPH TLC screening . SRFK) was registered and deposited for ready reference. In this study, the results of DPPH assay at 33.33 µg/mL Air-dried stem bark of M. tomentosa was reduced to fine indicated maximum antioxidant activity at 80%. The powder (1000 g) and macerated in 10 L of distilled water aforementioned results indicated that the extract of M. for 48 h at room temperature and then the mixture was tomentosa could be a source of natural antioxidants use- filtered through Whatman filter paper no. 3. The aque - ful for preventing oxidative stress damage with relevance ous extract was then lyophilized to obtain powder used AD condition. for our various tests. Percentage yield (w/w) of 3.70% Recently, Ibrahim et al.  reported in a review was obtained. The dried extract was dissolved in distilled that the main phytochemical identified constituents of water and administered by gastric gavage to animals at Markhamia species were phenylpropanoid glycosides, the doses of 50 and 200 mg/kg body weight. Ionita et al. Behav Brain Funct (2017) 13:5 Page 3 of 13 HPLC–DAD analysis PA). The volume administered was 10 mL/kg of body HPLC analysis of the aqueous extract from M. tomentosa weight, daily, for 10 consecutive days. Moreover, animals stem bark was performed using a Thermo UltiMate3000 received extract treatment during training in the Y-maze gradient chromatograph equipped with quaternary and the radial arm-maze tasks. The aqueous extract doses pumps controlled by Chromeleon interface, an autosam- (50 and 200 mg/kg) used in this experiment were chosen pler and multidiode array detector (DAD). Solvents were since they have been demonstrated by our group to pro- filtered using a Millipore system and analysis was per - vide significant analgesic and anti-inflammatory effects formed on an Accucore XL C18 column (150 × 4.6 mm, as claimed by traditional healers . Scopolamine hyd- 4 µm). All the samples were filtered through 0.22 µm robromide (Sigma-Aldrich, Germany) was dissolved in filter before being analyzed. The mobile phase was ace - an isotonic solution (0.9% NaCl) and 0.7 mg/kg scopola- tonitrile (A) and water containing 0.1% acetic acid (B) mine was injected intraperitoneally (i.p.), 30 min before and the composition gradient was: 10–23% (A) in 5 min; the behavioral testing in the Y-maze and radial arm-maze 23% (A) isocratic for 10 min and then 23–35% (A) in tasks. Rats were treated in accordance with the guidelines 12 min; 35–70% (A) for 5 min. The injection volume of animal bioethics from the act on animal experimenta- was 20 µL scanning absorbance wavelengths from 240 tion and animal health and welfare from Romania and all to 520 nm, typical for phenols including flavonols, fla - procedures were in compliance with Directive 2010/63/ vones, hydroxycinnamic acids, and anthocyanins. The EU of the European Parliament and of the Council of 22 flow rate increased from 0.2 to 1 mL/min. HPLC grade September 2010 on the protection of animals used for solvents and bidistilled water were used in the chroma- scientific purposes. tographic studies. All chromatographic experiments were performed at 25 °C. Standard curves for authentic sam- Y‑maze task ples of the polyphenols were obtained from purchased Short-term memory was assessed by spontaneous alter- reagents (Sigma Chemical Co., USA) of analytical or nation behavior in the Y-maze task. The Y-maze used in high-performance liquid chromatography (HPLC) grade. the present study consisted of three arms (35 cm long, Each solution was injected in triplicate and the calibra- 25 cm high and 10 cm wide) and an equilateral triangu- tion curves were constructed with the averages. A stock lar central area. 30 min after the aqueous extract from M. solution of the investigated samples was obtained by dis- tomentosa stem bark administration, rats were placed at solving 1.915 mg of dry extract in 1 mL of HPLC grade the end of one arm and allowed to move freely through methanol. Different amounts (1–20 µL) were injected by the maze for 8 min. An arm entry was counted when the the autosampler. The final results