Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus

Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus

Progress in Neuro-Psychopharmacology & Biological Psychiatry 43 (2013) 79–88 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Ps...

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Progress in Neuro-Psychopharmacology & Biological Psychiatry 43 (2013) 79–88

Contents lists available at SciVerse ScienceDirect

Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp

Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus Walther Bild a, c, Lucian Hritcu b, Cristinel Stefanescu a, Alin Ciobica b, c,⁎ a b c

Gr. T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania Alexandru Ioan Cuza University, 11 Carol I Blvd., 700506, Iasi, Romania Center of Biomedical Research of the Romanian Academy, Iasi Branch, Romania

a r t i c l e

i n f o

Article history: Received 5 July 2012 Received in revised form 11 December 2012 Accepted 11 December 2012 Available online 20 December 2012 Keywords: Angiotensin II Memory Oxidative stress

a b s t r a c t While it is now well established that the independent brain renin–angiotensin system (RAS) has some important central functions besides the vascular ones, the relevance of its main bioactive peptide angiotensin II (Ang II) on the memory processes, as well as on oxidative stress status is not completely understood. The purpose of the present work was to evaluate the effects of central Ang II administration, as well as the effects of Ang II inhibition with either AT1 and AT 2 receptor specific blockers (losartan and PD-123177, respectively) or an angiotensin-converting enzyme (ACE) inhibitor (captopril). These effects were studied on the short-term memory (assessed through Y-maze) or long-term memory (as determined in passive avoidance) and on the oxidative stress status of the hippocampus. Our results demonstrate memory deficits induced by the administration of Ang II, as showed by the significant decrease of the spontaneous alternation in Y-maze (p = 0.015) and latency-time in passive avoidance task (p=0.001) when compared to saline. On the other side, the administration of all the aforementioned Ang II blockers significantly improved the spontaneous alternation in Y-maze task, while losartan also increased the latency time as compared to saline in step-through passive avoidance (p=0.042). Also, increased oxidative stress status was induced in the hippocampus by the administration of Ang II, as demonstrated by increased levels of lipid peroxidation markers (malondialdehyde-MDA concentration) (pb 0.0001) and a decrease in both antioxidant enzymes determined: superoxide dismutase-SOD (pb 0.0001) and glutathione peroxidase-GPX (p=0.01), as compared to saline. Additionally, the administration of captopril resulted in an increase of both antioxidant enzymes and decreased levels of lipid peroxidation (p=0.001), while PD-123177 significantly decreased MDA concentration (p>0.0001) vs. saline. Moreover, significant correlations were found between all of the memory related behavioral parameters and the main oxidative stress markers from the hippocampus, which is known for its implication in the processes of memory and also where RAS components are well expressed. This could be relevant for the complex interactions between Ang II, behavioral processes and neuronal oxidative stress, and could generate important therapeutic approaches. © 2012 Elsevier Inc. All rights reserved.

1. Introduction It is now well known that the brain has its own intrinsic renin– angiotensin system (RAS) and this could serve as a model for the action of peptides on neuronal function in general (Haulica et al., 2005; von Abbreviations: Abeta, amyloid beta; ACE, angiotensin-converting enzyme; AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; Ang, angiotensin; ANOVA, analysis of variance; GPX, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; i.c.v., intracerebroventricularly; ICAM-1, intercellular adhesion molecule-1; LTP, long term potentiation; MDA, malondialdehyde; NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase; RAS, renin–angiotensin system; ROS, reactive oxygen species; SEM, standard error of the mean; SOD, superoxide dismutase; TOP, 3-thienylalanine-ornithine-proline; WST, water soluble tetrazolium. ⁎ Corresponding author at: Alexandru Ioan Cuza University, Dept. of Biology, B dul Carol I, 11, 700506, Iasi, Romania. Tel.: +40 751218264; fax: +40 232201472. E-mail address: [email protected] (A. Ciobica). 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2012.12.009

Bohlen und Halbach and Albrecht, 2006). Additionally, it is now known that brain RAS is implicated not only in the mechanisms of blood pressure, but also in the modulation of complex functions in the brain, including emotional responses and memory (Braszko et al., 2003b; Ciobica et al., 2009; Gard, 2002; Gard and Rusted, 2004; McKinley et al., 2003; Saavedra, 2005). We have previously demonstrated the implications of brain RAS in anxiety-related processes (Bild and Ciobica, 2012; Ciobica et al., 2011). Also, our group was among the first to demonstrate the involvement of the brain RAS in pain perception (Haulica et al., 1986). The brain RAS is represented by a number of bioactive angiotensin (Ang) peptides, which could have variable and sometimes opposite neurobiological activities (Llorens-Cortes and Mendelsohn, 2002; Santos et al., 2000; von Bohlen und Halbach, 2003; von Bohlen und Halbach and Albrecht, 2006). These include Ang II, Ang IV and Ang-(1–7). However, the most important angiotensin peptide is Ang II, which acts through

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two different highly-specific receptors called AT1 and AT2 (Culman et al., 2001, 2002). Although it is accepted that this peptide has interesting cognitive properties (Ciobica et al., 2009; Haulica et al., 2005; McKinley et al., 2003), behavioral data regarding Ang II have been difficult to interpret, considering that there are reports showing beneficial (Braszko, 2002, 2005; Braszko et al., 1988a,b, 2006), negative (Bonini et al., 2006; Inaba et al., 2009; Kerr et al., 2005; Lee et al., 1995; Maul et al., 2008) or no significant effect at all (Shepherd et al., 1996; Walther et al., 1999) for Ang II on cognitive processes. Thus has been stated that central administration of Ang II induces a facilitated aversive memory in rodents (Braszko, 2002), while the use of similar behavioral tests demonstrated impaired or no changes on memory retention, following Ang II administration (Bonini et al., 2006; Kerr et al., 2005). Controversial results were reported too, concerning the Ang II receptor antagonists, losartan and PD-123177 (selective for the AT1 and AT2 receptor, respectively), since Shepherd et al. reported no effects of either compound in two different models of working memory in rats (Shepherd et al., 1996), while other studies have shown that low doses of losartan and PD123177 improve scopolamine-impaired performance in a light/dark box habituation task (Chalas and Conway, 1996). Several authors (Kumaran et al., 2008; Manschot et al., 2003) allowed for limited beneficial effects on memory functions for the angiotensinconverting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, have been demonstrated, but there are also very recent reports stating that the role of ACE in memory function is still ambiguous or insufficiently explored (Tota et al., 2012a,b). Additionally, the effects of Ang II on the oxidative status are controversial, with reports stating both pro-oxidant actions, exerted by an increase of reactive oxygen species (ROS) generation, mainly through the stimulation of NAD(P)H oxidase, which then meditates the activation of superoxide (Basso et al., 2007; Inaba et al., 2009; Miller et al., 2007; Wang et al., 2006), as well as authors stating no changes of the oxidative stress status as a result of Ang II administration in terms of all oxidative stress markers determined, as in the work of Gonzales group, which showed no significant change of SOD, GPX and catalase specific activity, as well as no changes in MDA levels, as an index of lipid peroxidation processes (Gonzales et al., 2002). In this context, the aim of the present work was to evaluate the effects of central Ang II inhibition using either AT1 and AT 2 receptor specific blockers (losartan and PD-123177, respectively) or an ACE inhibitor (captopril) on short-term memory (assessed through Y-maze) or long-term memory (as determined in passive avoidance), and on the oxidative stress status from the hippocampus, which is known for its implication on memory processes (Eichenbaum and Cohen, 1993) and also where RAS components are very well expressed (von Bohlen und Halbach and Albrecht, 2006). Moreover, we were interested in studying if there is a correlation between the behavioral parameters we determined in Y maze or passive avoidance tasks and the levels of the oxidative stress markers (two antioxidant enzymes: superoxide dismutase-SOD and glutathione peroxidase-GPX, as well as a lipid peroxidation marker: malondialdehyde-MDA) within the hippocampus.