represent the mean of hind paws of the rat were completely within the arm. three to five measurements. Spontaneous alternation behavior was defined as entry into all three arms on consecutive choices. The number Animals of maximum spontaneous alternation behaviors was then Twenty male Wistar rats weighing 350 ± 10 g the total number of arms entered minus two and per- (4–5-month-old) at the start of the experiment were cent spontaneous alternation was calculated as (actual used. The animals were housed in a temperature and alternations/maximum alternations) × 100. The maze light-controlled room (22 °C, a 12-h cycle starting at was cleaned with a 10% ethanol solution and dried with 08:00 h) and were fed and allowed to drink water ad libi- a cloth before the next animal was tested. Spontaneous tum. The experiments were conducted in the quiet labo - alternation behavior is considered to reflect spatial work - ratory between hours of 10:00–16:00 h. The rats were ing memory, which is a form of short-term memory [26, divided into four groups (five animals per group): (1) 27]. the control group received the distilled water treatment; (2) the scopolamine (Sco)-alone-treated group received Radial arm‑maze task the distilled water treatment, as negative control; (3) The radial arm-maze used in the present study con - the scopolamine-treated group received 50 mg/kg of sisted of eight arms, numbered from 1 to 8 (48 × 12 cm), the aqueous extract from M. tomentosa stem bark treat- extending radially from a central area (32 cm in diame- ment [Sco+ME (50 mg/kg)]; (4) the scopolamine-treated ter). The apparatus was placed 40 cm above the floor and group received 200 mg/kg of the aqueous extract from surrounded by various extra-maze visual cues placed at M. tomentosa stem bark treatment [Sco+ME (200 mg/ the same position during the study. At the end of each kg)]. The aqueous extract from M. tomentosa stem bark arm, there was a food cup that had a single 50 mg food was dissolved in distilled water. The administration of the pellet. Prior to the performance of the maze task, the distilled water and the aqueous extract was performed by animals were kept on restricted diet and body weight 15-gauge oral gavage needle (Instech, Plymouth Meeting, was maintained at 85% of their free-feeding weight over Ionita et al. Behav Brain Funct (2017) 13:5 Page 4 of 13 a week period, with water being available ad libitum. volume) contained 0.26 M phosphate buffer with pH 7.4, Before the actual training began, three or four rats were 1 mM 5,5′-dithio-bis-2-nitrobenzoic acid (DTNB) and simultaneously placed in the radial maze and allowed 5 mM ATC chloride. The assay was started by adding to explore for 5 min and take food freely. The food was supernatant and following the developing of the yellow initially available throughout the maze but was gradu- color at 412 nm for 10 min at room temperature. Suitable ally restricted to the food cup. The animals were trained controls were performed for the non-enzymatic hydroly- for 4 days to run to the end of the arms and consume the sis of ATC. The enzyme activity is expressed as nmol of bait. To evaluate the basal activity of rats in radial eight ACT/min per/mg of protein. arm-maze, the rats were given one training trial per day to run to the end of the arms and consume the bait. The Determination of hippocampal SOD activity training trial continued until all the five baits had been The activity of superoxide dismutase (SOD, EC 188.8.131.52) consumed or until 5 min has elapsed. After adaptation, was assayed by monitoring its ability to inhibit the pho- all rats were trained with one trial per day. Briefly, 30 min tochemical reduction of nitroblue tetrazolium (NBT). after the aqueous extract from M. tomentosa stem bark Each 1.5 mL reaction mixture contained 100 mM TRIS/ administration, each animal was placed individually in HCl (pH 7.8), 75 mM NBT, 2 μM riboflavin, 6 mM EDTA the center of the maze and subjected to working and ref- and 200 μL of supernatant. Monitoring the increase in erence memory tasks, in which same 5 arms (no. 1, 2, 4, 5 absorbance at 560 nm followed the production of blue and 7), were baited for each daily training trial. The other formazan. One unit of SOD is defined as the quantity 3 arms (no. 3, 6 and 8) were never baited. An arm entry required to inhibit the rate of NBT reduction by 50% as was counted when all four limbs of the rat were within previously described by Winterbourn et al. [32, 33]. The an arm. Measures were made of the number of working enzyme activity is expressed as units/mg protein. memory errors (entering an arm containing food, but previously entered), reference memory errors (entering Determination of hippocampal GPX activity an arm that was not baited). The maze was cleaned with Glutathione peroxidase (GPX, E.C. 184.108.40.206) activity was a 10% ethanol solution and dried with a cloth before the analyzed by a spectrophotometric assay. A reaction mix- next animal was tested. Reference memory is regarded ture consisting of 1 mL of 0.4 M phosphate buffer (pH as a long-term memory for information that remains 7.0) containing 0.4 mM EDTA, 1 mL of 5 mM NaN , constant over repeated trials (memory for the positions 1 mL of 4 mM glutathione (GSH), and 200 μL of super- of baited arms), whereas working memory is considered natant was pre-incubated at 37 °C for 5 min. Then 1 mL a short-time memory in which the information to be of 4 mM H O was added and incubated at 37 °C for fur- 2 2 remembered changes in every trial (memory for the posi- ther 5 min. The excess amount of GSH was quantified by tions of arms that had already been visited in each trial) the 5,5′-dithiobis-2-nitrobenzoic acid (DTNB) method as [26, 28]. previously described by Sharma and Gupta [34, 35]. One unit of GPX is defined as the amount of enzyme required Biochemical parameter assay to oxidize 1 nmol GSH/min. The enzyme activity is After the behavioral tests, all rats were deeply anesthe- expressed as units/mg protein. tized (using sodium pentobarbital, 100 mg/kg b.w., i.p., Sigma-Aldrich, Germany), decapitated and whole brains Total hippocampal content of reduced GSH were removed. The hippocampi were carefully excised. Glutathione (GSH) was measured following the method Each of the hippocampal samples was weighed and of Fukuzawa and Tokumura [36, 37]. 200 µL of superna- homogenized (1:10) with Potter Homogenizer coupled tant was added to 1.1 mL of 0.25 M sodium phosphate with Cole-Parmer Servodyne Mixer in ice-cold 0.1 M buffer (pH 7.4) followed by the addition of 130 µL DTNB potassium phosphate buffer (pH 7.4), 1.15% KCl. The 0.04%. Finally, the mixture was brought to a final vol - homogenate was centrifuged (15 min at 960×g) and the ume of 1.5 mL with distilled water and absorbance was supernatant was used for assays of AChE, SOD, and GPX read in a spectrophotometer at 412 nm and results were specific activities, the total content of reduced GSH, pro - expressed as µg GSH/µg protein. tein carbonyl, and MDA levels. Determination of hippocampal protein carbonyl level Determination of hippocampal AChE activity The extent of protein oxidation in the hippocampus was The activity of acetylcholinesterase (AChE) in the rat hip - assessed by measuring the content of protein carbonyl pocampus was determined according to the method of groups, using 2,4-dinitrophenylhydrazine (DNPH) deri- Ellman et al.  using acetylthiocholine (ATC) as artifi - vatization as described by Oliver et al.  and follow- cial substrate [30, 31]. The reaction mixture (600 µL final ing the indications of Luo and Wehr [39, 40]. Basically, Ionita et al. Behav Brain Funct (2017) 13:5 Page 5 of 13 the supernatant fraction was divided into two equal ali- between-subject factor and days (1–7) as within-subjects quots containing approximately 2 mg of protein each. factors. All results are expressed as a mean ± standard Both aliquots were precipitated with 10% trichloro- error of the mean (SEM). F values for which p < 0.05 were acetic acid (TCA, w/v, final concentration). One sample regarded as statistically significant. Pearson’s correlation was treated with 2 N HCl, and the another sample was