Committee and also efforts were made to minimize animal suffering and to reduce the number of animals used. 2.2. Materials Ang II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), Captopril (N-[(S)-3Mercapto-2-methylpropionyl]-L-proline), Losartan (2-Butyl-4-chloro1-{[2′-(1H-tetrazol-5-yl)(1,1′-biphenyl)-4-yl]methyl}-1H-imidazole-5methanol monopotassium) and PD 123177 ((S)-1-[(4-Amino-3-methyl phenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-Imidazo[4,5c]pyridine-6-carboxylic acid trifluoroacetate salt hydrate) were obtained from Sigma-Aldrich. SOD Assay Kit was obtained from Fluka (product number: 19160), while GPX cellular activity assay kit CGP-1 was also purchased from Sigma Chemicals. 2.3. Experimental design 2.3.1. Neurosurgery All surgical procedures were conducted in aseptic conditions, anesthesia with sodium pentobarbital (45 mg/kg b.w., i.p., Sigma). Rats were mounted in the stereotaxic apparatus with the nose oriented 11° below the horizontal zero plane. A plastic cannula (Portex, 0.44 inner diameter, 0.9 mm outer diameter) was stereotaxically implanted in the left lateral ventricle at the following coordinates: 0.5 mm posterior to bregma; 1.3 mm lateral to the midline; 4.3 mm ventral to the surface of the cortex (Paxinos and Watson, 2006). The cannula was positioned with acrylic dental cement and secured with one stainless steel screw. 2.3.2. Pharmacological treatment The animals were randomly divided into five groups of 5 animals each. All the drug solutions were freshly prepared before use. Angiotensin II, losartan, PD-123177 and captopril were dissolved in saline (0.9% NaCl) a few minutes before the injection and administered intracerebroventricularly (i.c.v.) in doses of 0.1 mg/kg/b.w. for 7 consecutive days. The control rats were also injected with saline. The i.c.v. injections were made manually with a 10 μl Hamilton syringe. The procedure was nontraumatic for the rat, which was gently held in the hand of the experimenter. The injection volume was always 2 μl introduced over approximately 5 s. The treatment began 3 days after the neurosurgery and lasted for 7 days. Memory functions were tested through Y-maze and passive avoidance tasks, performed during the last 3 days of treatment (Y maze on the 5th day and passive avoidance in the last 2 days). Thus, only one set of animals was used for both behavioral tasks. In the testing days, the aforementioned drugs were given 15 min before performing the behavioral task. The aforementioned dosage and the duration of treatment were selected using our pilot studies and previously published reports regarding RAS behavioral effects (Bild and Ciobica, 2012; Braszko, 2002; Braszko et al., 1988a,b; Ciobica et al., 2010; Tota et al., 2012b; Winnicka et al., 1998).

2. Material and methods

2.4. Evaluation of memory function

2.1. Animals

2.4.1. Y-maze task Short-term memory was assessed by spontaneous alternation behavior in the Y-maze task. The Y-maze used in the present study consisted of three arms (35 cm long, 25 cm high, and 10 cm wide) and an equilateral triangular central area. The rat was placed at the end of one arm and allowed to move freely through the maze for 8 min. An arm entry was counted when the hind paws of the rat were completely within the arm. Also, the maze was cleaned with alcohol-free disinfectant wipes between each trial. Spontaneous alternation behavior was defined as the entry into all three arms on consecutive choices. The number of maximum spontaneous alternation behaviors was calculated as the total

Adult male Wistar (n=25) rats, weighing 200–250 g at the beginning of the experiment, were housed in groups of five animals per cage and kept in a room with controlled temperature (22 °C) and a 12:12-h light/dark cycle (starting at 08:00 h), with food and water ad libitum. The animals were treated in accordance with the guidelines of animal bioethics from the Act on Animal Experimentation and Animal Health and Welfare Act from Romania and all procedures were in compliance with the European Communities Council Directive of 24 November 1986 (86/609/EEC). This study was approved by the local Ethics

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number of arms entered minus 2 and percent spontaneous alternation was calculated as (actual alternations/maximum alternations)×100. Spontaneous alternation behavior is considered to reflect spatial working memory, which is a form of short-term memory (Hritcu et al., 2007). 2.4.2. Step-through passive avoidance task In brief, a step-through type passive avoidance apparatus (Coulbourn Instruments) consisting of two compartments (25×15×15 cm high), one illuminated and one dark, both equipped with a grid floor was used. The two compartments were separated by a guillotine door. In the acquisition trial, each rat was placed in the illuminated compartment; when the animal entered the dark compartment, the door was closed and an inescapable foot shock (0.3 mA, 5 s) was delivered through the grid floor. The rat was removed after receiving the foot shock and was placed back into the light compartment. The door was again opened 30 s later to start the next trial. The training continued until the rat stayed in the light compartment for a 120-s period on a single trial. The rats were given 3–5 trials and trained to avoid punishment (remain on shock-free zone). After 24 h, each rat was placed in the light compartment and the step-through latency was recorded until 300 s had elapsed (retention trial). The step-through latency in the retention trial was used as the index of retention of the training experience. Longer retention latencies were interpreted as indicating better retention of the training experience (Hefco et al., 2003; Hritcu et al., 2007).

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2.5.3. Determination of malondialdehyde Malondialdehyde (MDA) levels were determined by thiobarbituric acid reactive substances (TBARs) assay. 200 μl of supernatant was added and briefly mixed with 1 ml of trichloroacetic acid at 50%, 0.9 ml of Tris–HCl (pH 7.4) and 1 ml of thiobarbituric acid 0.73%. After vortex mixing, samples were maintained at 100 °C for 20 min. Afterwards, samples were centrifuged at 3000 rpm for 10 min and supernatant read at 532 nm. The signal was read against an MDA standard curve and the results were expressed as nmol/mg protein (Ciobica et al., 2012). 2.5.4. Data analysis The animal's behavior in Y maze (as expressed through spontaneous alternation and number of arm entries) and passive avoidance (as expressed through the step-through latency time) and the levels of oxidative stress markers (SOD, GPX and MDA) were statistically analyzed by using one-way analysis of variance (ANOVA). All results are expressed as mean ± SEM. Post hoc analysis were performed using Tukey's honestly significant difference test in order to compare groups. F values for which p b 0.05 were regarded as statistically significant. Pearson's correlation coefficient was used to investigate possible correlations between the behavioral parameters in Y maze and passive avoidance tasks and hippocampal oxidative stress markers. 3. Results

2.4.3. Histological control After the behavioral test, all rats were anesthetized, rapidly decapitated and the whole brain was removed. The location of the i.c.v. cannulas was verified by injecting a dye (Trypan Blue, Sigma) through each cannula at the end of the experiment. In this way, after the end of experiments the brains were removed and the cannula placement was verified under light microscopy. All cannulas were found to be in the right position. 2.4.4. Hippocampus dissection Also, considering the importance of hippocampus in memory processes (Eichenbaum and Cohen, 1993) and also the fact that RAS components are very well expressed here (von Bohlen und Halbach and Albrecht, 2006), the hippocampi were then collected. Each of the samples was weighed and homogenized with a Potter Homogenizer coupled with Cole-Parmer Servodyne Mixer in bidistilled water (1 g tissue/10 ml bidistilled water). Samples were centrifuged for 15 min at 3000 rpm. Following centrifugation, the supernatant was separated and pipetted into tubes. 2.5. Biochemical estimations 2.5.1. Determination of superoxide dismutase Superoxide dismutase (SOD) activity was measured by the percentage of reaction inhibition rate of enzyme with WST-1 substrate (a water soluble tetrazolium dye) and xanthine oxidase using a SOD Assay Kit (Fluka, product number: 19160) according to the manufacturer's instructions. Each endpoint assay was monitored by absorbance at 450 nm (the absorbance wavelength for the colored product of WST-1 reaction with superoxide) after 20 min of reaction time at 37 °C. The percent inhibition was normalized by mg protein and presented as SOD activity units. 2.5.2. Determination of glutathione peroxidase Glutathione peroxidase (GPX) activity was measured using the GPX cellular activity assay kit CGP-1 (Sigma Chemicals). This kit uses an indirect method, based on the oxidation of glutathione (GSH) to oxidized glutathione (GSSG) catalyzed by GPX, which is then coupled with recycling GSSG back to GSH utilizing glutathione reductase (GR) and NADPH. The decrease in NADPH at 340 nm during oxidation of NADPH to NADP is indicative of GPX activity.

Regarding the behavioral performance of rats in Y-maze task, we observed a significant group difference in terms of spontaneous alternation (F(4,20)=25, pb 0.0001) (Fig. 1), suggesting significant effects on shortterm spatial memory. Post hoc comparisons showed a significant decrease of spontaneous alternation in Ang II treated rats (p =0.015) vs. saline group and also an increase in captopril (p =0.01), losartan (p =0.001) or PD-123177 (p= 0.007) groups when compared to saline treated rats. A significant increase of the spontaneous alternation was also found for losartan (pb 0.0001), PD-123177 (pb 0.0001) and captopril (p b 0.0001) treated rats, when each group was compared to Ang II group (Fig. 1). However, the comparison between the Ang II blockers and the ACE blocker showed no significant differences regarding the spontaneous alternation: losartan vs captopril (p=0.07), PD-123177 vs captopril (p=0.6) and losartan vs. PD-123177 (p=0.1). Moreover, this effect could not be attributed to the motor activity, since the number of arm entries in the Y-maze task was not significantly changed in the groups (F(4,20) = 0.8, p = 0.5), as showed by Fig. 2. As for the multi-trial passive avoidance task, the behavior of rats was assessed through the step-through-latency. In this way, we also observed a significant overall effect of the treatment on the latency time (F(4,20)= 26, pb 0.0001), suggesting significant effects on long-term memory. Additionally, post hoc analysis revealed a significant decrease of the latency time in Ang II group when compared to saline-treated rats (p=0.001) and a significant increase of this time in the case of losartan when compared to saline group (p=0.042). Still, no significant differences were noticed in the case of saline vs. PD-123177 (p=0.6) and saline vs. captopril (p=0.4) (Fig. 3). Also, a significant increase of latency time was seen in losartan (pb 0.0001), PD-123177 (p= 0.001) and captopril (pb 0.0001) groups, when they were compared individually with the Ang II-treated rats. Regarding the group differences between the Ang II blockers, we noticed a significant increase in the latency time for the losartan group when compared to PD-123177 (p=0.008) and no significant differences between losartan vs. captopril (p=0.077) and PD-123177 vs. captopril (p=0.067) (Fig. 3). In what concerns the oxidative stress markers, when we analyzed the overall effect of treatment on SOD specific activity we also found significant differences (F(4,20) = 30, p b 0.0001). Post hoc comparisons also showed a significant decreased of SOD activity in Ang II group

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Fig. 1. The effects of angiotensin II, captopril, losartan and PD-123177 administration on the spontaneous alternation percentage in the Y-maze task. The values are mean ± S.E.M. (n = 5 per group). *p = 0.01 vs. saline, **p = 0.007 vs. saline and ***p = 0.001 vs. saline.

(pb 0.0001) when compared with saline, as well as increase of SOD in captopril (p= 0.005) group, as compared to saline-treated rats. Still, no significant differences were noted between saline and losartan groups (p= 0.1), while in the case of PD-123177 group we even saw a significant decrease (p= 0.049) of SOD, as compared to saline (Fig. 4). Additionally, we observed a significant increase of SOD specific activity in losartan (pb 0.0001), PD-123177 (p= 0.007) and captopril (pb 0.0001) groups when every one of them was compared to Ang II-treated rats. When we compared the Ang II receptor blockers with ACEI-blockers, we observed a significant increase of SOD specific activity in captopril group, as compared to losartan (pb 0.0001) and PD-123177 (pb 0.0001) groups, while no significant difference was seen between losartan vs. PD-123177 (p=0.49) treated rats (Fig. 4). Also we observed significant modifications of GPX specific activity in our experimental groups (F(4,20)=25, pb 0.0001). Additionally, post hoc comparisons revealed a significant decrease of GPX in Ang II group

(p=0.01) when compared to saline treated rats, as well as an increase in captopril group (p=0.002), as compared to saline group. Still, no significant modifications were reported in the case of losartan (p=0.8) and PD-123177 (p=0.3), as compared to saline (Fig. 5). Additionally, we also observed a significant increase of GPX specific activity in losartan (pb 0.0001), PD-123177 (p= 0.017) and captopril (pb 0.0001) groups, when which one of them was compared to Ang II treated rats. Also, we observed a significant increase of GPX specific activity in captopril group, as compared to losartan (p b 0.0001) and PD-123177 (p b 0.0001) groups, while no significant differences were noticed between losartan and PD-123177 (p = 0.09) groups (Fig. 5). Regarding the levels of MDA from the hippocampus we also found significant differences between our treatment groups (F(4,20)= 51, p b 0.0001). Moreover, when we performed the post hoc analysis, we observed a significant increase for the MDA levels in the Ang-II group (p> 0.0001), as compared to saline rats, and a significant decrease of

Fig. 2. The effects of angiotensin II, captopril, losartan and PD-123177 administration on the number of arm entries in the Y-maze task. The values are mean±S.E.M. (n=5 per group).

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Fig. 3. The effects of angiotensin II, captopril, losartan and PD-123177 on the step-through-latency (s) in the multi-trial passive avoidance task. The values are mean ± S.E.M. (n = 5 per group). *p = 0.04 vs. saline and ***p = 0.001 vs. saline.