coefficient and regression analysis were used in order to treated with an equal volume of 0.2% (w/v) DNPH in 2 N evaluate the connection between behavioral measures, HCl. Both samples were incubated at 25 °C and stirred the antioxidant defense, and lipid peroxidation. at 5 min intervals. The samples were then reprecipitated with 10% TCA (final concentration) and subsequently Results extracted with ethanol–ethyl acetate (1:1, v/v) and then Phytochemical screening reprecipitated at 10% TCA. The pellets were carefully A stock solution of the investigated samples was obtained drained and dissolved in 6 M guanidine hydrochloride by dissolving 1.915 mg of dry extract in 1 mL of HPLC with 20 mM sodium phosphate buffer, pH 6.5. Insolu - grade methanol. Different amounts (1–20 µL) were ble debris was removed by centrifugation at 13,000×g injected by the autosampler. The final results represent at 4 °C. The absorbance at 370 nm of the DNPH-treated the mean of 3–5 measurements. sample vs. the HCl control was recorded, and the results Regarding M. tomentosa stem bark there are no stud- are expressed as nmols of DNPH incorporated/mg of ies available in regards to the chemical composition of protein based on an average absorptivity of 21/mM cm this vegetal product. Although some researchers have for most aliphatic hydrazones. evaluated the biologic properties of M. tomentosa leaves extracts, there is no data confirming the presence of spe - Determination of MDA level cific compounds, but rather major groups of substances. Malondialdehyde (MDA), which is an indicator of lipid u Th s, from the 14 standards used, we were able to iden - peroxidation, was spectrophotometrically measured tify and quantify catechin, epicatechin, rosmarinic acid by using the thiobarbituric acid assay as previously and several catechin/epicatechin derivatives (without described by Ohkawa et al. [41, 42]. 200 μL of super- being able to specify which) as indicated in the chroma- natant was added and briefly mixed with 1 mL of 50% togram below (Fig. 1). trichloroacetic acid in 0.1 M HCl and 1 mL of 26 mM The amounts detected/mg of dry extract were: thiobarbituric acid. After vortex mixing, samples were 541.5 µg/mg rozmarinic acid; 11.37 µg/mg (+)-catechin; maintained at 95 °C for 20 min. Afterward, samples were 15.86 µg/mg procyanidin dimer; 42.47 µg/mg (−)-epicat- centrifuged at 960×g for 10 min and supernatants were echin and 14.65 µg/mg cyanidin trimmers. Such chemi- read at 532 nm. A calibration curve was constructed cal composition is related to strong antioxidant and using MDA as standard and the results were expressed as radical chelating activities, as many researchers state the nmol/mg protein. importance of catechin derivatives in protective mecha- nisms . Estimation of protein concentration Estimation of protein was done using a bicinchoninic Eec ff t of the aqueous extract from Markhamia tomentosa acid (BCA) protein assay kit (Sigma-Aldrich, Germany). stem bark on behavioral performance The BCA protein assay is a detergent-compatible formu - In the Y-maze test, significant overall differences between lation based on BCA for the colorimetric detection and groups (F(3, 16) = 3.68, p < 0.01) on the spontaneous quantification of total protein, as previously described by alternation percentage were evidenced (Fig. 2a). The Smith et al. [43, 44]. results suggest that scopolamine treatment decreased the spontaneous alternation percentage (p < 0.01) as com- Statistical analysis pared to control group. The scopolamine treated rats Behavioral scores within Y-maze and radial arm-maze with both doses of studied extract, but especially the dose tasks and biochemical data were analyzed by two-way of 200 mg/kg, displayed significant differences (p < 0.001) analysis of variance (ANOVA) followed by Tukey post for spontaneous alternations percentage as compared to hoc test using GraphPad Prism 6 software for Win- scopolamine-alone treated group. dows, La Jolla California USA. In order to evaluate dif- In the radial arm-maze task, significant overall differ - ferences between groups