MDA in captopril (p= 0.001) and PD-123177 (p>0.0001) groups when compared to saline. However, no significant modifications are reported for the losartan-treated group (p= 0.6) vs. saline (Fig. 6). Also a very significant decrease of MDA levels was observed in the case of captopril (p> 0.0001), losartan (p>0.0001) and PD-123177 (p>0.0001) groups when each one of them was compared to Ang II-treated rats. Additionally, we noticed a significant decrease of MDA in captopril (p=0.005) and PD-123177 (p> 0.0001) groups when compared to losartan. Also, the MDA concentration was significantly decreased in PD-123177 (p=0.003) group, as compared to captopril (Fig. 6). Interestingly, when we performed the Pearson correlations between the behavioral parameters which we determined in here (spontaneous alternation percentage in Y-maze/step-through-latency in passive avoidance task) and the main oxidative stress markers from the hippocampus, we obtained significant correlations in all six cases: spontaneous alternation vs. GPX (n=25, r=0.478, p=0.016), spontaneous alternation vs. SOD (n=25, r=0.385, p=0.047), spontaneous alternation vs. MDA (n=24, r=−0.593, p=0.002), and also for step-through-latency vs. SOD (n=25, r=0.610, p=0.001), step-through-latency vs. GPX

(n = 25, r = 0.6, p = 0.002) or step-through-latency vs. MDA (n= 25, r = −0.476, p = 0.016). 4. Discussion The present study investigated the effects of central Ang II inhibition with either AT1 and AT 2 receptor specific blockers or an ACE inhibitor on short-term and long-term memory and on the oxidative stress status of the hippocampus, known for its implication in memory processes (Eichenbaum and Cohen, 1993) and also where RAS components are very well expressed (von Bohlen und Halbach and Albrecht, 2006). Our results provide additional evidence regarding the memory alteration and increased oxidative stress induced by the administration of Ang II, while its blocking through the aforementioned methods resulted in opposite effects. Moreover, we found here significant correlations between the memory related behavioral parameters from the Y-maze and passive avoidance tasks and the main three markers of the oxidative stress status from the hippocampus. As previously mentioned, a complete brain RAS exists aside from the peripheral one and has all necessary precursors and enzymes required

Fig. 4. The effects of angiotensin II, captopril, losartan and PD-123177 on SOD specific activity in hippocampus. The values are mean ± S.E.M. (n = 5 per group). *p = 0.04 vs. saline, **p = 0.005 vs. saline and ***p = 0.0001 vs. saline.

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Fig. 5. The effects of angiotensin II, captopril, losartan and PD-123177 on GPX specific activity in hippocampus. The values are mean± S.E.M. (n = 5 per group). *p = 0.01 vs. saline and **p = 0.002 vs. saline.

for the formation and metabolism of the biologically active forms of angiotensin (von Bohlen und Halbach & Albrecht, 2000; von Bohlen und Halbach and Albrecht, 2006; Llorens-Cortes and Mendelsohn, 2002; McKinley et al., 2003). However, as we previously mentioned, when it comes to the cognitive effects of Ang II the results are controversial. Thus, when angiotensin II is administered in the dorsal neostriatum, the retention in the step-down shock avoidance is significantly decreased (Morgan and Routtenberg, 1977), while retrieval in the passive avoidance task was significantly increased after intracerebroventricular administration of the same angiotensin II (Braszko, 2002; Braszko et al., 1988a,b; von Bohlen und Halbach and Albrecht, 2006). It was also demonstrated that Ang II administered to the hippocampus impaired retention of the single trial step through shock avoidance response by the activation of AT1 receptors (Lee et al., 1995). Other studies have provided evidence that Ang II applied to the hippocampal area CA1 blocked memory formation through a mechanism involving

the activation of AT2 receptors (Kerr et al., 2005). Additionally, it was also stated that there is a possible role of hippocampal angiotensin II receptors in voluntary exercise-induced enhancement of learning and memory in rat (Akhavan et al., 2008). Still, it has been shown that angiotensin II-deficient mice present normal retention of spatial memory (Walther et al., 1999). Also, Maul et al. (2008) demonstrated that mice deficient for the AT2 receptor gene have poor performances in spatial memory tasks and one-way active avoidance. The same authors stated that these mice have abnormal dendritic spine morphology and length, features which are associated with mental retardation (Mavroudis et al., 2011). It has been also reported that Ang II receptor blockers could facilitate long term potentiation (LTP), in the hippocampus of AD mice (Manschot et al., 2003), while it was previously demonstrated that Ang II blocks long-term potentiation in both hippocampus (Armstrong et al., 1996) and amygdala (von Bohlen und Halbach and Albrecht, 1998). Still, the

Fig. 6. The effects of angiotensin II, captopril, losartan and PD-123177 on MDA concentration in hippocampus. The values are mean ± S.E.M. (n = 5 per group). **p = 0.001 vs. saline and ***p b 0.0001 vs. saline.

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effects of losartan vs PD 123319 on this kind of specific forms of synaptic plasticity could be extremely different, as showed by Tchekalarova and Albrecht, 2007. Additionally, it was demonstrated that the administration of telmisartan, an AT1 receptor blocker, significantly decreased some hypertension-induced learning and memory deficits in the water maze task (Sharma and Singh, 2012). Also, Inaba group demonstrated that the administration of olmesartan (another AT1 blocker) diminished the cognitive alterations observed in shuttle-box avoidance task for the human renin and human angiotensinogen gene chimeric transgenic mice, together with an increase of the cerebral blood flow (Inaba et al., 2009). On the other side, it was very recently reported that the administration of Compound 21, an AT2 receptor agonist, can in fact ameliorate the cognitive decline observed in a specific type 2 diabetes mellitus model in mice (Mogi et al., 2012). The abovementioned conflicting results can be explained by the fact that the cognitive effects of Ang II are very sensible to the various methodological approaches (e.g. time and type of administration), differences in dosage, duration of treatment, number and frequency of training sessions, animal strains or type of memory task evaluated. This is why authors stated that data suggesting the facilitatory effect of angiotensin II on the memory should be interpreted with care, since Ang II is also a precursor for neuroactive angiotensin fragments such as Ang IV, which is known for its enhancing effects on the cognitive processes (Gard, 2008; von Bohlen und Halbach, 2003). Thus, different results might be obtained also depending on the time interval between the injection of Ang II and the performing of the behavioral paradigm (Braszko et al., 2006). ACE inhibitors were reported to enhance conditioned avoidance and also effects of other enzymes involved in the degradation of Ang II to various other bioactive fragments and habituation memory (Braszko et al., 2003a; Nikolova et al., 2000). Therefore, when administrated prior to training, captopril facilitated learning in the second trial of the active avoidance task in mice (Raghavendra et al., 2001), while ACE inhibition improved the impaired performance in different models of animal learning (Manschot et al., 2003; Wyss et al., 2003). This could be perhaps explained by the fact that treatment with ACE inhibitors, such as captopril, improves cerebral blood flow and protects against damage induced by cerebral ischemia in normal (Kumaran et al., 2008) and hypertensive (Braszko et al., 2003a) rats. Also it was very recently demonstrated that seven days of oral administration of perindopril (a long-acting ACE inhibitor), resulted in significant improvements in scopolamine-induced deficiencies on transfer latency time, path length and platform crossings, as studied in the water-maze task (Tota et al., 2012b). Interestingly enough, it was reported that perindopril per se had no significant effects on the said behavioral parameters, suggesting that besides an improvement of the cerebral blood flow (Tota et al., 2011), the beneficial effects of ACE inhibitors could be also connected with the cholinergic neurotransmission (Tota et al., 2012b). It was also demonstrated that perindopril could improve the memory deficits generated in Water maze task, as a result of streptozotocin administration. Additionally, this improvement was followed by an increase of the brain energy metabolism and of the cerebral blood flow, as well as diminished streptozotocin-induced neuronal damage in hippocampus, entorhinal cortex and periventricular cortical region (Tota et al., 2012a). Similar aspects were also demonstrated for another ACE inhibitor, enalapril, which partially prevents some deficits in water maze task, by facilitating the long-term potentiation in the hippocampus, as well as the blood flow of this area in diabetic rats, when compared with untreated diabetics (Manschot et al., 2003). Regarding our results, we report here an increase of the spontaneous alternation percentage in Y-maze task, which is known to be an index for the short-term spatial memory, in the groups treated with AT1 and AT2 receptor blockers (losartan and PD-123177, respectively) or with an ACE inhibitor (captopril). Additionally, Ang II administration resulted in decreased alternation percentage. Similar aspects were

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also observed in the multi-trial passive avoidance task, where we found a decrease in the step-through-latency, a parameter believed to be relevant for the long-term memory, in the Ang II-treated group, while the administration of losartan resulted in increased values of this latency. This confirms that some of these antihypertensive drugs, particularly ACE inhibitors (such as captopril) and some angiotensin receptor blockers (losartan and PD-123177) may be associated with a lower rate of memory decline. Regarding the effects of Ang II on the oxidative stress, previous reports also showed varying results. Thence, it has been reported that the administration of this peptide increases oxidative stress levels (Basso et al., 2007; Wang et al., 2006) by stimulating the activation of the NAD(P)H oxidase (Chabrashvili et al., 2003; Miller et al., 2007; Rajagopalan et al., 1996), which then triggers the formation of free radicals such as superoxide anion (Griendling et al., 2000; Inaba et al., 2009). These aspects are confirmed by the hypertensive bouts induced by the activation of RAS in experimental animals, later demonstrated to be associated with an increased production of vascular superoxide (Laursen et al., 1997; Munzel and Keaney, 2001). However, on the other side it was also reported that Ang II administration results in no significant changes of the lipid peroxidation levels, as expressed through the MDA concentration or in SOD, GPX and catalase enzymatic activity (Gonzales et al., 2002). In what concerns the Ang II blockers, it was shown that the administration of losartan or PD-123319 resulted in a decreased oxidative stress status in the cerebral blood or glial cells (Antelava et al., 2007; Yao et al., 2007), while in other experiments losartan significantly decreased angiotensin II-induced oxidative stress, but PD-123319 did not (Yanagitani et al., 1999). Additionally, it has been previously demonstrated that the administration of two different doses of the AT1 blocker telmisartan resulted in the significant improvement of an experimental hypertension-induced oxidative stress shown by a significant increase in the aortic superoxide anion levels, brain and serum thiobarbituric acid reactive species, as well as a significant decrease in the brain levels of the reduced form of glutathione (Sharma and Singh 2012). Advanced genetic studies also demonstrated that blocking the AT1 receptors with olmesartan results in decreased oxidative stress levels in transgenic mice for renin and angiotensinogen (Inaba et al., 2009). Very recent reports also showed that the administration of perindopril resulted in a significant decrease of a scopolamine-induced oxidative stress status in mice, both in the cortex and the hippocampus, as showed by the decreased levels of MDA and increased levels of glutathione (Tota et al., 2012b). Additionally, the increased oxidative and nitrosative stress status, as a result of STZ-induced diabetes in rats, was ameliorated by perindopril within the hippocampus and cortex. This improvement was mainly shown by the increased levels of GSH, as well as the decreased intracellular reactive oxygen species, MDA and nitrite concentrations in the aforementioned central areas (Tota et al., 2012a). It was also reported that the use of sulfur-containing ACE inhibitors, such as 3-thienylalanine-ornithine-proline (TOP), was associated with reduced oxidative stress in Spontaneously Hypertensive Rats, as showed by the increased levels of antioxidants and decreased levels of lipid peroxidation markers (Hanif et al., 2009). Additionally, the same authors reported an increased scavenging activity of TOP, as compared to captopril (Hanif et al., 2009). As for our results, we observed a significant decrease of both SOD and GPX specific activities in the Ang II-treated rats, together with an increase of MDA concentrations from the hippocampus, suggesting pro-oxidant effects. Also, blocking Ang II with the ACE inhibitor captopril, resulted in decreased levels of MDA and increased specific activities for both SOD and GPX. Still, no significant modifications of the oxidative stress markers were observed in the case of AT 1 blocker losartan. Moreover, we observed a significant decrease of SOD specific activity in the PD-123177 treated group, as compared to saline. This could be perhaps explained by the fact that SOD is the first line of defense against ROS,

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catalyzing the conversion of superoxide radicals to hydrogen peroxide, which is then converted into water by GPX and catalase (Sies, 1997), and in this way this could be a compensatory mechanism, especially since the levels of MDA were significantly decreased in PD-123177 group, as compared to saline-treated rats. Also, the decrease of SOD in PD-123177 treated rats was minimally significant with a p value of 0.049. The abovementioned results can be linked to the fact that Ang II may coordinate some important events in the brain inflammatory processes that together with ROS generation could explain some of the neurodegenerative effects of this peptide (Benigni et al., 2010). Vargas et al. (2012) reported the increased expression of Ang II, monocyte/macrophage (ED-1 positive cells), CD8, the intercellular adhesion molecule-1 (ICAM-1) and the lymphocyte function-associated antigen-1 (LFA-1) were reported in an experimental model of diabetes in rats. More importantly, the expression of these molecules was reduced by the administration of losartan and enalapril. Still, the administration of Ang II receptor blockers had no effect on some oxidative and nitrosative stress markers, such as superoxide anion and catalase expression, nitrite content or lipid peroxidation markers (Vargas et al., 2012). Other reports also stated that the administration of AT1 blockers could ameliorate the levels of inflammatory stress in rats (Saavedra, 2012). Moreover, a significant correlation was demonstrated between Ang II expression and the levels of some pro-inflammatory molecules in diabetic rats' cerebellum (Vargas et al., 2012). Also, Zhang group demonstrated that Ang II induces cerebral microvascular inflammation via oxidative stress (Zhang et al., 2010). The role of Ang II-induced oxidative stress was also demonstrated in depression, another very well known inflammatory disorder (Maes et al., 2012; Stefanescu and Ciobica, 2012), since rats performing the forced swimming test displayed increased concentrations of both superoxide anion and angiotensin II in the cerebrum and cerebellum (Pedreanez et al., 2006). Our group also previously demonstrated that the administration of Ang-(1–7), which is known for its opposite effects to Ang II (Haulica et al., 2003; Machado et al., 2000), resulted in anxiolytic actions exerted in the elevated plus maze task, as well as decreased levels of oxidative stress in the amygdala (Bild and Ciobica, 2012). The results we report in the present work could be also connected with the theories stating that inhibition of the RAS, with these pharmacological agents (ACE inhibitor or AT1 and AT2 blockers) could play an important role in the protection of both the nervous and cardiovascular systems during aging (Akhavan et al., 2008; Culman et al., 2002; Saavedra, 2005; Thone-Reineke et al., 2004). Also this could be relevant for the implications of oxidative stress in aging, as well as in different neuropsychiatric disorders and especially in dementia (Padurariu et al., 2010a,b). On the other hand, it has been shown that these types of compounds substantially prolonged life span (Yao et al., 2007). Additionally, the analysis of the oxidative stress markers suggests that this protective effect is related to an antioxidant action of the RAS inhibitors (as we demonstrated here mainly in the case of captopril) and also to a reduced formation of reactive oxygen species. Increasing amounts of evidence are also showing that RAS is involved in several neurodegenerative diseases, such as AD and PD (Becker et al., 2008; Danielyan et al., 2010; Davies et al., 2011; Li et al., 2011; Lopez-Real et al., 2005; Ohrui et al., 2004; Patrick and Gordon, 2007; Rosenberg et al., 2008; Wright and Harding, 2011; Yasar et al., 2008). In this way, a significant negative correlation was recently reported between anti-hypertensive therapies and the incidence of dementia (Duron and Hanon, 2010). Additionally, increased ACE concentrations were demonstrated in the various brain regions involved in the modulation of learning and memory processes (Wright and Harding, 2011), while it also seems that ACE inhibitors could delay the onset of dementia (Li et al., 2011). A clear association was demonstrated by several authors between the ACE gene and AD, as well as between the gene for ACE and the atrophy of hippocampus and amygdala (Sleegers et al., 2005). Advanced genetic studies have shown that there is a significant correlation between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D)