in the radial arm-maze task, ences between groups (F(3,16) = 43.64, p < 0.0001) on separate repeated-measures ANOVA were calculated the working memory were evidenced (Fig. 2b). Scopola- on the number of working memory errors and the num- mine significantly increased (p < 0.0001) the working ber of reference memory errors with group [Control, memory errors as compared to control group. The sco - Sco, Sco+ME (50 mg/kg) and Sco+ME (200 mg/kg)] as polamine treated rats with both doses of the aqueous Ionita et al. Behav Brain Funct (2017) 13:5 Page 6 of 13 Fig. 1 HPLC chromatogram the aqueous extract from Markhamia tomentosa stem bark. The major identified compounds were rozmarinic acid, (+)-catechin, procyanidin dimer, (−)-epicatechin and cyanidin trimmers extract showed a decreased (p < 0.0001) working memory group, while administration of the studied extract, in errors as compared to scopolamine-alone treated group. a dose of 50 mg/kg (p < 0.01), but especially at the dose Moreover, repeated-measures ANOVA revealed a signifi - of 200 mg/kg, decreased the AChE specific activity cant group difference (F(3,252) = 34.62, p < 0.0001) for (p < 0.001) as compared to the scopolamine-alone treated the working memory errors. Additionally, Tukey’s post group. hoc analysis revealed a significant difference between group vs. working memory errors (p < 0.0001). Eec ff t of the aqueous extract from Markhamia tomentosa ANOVA revealed significant overall differences stem bark on the SOD and GPX activities between groups (F(3,16) = 17.78, p < 0.0001) on the For the SOD specific activity estimated in the rat hip - reference memory (Fig. 2c). Scopolamine significantly pocampal homogenates, significant overall differ - increased (p < 0.01) the reference memory errors as ences between groups (F(3,16) = 34.41, p < 0.0001) compared to control group. Rats in the scopolamine were noticed (Fig. 3b). While scopolamine treatment group pretreated with the extract showed a decreased decreased SOD specific activity (p < 0.0001) as com - (p < 0.0001) reference memory errors especially at the pared to control group, the administration of the aque- dose of 200 mg/kg as compared to scopolamine-alone ous extract in a dose of 50 mg/kg, significantly reverse treated group. Moreover, repeated-measures ANOVA the SOD activity (p < 0.001), but especially at the dose revealed a significant group difference (F(3,252) = 3.31, of 200 mg/kg (p < 0.0001), as compared to scopolamine- p < 0.01) for the reference memory errors. Addition- alone treated group. ally, Tukey’s post hoc analysis revealed a significant In the rat hippocampal homogenates, significant difference between group vs. reference memory errors overall differences between groups (F(3, 16) = 75.15, (p < 0.0001). p < 0.0001) were evidenced for the GPX specific activity (Fig. 3c). Scopolamine group displayed markedly decline Eec ff t of the aqueous extract from Markhamia tomentosa for the GPX specific activity (p < 0.0001) compared stem bark on the AChE activity with control group. In addition, the results revealed For the AChE specific activity estimated in the rat hip - that administration of the aqueous extract in a dose of pocampal homogenates, significant overall differences 50 mg/kg (p < 0.01), but especially at the dose of 200 mg/ between groups (F(3,16) = 9.00, p < 0.001) were evi- kg (p < 0.001) could effectively reverse the GPX specific denced (Fig. 3a). Scopolamine treatment increases the activity in scopolamine-induce decreasing of the GPX AChE specific activity (p < 0.01) as compared to control specific activity. Ionita et al. Behav Brain Funct (2017) 13:5 Page 7 of 13 group. Treatment with both doses of 50 mg/kg (p < 0.01) and 200 mg/kg (p < 0.001) of the aqueous extract to sco- polamine administered rats significantly increased GSH content over normal levels. For the protein carbonyl level measured in the rat hip- pocampal homogenates, significant overall differences between groups (F(3, 16) = 37.84, p < 0.0001) were revealed (Fig. 3e). Protein carbonyl level showed a signifi - cant increase (p < 0.0001) as