polymorphism and the incidence of amnestic mild cognitive impairment (aMCI), an intermediate state between normal aging and dementia which mainly refers to episodic memory impairment and decline in the ability to learn new information (Zhang et al., 2012). Additionally, the same authors reported that ACE activity in aMCI group was negatively correlated with the scores of Auditory Verbal Learning Test-delayed recall (Zhang et al., 2012). Barnes et al. (1990) stated that Ang II receptor antagonists could reverse the Ang II-induced inhibitory effects on the acetylcholine release from the temporal cortex (Barnes et al., 1990). In addition, immunohistochemical data demonstrated an increased activity of ACE and angiotensin II in the parietal cortex of AD patients (Savaskan et al., 2001), as well as in the brain of AD rat models (Hou et al., 2008). There are also reports showing that treatment with Ang II blockers resulted in delayed AD pathogenesis (Hou et al., 2008), as well as large studies (e.g. PROGRESS) describing a protective effect of ACE inhibitors on the cognitive impairment from the vascular dementia (Tzourio et al., 2003). Additionally, it was demonstrated that ACE blockers could diminished the hypoperfusion-induced hippocampal neurodegeneration (Kumaran et al., 2008). On the other side, it was showed that the administration of both ACE and AT2 blockers was not associated in any way with better cognitive function in the GEMS study, which was however mainly designed to study the effects of Gingko biloba on memory function (Yasar et al., 2012). Similar studies regarding the lack of efficacy for Ang II blockers were reported in patients with recent ischemic stroke (Diener et al., 2008) or diabetes (Anderson et al., 2011). In fact, many results in this area of research are contradictory, with reports stating a strong correlations between ACE activity in AD and Braak stage (Miners et al., 2009), while other studies showed no correlations at all between ACE activity and age, as well as between insoluble and soluble Amyloid beta (Abeta) and ACE levels of AD patients (Miners et al., 2010). When it comes to the relation between Ang II blockers and Abeta the results are also conflicting, with human genetic studies demonstrating that ACE is modulating the susceptibility and the progression of AD via the degradation of Abeta (Hemming and Selkoe, 2005), while studies on mice showed that ACE deficiency does not alter in any way the concentrations of beta-amyloid (Eckman et al., 2006). Further studies are warranted in order to determine the role of the various angiotensin peptides and angiotensin receptors in some neuropathological states. Our group has also undergo studies regarding the possible co-administration of AT1 and AT2 receptor antagonists and their relevance on memory functions and oxidative stress status, considering that a functional interaction between AT1 and AT2 receptors seems to exist (Gelband et al., 1997), with reports stating that the simultaneous administration of AT1 and AT2 blockers could generate summative effects for example on the acquisition processes in a conditioned avoidance response task, as compared to their individual administration (Braszko, 2002). However, based on the increased memory performance and decreased oxidative stress mediated by Ang II inhibitors, which were also demonstrated in the present work, the manipulation of the central RAS could be considered as a promising therapeutic target in the treatment of cognitive dysfunctions. For this purpose, a better understanding of the complex interactions between Ang II, behavioral processes and neuronal oxidative stress is necessary and could lead to new important therapeutic aspects. 5. Conclusions This study demonstrates that the inhibition of central Ang II with either an ACE inhibitor (captopril) or AT1 and AT 2 blockers (losartan and PD-123177, respectively) resulted in a significant enhancement of both short term and long term memory as showed in Y-maze and passive avoidance task, as well as a significant decrease of the oxidative stress status in the hippocampus. Moreover, we demonstrated

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here a significant correlation between these memory related behavioral parameters and the specific markers of the oxidative stress status. Acknowledgments Ciobica Alin is supported by a POSDRU grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi. References Akhavan M, Emami-Abarghoie M, Sadighi-Moghaddam B, Safari M, Yousefi Y, Rashidy-Pour A. Hippocampal angiotensin II receptors play an important role in mediating the effect of voluntary exercise on learning and memory in rat. Brain Res 2008;1232:132–8. Armstrong DL, Garcia EA, Ma T, Quinones B, Wayner MJ. Angiotensin II blockade of long-term potentiation at the perforant path–granule cell synapse in vitro. Peptides 1996;17(4):689–93. Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T. Renin angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol 2011;10:43–53. Antelava N, Gongadze N, Gogolauri M, Kezeli T, Pachkoriia K. Comparative characteristic of angiotensin-converting enzyme inhibitor – captopril and the angiotensin II receptor blockers – losartan action on the oxidative metabolism in experimental hyperlipidemia in rabbits. Georgian Med News 2007;150:57–60. Barnes J, Barnes N, Costall B, Horovitz Z, Ironside J, Naylor R. Angiotensin II inhibits acetylcholine release from human temporal cortex: implications for cognition. Brain Res 1990;507:341–3. Basso N, Cini R, Pietrelli A, Ferder L, Terragno N. Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 2007;293:1351–8. Becker C, Jick S, Meier C. Use of antihypertensives and the risk of Parkinson disease. Neurology 2008;70:1438–44. Benigni A, Cassis P, Remuzzi1 G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2010;2:247–57. Bild W, Ciobica A. Angiotensin-(1–7) central administration induces anxiolytic-like effects in elevated plus maze and decreased oxidative stress in the amygdala. J Affect Disord 2012. http://dx.doi.org/10.1016/j.jad.2012.07.024. [Epub ahead of print] [PubMed PMID:22868060]. Bonini J, Bevilaqua L, Zinn C, Kerr D, Medina J, Izquierdo I, et al. Angiotensin II disrupts inhibitory avoidance memory retrieval. Horm Behav 2006;50:308–13. Braszko J. AT(2) but not AT(1) receptor antagonism abolishes angiotensin II increase of the acquisition of conditioned avoidance responses in rats. Behav Brain Res 2002;131:79–86. Braszko J. Valsartan abolishes most of the memory-improving effects of intracerebroventricular angiotensin II in rats. Clin Exp Hypertens 2005;27:635–49. Braszko J, Kupryszewski G, Witczuk B, Wiśniewski K. Angiotensin II-(3–8)-hexapeptide affects motor activity, performance of passive avoidance and a conditioned avoidance response in rats. Neuroscience 1988a;27:777–83. Braszko J, Kupryszewski G, Witczuk B, Wisniewski K. Angiotensin II(3–8) hexapeptide affects motor activity, performance of passive avoidance and a conditioned avoidance response in rats. Neuroscience 1988b;27:777–83. Braszko J, Karwowska-Polecka W, Halicka D, Gard P. Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol 2003a;14:323–43. Braszko J, Kulakowska A, Winnicka M. Effects of angiotensin II and its receptor antagonists on motor activity and anxiety in rats. J Physiol Pharmacol 2003b;54:271–81. Braszko J, Walesiuk A, Wielgat P. Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV. J Renin Angiotensin Aldosterone Syst 2006;7:168–74. Chabrashvili T, Kitiyakara C, Blau J, Karber A, Aslam S, Welch W, et al. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol 2003;285:117–24. Chalas A, Conway E. No evidence for involvement of angiotensin II in spatial learning in water maze in rats. Behav Brain Res 1996;81:199–205. Ciobica A, Bild W, Hritcu L, Haulica I. Brain renin–angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia. Acta Neurol Belg 2009;109:171–80. Ciobica A, Hritcu L, Nastasa V, Padurariu M, Bild W. Inhibition of central angiotensin converting enzyme exerts anxiolytic effects by decreasing brain oxidative stress. J Med Biochem 2010;30(2):109–14. Ciobica A, Hritcu L, Bild V, Padurariu M, Bild W. The effects of angiotensin II and its receptor blockers on anxiety status and central oxidative stress in rat. J Neurol 2011;258:69–70. Ciobica A, Olteanu Z, Padurariu M, Hritcu L. The effects of pergolide on memory and oxidative stress in a rat model of Parkinson's disease. J Physiol Biochem 2012;68:59–69. Culman J, Baulmann J, Blume A, Unger T. The renin–angiotensin system in the brain: an update. J Renin Angiotensin Aldosterone Syst 2001;2:96-102. Culman J, Blume A, Gohlke P, Unger T. The renin–angiotensin system in the brain: possible therapeutic implications for AT(1)-receptor blockers. J Hum Hypertens 2002;16:64–70. Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, Gleiter C. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res 2010;13:195–201.

87

Davies N, Kehoe P, Ben-Shlomo Y, Martin R. Associations of antihypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. J Alzheimers Dis 2011;26:699–708. Diener H, Sacco R, Yusuf S, Cotton D, Ounpuu S, Lawton W, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the prevention regimen for effectively avoiding second strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008;7:875–84. Duron E, Hanon O. Antihypertensive treatments, cognitive decline, and dementia. J Alzheimers Dis 2010;20:903–14. Eckman E, Adams S, Troendle F, Stodola B, Kahn M, Fauq A. Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. J Biol Chem 2006;281:30471–8. Eichenbaum H, Cohen N. Memory, amnesia, and the hippocampal system. MIT Press; 1993. Gard P. The role of angiotensin II in cognition and behaviour. Eur J Pharmacol 2002;438: 1-14. Gard P. Cognitive-enhancing effects of angiotensin IV. BMC Neurosci 2008;9:S15. Gard PR, Rusted JM. Angiotensin and Alzheimer's disease: therapeutic prospects. Expert Rev Neurother 2004;4(1):87–96. Gelband C, Zhu M, Lu D, Reagan L, Fluharty S, Posner P. Functional interactions between neuronal AT1 and AT2 receptors. Endocrinology 1997;138:2195–8. Gonzales S, Noriega G, Tomaro M, Peña C. Angiotensin-(1–7) stimulates oxidative stress in rat kidney. Regul Pept 2002;106:67–70. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000;86:494–501. Hanif K, Snehlata Pavar C, Arif E, Biswas P, Fahim M, Pasha M, et al. Effect of 3-thienylalanine-ornithine-proline, new sulfur-containing angiotensin-converting enzyme inhibitor on blood pressure and oxidative stress in spontaneously hypertensive rats. J Cardiovasc Pharmacol 2009;53:145–50. Haulica I, Neamtu C, Stratone A, Petrescu G, Branisteanu D, Rosca V, et al. Evidence for the involvement of cerebral renin–angiotensin system (RAS) in stress analgesia. Pain 1986;27:237–45. Haulica I, Bild W, Mihaila CN, Ionita T, Boisteanu CP, Neagu B. Biphasic effects of angiotensin (1–7) and its interactions with angiotensin II in rat aorta. J Renin Angiotensin Aldosterone Syst 2003;4:124–8. Haulica I, Bild W, Serban N. Angiotensin peptides and their pleiotropic actions. J Renin Angiotensin Aldosterone Syst 2005;6:121–31. Hefco V, Yamada K, Hefco A, Hritcu L, Tiron A, Nabeshima T. Role of the mesotelencephalic dopamine system in learning and memory processes in the rat. Eur J Pharmacol 2003;475:55–60. Hemming M, Selkoe D. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem 2005;280:37644–50. Hou Y, Wang L, Zhou K, Chen Y, Tian Z, Song J, et al. Altered angiotensin-converting enzyme and its effects on the brain in a rat model of Alzheimer disease. Chin Med J (Engl) 2008;121:2320–3. Hritcu L, Clicinschi M, Nabeshima T. Brain serotonin depletion impairs short-term memory, but not long-term memory in rats. Physiol Behav 2007;91:652–7. Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, et al. Continuous activation of renin–angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension 2009;53:356–62. Kerr D, Bevilaqua L, Bonini J, Rossato JI, Kohler C, Medina J, et al. Angiotensin II blocks memory consolidation through an AT2 receptor-dependent mechanism. Psychopharmacology (Berl) 2005;179:529–35. Kumaran D, Udayabanu M, Kumar M, Aneja R, Katyal A. Involvement of angiotensin converting enzyme in cerebral hypoperfusion induced anterograde memory impairment and cholinergic dysfunction in rats. Neuroscience 2008;155:626–39. Laursen J, Rajagopalan S, Galis Z, Tarpey M, Freeman B, Harrison D. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997;95:588–93. Lee E, Ma Y, Wayner M, Armstrong D. Impaired retention by angiotensin-II mediated by the AT(1) receptor. Peptides 1995;16:1069–71. Li N, Lee A, Whitmer R, Kivipelto M, Lawler E, Kazis L. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2011;340:b5465. Llorens-Cortes C, Mendelsohn F. Organisation and functional role of the brain angiotensin system. J Renin Angiotensin Aldosterone Syst 2002;1:39–48. Lopez-Real A, Rey P, Soto-Otero R, Mendez-Alvarez E, Labandeira-Garcia JL. Angiotensin-reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of Parkinsonism. J Neurosci Res 2005;81:865–73. Machado R, Santos R, Andrade S. Opposing actions of angiotensins on angiogenesis. Life Sci 2000;66:67–76. Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G, Berk M. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates — Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 2012;20:127–50. Manschot S, Biessels G, Cameron N, Cotter M, Kamal A, Kappelle L, et al. Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats. Brain Res 2003;966:274–82. Maul B, Von Bohlen Und Halbach O, Becker A, Sterner-Kock A, Voigt JP. Impaired spatial memory and altered dendritic spine morphology in angiotensin II type 2 receptordeficient mice. J Mol Med 2008;86:563–71. Mavroudis I, Fotiou D, Manani M, Njaou S, Frangou D, Costa V, et al. Dendritic pathology and spinal loss in the visual cortex in Alzheimer's disease: a Golgi study in pathology. Int J Neurosci 2011;121:347–54.