compared to control group. Treatment of the aqueous extract, either with 50 mg/kg (p < 0.0001) and 200 mg/kg (p < 0.00001) to scopolamine administered rats significantly reduced protein carbonyl level close to normal levels. For the lipid peroxidation (MDA) level measured in the rat hippocampal homogenates, significant overall dif - ferences between groups (F(3, 16) = 62.99, p < 0.0001) were evidenced (Fig. 3f ). Administration of scopolamine resulted in increasing of the MDA level (p < 0.0001) as compared to control group. The results also revealed that in the scopolamine treated group, administration of the aqueous extract, at the doses of 50 mg/kg (p < 0.0001) and 200 mg/kg (p < 0.00001), markedly decreased MDA level under normal levels. Importantly, when linear regression was determined, significant correlations between the spontaneous alterna - tion percentage vs. AChE (n = 20, r = −0.657, p < 0.01) (Fig. 4a), spontaneous alternation percentage vs. MDA (n = 20, r = −0.664, p < 0.01) (Fig. 4b), working memory errors vs. AChE (n = 20, r = 0.856, p < 0.0001) (Fig. 4c), working memory errors vs. MDA (n = 20, r = 0.969, p < 0.001) (Fig. 4d), reference memory errors vs. AChE (n = 20, r = 0.826, p < 0.001) (Fig. 4e) and reference Fig. 2 Eec ff ts of the aqueous extract from Markhamia tomentosa memory errors vs. MDA (n = 20, r = 0.966, p < 0.0001) stem bark (50 and 200 mg/kg) in the Y-maze on spontaneous (Fig. 4f ) were evidenced. alternation % (a) and on the working memory errors (b) and the Additionally, a significant correlation was evidenced by reference memory errors (c) during 7 days training in radial arm-maze determination of the linear regression between SOD vs. task in the scopolamine-treated rats. Values are mean ± SEM (n = 5 ## MDA (n = 20, r = −0.953, p < 0.0001) (Fig. 5a), GSH vs. animals per group). For Tukey’s post hoc analysis— Control vs. # ## Sco: p < 0.001, Sco vs. Sco+ME (50 mg/kg): p < 0.01 and Sco vs. MDA (n = 20, r = −0.766, p < 0.001) (Fig. 5b), protein car- ## # Sco+ME (200 mg/kg): p < 0.001 (a), Control vs. Sco: p < 0.0001, Sco bonyl vs. MDA (n = 20, r = 0.877, p < 0.001) (Fig. 5c) and ## vs. Sco+ME (50 mg/kg): p < 0.001 and Sco vs. Sco+ME (200 mg/kg): AChE vs. MDA (n = 20, r = 0.877, p < 0.0001) (Fig. 5d). # ## p < 0.0001 (b) and Control vs. Sco+ME (50 mg/kg): p < 0.001, Con- ## However, the significant correlation between MDA levels trol vs. Sco+ME (50 mg/kg): p < 0.001, Sco vs. Sco+ME (50 mg/kg): ### and behavioral measures, as well as MDA and biochemi- p < 0.0001 and Sco vs. Sco+ME (200 mg/kg): p < 0.0001 (c) cal measures, consistently displayed three rats all scopola- mine-treated that were driving the significant relationship. Discussion Eec ff t of the aqueous extract from Markhamia tomentosa In the present study, a series of experiments were stem bark on the total content of reduced GSH, protein designed in order to investigate the cognitive improve- carbonyl, and MDA levels ment of the aqueous extract from M. tomentosa stem In the rat hippocampal homogenates, significant overall bark in a scopolamine-induced a rat model of cognitive differences between groups (F(3, 16) = 57.92, p < 0.01) impairment in vivo. were displayed for the total content of reduced GSH Scopolamine is a muscarinic acetylcholine receptor (Fig. 3d). The total content of reduced GSH decreased (MAChR) antagonist known to block signals underlying in scopolamine group (p < 0.01) as compared to control Ionita et al. Behav Brain Funct (2017) 13:5 Page 8 of 13 Ionita et al. Behav Brain Funct (2017) 13:5 Page 9 of 13 (See figure on previous page.) Fig. 3 Eec ff ts of the aqueous extract from Markhamia tomentosa stem bark (50 and 200 mg/kg) on AChE (a), SOD (b) and GPX (c) specific activities, on reduced GSH (d), protein carbonyl (e) and MDA (f) levels in the scopolamine-treated rats. Values are mean ± SEM. (n = 5 animals per group). For # # ## ### Tukey’s post hoc analysis— Control vs. Sco: p < 0.01, Sco vs. Sco+ME (50 mg/kg): p < 0.01 and Sco vs. Sco+ME (200 mg/kg: p < 0.001 (a), Con- ## ### ### trol vs. Sco: p < 0.0001, Sco vs. Sco+ME (50 mg/kg): p < 0.001 and Sco vs. Sco+ME (200 mg/kg): p < 0.0001 (b), Control vs. Sco: p < 0.0001, ### ### # ## Control vs. Sco+ME (50 mg/kg): p < 0.0001, Control vs. Sco+ME (200 mg/kg): p < 0.0001, Sco vs. Sco+ME (50 mg/kg): p < 0.01 and Sco vs. # # ## Sco+ME (200 mg/kg): p < 0.001 (c), Control vs. Sco: p < 0.01, Sco vs. Sco+ME (50 mg/kg): p < 0.01 and Sco vs. Sco+ME (200 mg/kg): p < 0.001 ## ## ### ## (d), Control vs. Sco: p < 0.0001, Sco vs. Sco+ME (50 mg/kg): p < 0.0001 and Sco vs. Sco+ME (200 mg/kg): p < 0.00001 (e) and Control vs. Sco: ## ### p < 0.0001, Sco vs. Sco+ME (50 mg/kg): p < 0.0001 and Sco vs. Sco+ME (200 mg/kg): p < 0.00001 (f) Fig. 4 Pearson’s correlation between the spontaneous alternation percentage vs. AChE (a), spontaneous alternation percentage vs. MDA (b), work- ing memory errors vs. AChE (c), working memory errors vs. MDA (d), reference memory errors vs. AChE (e) and reference memory errors vs. MDA (f) in control group (filled circle), scopolamine alone treated-group (filled square), Sco+ME (50 mg/kg) group (filled diamond) and Sco+ME (200 mg/kg) group (filled triangle) Ionita et al. Behav Brain Funct (2017) 13:5 Page 10 of 13 Fig. 5 Pearson’s correlation between SOD vs. MDA (a), GSH vs. MDA (b), protein carbonyl vs. MDA (c) and AChE vs. MDA (d) in control group (filled circle), scopolamine alone treated-group (filled square), Sco+ME (50 mg/kg) group (filled diamond) and Sco+ME (200 mg/kg) group (filled triangle) memory . Our results are in line with previous data Similarly, strong inhibition of the brain AChE activ- showing that the rats with a model of scopolamine- ity was evidenced by administration of different herbal impaired memory significantly decreased their scores extracts in the scopolamine treated-rats [52, 53]. during training sessions within Y-maze and radial As an argument supporting this mechanism, the arm-maze tests [47–49]. Administration of the aque- HPLC–DAD analysis of the aqueous extract from M. ous extract from M. tomentosa stem bark at both doses tomentosa stem bark showed that the most important improved the impairment effect of scopolamine on mem - group of components isolated were water-soluble poly- ory formation, suggesting that the aqueous extract could phenolic derivatives (catechins, hydroxycinnamic acid act as an unspecific enhancer of the cholinergic activity. compounds), mainly rozmarinic acid (541.5 µg/mg of dry The possible underlying mechanism of the aqueous extract), (+)-catechin (11.37 µg/mg of dry extract), pro- extract action could be the increase of the brain cholin- cyanidin dimer (15.86 µg/mg of dry extract), (−)-epicate- ergic receptor sensitivity or the decrease of the AChE chin (42.47 µg/mg of dry extract) and cyaniding trimmers activity. Sugisaki et al.  reported that hippocampal- (14.65 µg/mg of dry extract). We can thus suggest that dependent memory is dependent by the increasing of the effect of the aqueous extract on memory formation extracellular acetylcholine (ACh) level. Also, the cho- may be due to the presence of polyphenolic compounds linergic synaptic transmission could by impaired by an such as rosmarinic acid and (−)-epicatechin. overexpression of AChE activity-induced decreasing of It has been reported that rosmarinic acid exerted vari- ACh level . AChE activity estimated in the rat hip- ous beneficial biological effects such as antioxidant and pocampal homogenates was significantly increased by neuroprotective effects and anti-AChE activity [54–56]. scopolamine as compared to control group. The aqueous Also, rosmarinic acid has positive effects on learning extract administration significantly decreased the AChE and memory in the SAMP8 mouse model of accelerated activity in the scopolamine-treated rats, suggesting that aging  and decreased memory deficits in ischemic the aqueous extract may confer anti-amnesic effects. mice . Furthermore, Zhang et al.  demonstrated Ionita et al. Behav Brain Funct (2017) 13:5 Page 11 of 13 that epicatechin plus treadmill exercise are neuroprotec- tive against moderate-stage amyloid precursor protein/ Abbreviations