88

W. Bild et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 43 (2013) 79–88

McKinley M, Albiston A, Allen A, Mathai M, May C, McAllen R, et al. The brain renin–angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003;35:901–18. Miller S, Norton L, Murphy M, Dalsing M, Unthank J. The role of the renin–angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment. Am J Physiol Heart Circ Physiol 2007;292: 2523–31. Miners S, Ashby E, Baig S, Harrison R, Tayler H, Speedy E. Angiotensinconverting enzyme levels and activity in Alzheimer's disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res 2009;1:163–77. Miners J, van Helmond Z, Kehoe P, Love S. Changes with age in the activities of beta-secretase and the Abeta-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. Brain Pathol 2010;20:794–802. Mogi M, Iwanami Jun, Jing Fei, Tsukuda Kana, Horiuchi Masatsugu. Co-treatment with memantine and compound 21, an angiotensin II type 2 receptor agonist, prevents cognitive decline in type 2 diabetic mice. Alzheimers Dement 2012;8:P707. Morgan J, Routtenberg A. Angiotensin injected into the neostriatum after learning disrupts retention performance. Science 1977;196:87–9. Munzel T, Keaney Jr JF. Are ACE inhibitors a “magic bullet” against oxidative stress? Circulation 2001;104:1571–4. Nikolova J, Getova D, Nikolov F. Effects of ACE inhibitors on learning and memory processes in rats. Folia Med (Plovdiv) 2000;42:47–51. Ohrui T, Matsui M, Yamaya H, Arai S, Ebihara M, Maruyama H. Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in Japan. J Am Geriatr Soc 2004;52:649–50. Padurariu M, Ciobica A, Dobrin I, Stefanescu C. Evaluation of antioxidant enzymes activities and lipid peroxidation in schizophrenic patients treated with typical and atypical antipsychotics. Neurosci Lett 2010a;479:317–20. Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease. Neurosci Lett 2010b;469:6-10. Patrick G, Gordon KW. Is inhibition of the renin–angiotensin system a new treatment option for Alzheimer's disease? Lancet Neurol 2007;6:373–8. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. San Diego: Academic Press Elsevier; 2006. Pedreanez A, Arcaya JL, Carrizo E, Mosquera J. Forced swimming test increases superoxide anion positive cells and angiotensin II positive cells in the cerebrum and cerebellum of the rat. Brain Res Bull 2006;71:18–22. Raghavendra V, Chopra K, Kulkarni S. Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm. Neuropeptides 2001;35:65–9. Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman B, Griendling K, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. J Clin Invest 1996;97:1916–23. Rosenberg P, Mielke M, Tschanz J, Cook L, Corcoran C, Hayden K, et al. Effects of cardiovascular medications on rate of functional decline in Alzheimer disease. Am J Geriatr Psychiatry 2008;16:883–92. Saavedra J. Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol 2005;25:485–512. Saavedra J. Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders. Cell Mol Neurobiol 2012;32:667–81. Santos RAS, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1–7): an update. Regul Pept 2000;91:45–62. Savaskan KC, Hock G, Olivieri S, Bruttel C, Rosenberg C, Hulette F, et al. Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer's dementia. Neurobiol Aging 2001;22:541–6. Sharma B, Singh N. Experimental hypertension induced vascular dementia: pharmacological, biochemical and behavioral recuperation by angiotensin receptor blocker and acetylcholinesterase inhibitor. Pharmacol Biochem Behav 2012;102:101–8. Shepherd J, Bill D, Dourish C, Grewal S, Mclenachan A, Stanhope K. Effects of the selective angiotensin II receptor antagonists losartan and PD123177 in animal models of anxiety and memory. Psychopharmacology (Berl) 1996;126:206–18. Sies H. Oxidative stress: oxidants and antioxidants. Exp Physiol 1997;82:291–5. Sleegers KT, Heijer EJ, van Dijk A, Hofman AM, Bertoli-Avella PJ, Koudstaal MM, et al. ACE gene is associated with Alzheimer's disease and atrophy of hippocampus and amygdala. Neurobiol Aging 2005;26:1153–9.

Stefanescu C, Ciobica A. The relevance of oxidative stress status in first episode and recurrent depression. J Affect Disord 2012;143(1–3):34–8. Tchekalarova J, Albrecht D. Angiotensin II suppresses long-term potentiation in the lateral amygdala of mice via L-type calcium channels. Neurosci Lett 2007;415:68–72. Thone-Reineke C, Zimmermann M, Neumann C, Krikov M, Li J, Gerova N, et al. Are angiotensin receptor blockers neuroprotective? Curr Hypertens Rep 2004;6:257–66. Tota S, Kamat P, Saxena G, Hanif K, Najmi A, Nath C. Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 2011;226:317–30. Tota S, Kamat P, Saxena G, Hanif K, Najmi A, Nath C. Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 2012a;226:317–30. Tota S, Nath C, Najmi AK, Shukla R, Hanif K. Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism. Behav Brain Res 2012b;232:66–76. Tzourio C, Anderson N, Chapman M, Woodward B, Neal S, MacMahon J, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163:1069–75. Vargas R, Rincón J, Pedreañez A, Viera N, Hernández-Fonseca JP, Peña C, et al. Role of angiotensin II in the brain inflammatory events during experimental diabetes in rats. Brain Res 2012;1453:64–76. von Bohlen und Halbach O, Albrecht D. Angiotensin II inhibits long-term potentiation within the lateral nucleus of the amygdala through AT1 receptors. Peptides 1998;19(6):1031–6. von Bohlen und Halbach O, Albrecht D. Identification of angiotensin IV binding sites in the mouse brain by a fluorescent binding study. Neuroendocrinology 2000;72(4): 218–23. von Bohlen und Halbach O. Angiotensin IV in the central nervous system. Cell Tissue Res 2003;311:1–9. von Bohlen und Halbach O, Albrecht D. The CNS renin–angiotensin system. Cell Tissue Res 2006;326:599–616. Walther T, Voigt J, Fukamizu A, Fink H, Bader M. Learning and anxiety in angiotensindeficient mice. Behav Brain Res 1999;100:1–4. Wang D, Chabrashvili T, Borrego L, Aslam S, Umans J. Angiotensin II infusion alters vascular function in mouse resistance vessels: roles of O and endothelium. J Vasc Res 2006;43:109–19. Winnicka M, Braszko J, Wiśniewski K. 6-OHDA lesions to amygdala and hippocampus attenuate memory-enhancing effect of the 3–7 fragment of angiotensin II. Gen Pharmacol 1998;30:801–5. Wright J, Harding J. The brain RAS and Alzheimer's disease. Exp Neurol 2011;223: 326–33. Wyss J, Kadish I, van Groen T. Age-related decline in spatial learning and memory: attenuation by captopril. Clin Exp Hypertens 2003;25:455–74. Yanagitani Y, Rakugi H, Okamura A, Moriguchi K, Takiuchi S, Ohishi M. Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 1999;33:335–9. Yao E, Fukuda N, Matsumoto T, Kobayashi N, Katakawa M, Yamamoto C, et al. Losartan improves the impaired function of endothelial progenitor cells in hypertension via an antioxidant effect. Hypertens Res 2007;30:1119–28. Yasar S, Zhou J, Varadhan R, Carlson C. The use of angiotensin converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women. Clin Pharmacol Ther 2008;84:119–26. Yasar S, Lin F, Fried L, Kawas C, Sink K, DeKosky S, et al, Ginkgo Evaluation of Memory (GEM) Study Investigators. Diuretic use is associated with better learning and memory in older adults in the Ginkgo Evaluation of Memory Study. Alzheimers Dement 2012;8:188–95. Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T. Angiotensin II induced cerebral microvascular inflammation and increased blood–brain barrier permeability via oxidative stress. Neuroscience 2010;171:852–8. Zhang Z, Deng L, Yu H, Shi Y, Bai F, Xie C, Yuan Y, Jia J, Zhang Z. Association of angiotensin-converting enzyme functional gene I/D polymorphism with amnestic mild cognitive impairment. Neurosci Lett 2012;514(1):131–5.