presenilin 1 mice. Also, epicatechin display a potent anti- AD: Alzheimer’s disease; Aβ: amyloid-beta peptide; Aβ1–42: amyloid-beta AChE activity as previously reported . Tseng et al. peptide 1–42; ACh: acetylcholine; AChE: acetylcholinesterase; ANOVA: analysis of variance; BCA: bicinchoninic acid; DAD: multidiode array detector; DPPH  reported that (−)-epigallocatechin-3-gallate pre- TLC: 2,2-diphenyl-1-picrylhydrazyl thin-layer chromatography; DNPH: 2,4-dini- vents the reserpine-induced impairment of short-term trophenylhydrazine; DTNB: 5,5′-dithiobis-2-nitrobenzoic acid; GPX: glutathione social memory in rats most probably through its power- peroxidase; GSH: glutathione; HPLC: high-performance liquid chromatogra- phy; MAChR: muscarinic acetylcholine receptor; MDA: malondialdehyde; NBT: ful antioxidant activities. nitroblue tetrazolium; SOD: superoxide dismutase. One of the important mechanism in the development and progression of AD is oxidative stress. In the present Authors’ contributions RI, GJB, PAP, MM, BAP, OC and LH performed the experimental studies and study, scopolamine decreased SOD, GPX, and GSH and drafted the manuscript. LH, MM, MH and OC played roles in the writing and increased the MDA and protein carbonyl levels in the editing of the manuscript. LH on OC participated in the design and coordina- rat hippocampal homogenates. It has been documented tion of the study, supervised the study and revised the manuscript. All authors read and approved the final manuscript. that scopolamine administration induced a neurochemi- cal alteration in the brain along with changes in oxida- Author details tive status of the brain . u Th s, scopolamine created Department of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania. Laboratory of Animal Physiology, Faculty an imbalance between antioxidant and oxidant defense of Science, University of Yaoundé I, PO Box, 812, Yaoundé, Cameroon. Depart- systems which may be responsible for observed impair- ment of Biological Sciences, Faculty of Science, University of Maroua, PO Box, ment of memory in rats. Furthermore, many studies 814, Maroua, Cameroon. Department of Chemistry, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania. Faculty of Phar- have reported that the scopolamine-induced amnesic macy, University of Medicine and Pharmacy “Gr. T. Popa”, 16 University Str., rats show similar patterns of memory impairments and 700115 Iasi, Romania. oxidative damage with amnestic mild cognitive impair- Acknowledgements ment (MCI) patients . Evidence suggested that dif- Not applicable. ferent plant extracts have potent anti-amnesic effects that may be mediated by improving the brain oxidative Competing interests The authors declare that they have no competing interests. status [63–65]. Consequently, the aqueous extract treat- ment restored the antioxidants status as evidenced by an Availability of data and materials increase of SOD, GPX, and GSH while the levels of MDA The datasets analyzed during the current study available from the correspond- ing author on reasonable request. (lipid peroxidation) and protein carbonyl significantly decrease which supports its antioxidant property. Ethics approval and consent to participate Moreover, we found a significant correlation between This study was approved by the Committee on the Ethics of Animal Experi- ments of the Alexandru Ioan Cuza University of Iasi (Permit Number: 2194) the spontaneous alternation percentage vs. AChE, sponta- and also, efforts were made to minimize animal suffering and to reduce the neous alternation percentage vs. MDA, working memory number of animals used. errors vs. AChE, working memory errors vs. MDA, refer- Funding ence memory errors vs. AChE, reference memory errors Galba Jean Beppe was supported by Doctoral scholarship Eugen Ionescu vs. MDA, SOD vs. MDA, GSH vs. MDA, protein carbonyl (2012/2013), Alexandru Ioan Cuza University, Iasi, Romania. vs. MDA and AChE vs. MDA when linear regression was Received: 30 November 2016 Accepted: 21 March 2017 determined. 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