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

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Abstract

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) (p < 0.0001) and a decrease in both antioxidant enzymes determined: superoxide dismutase-SOD (p < 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.

Highlights

► Ang II induced memory deficits in Y-maze/passive avoidance and oxidative stress ► Ang II receptor or ACE blockers resulted in memory improvement especially in Y-maze. ► Ang II receptor or ACE blockers reduced oxidative stress status in the hippocampus.

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 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 two different highly-specific receptors called AT1 and AT2 (Culman et al., 2001, Culman et al., 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, Braszko, 2005, Braszko et al., 1988a, Braszko et al., 1988b, Braszko et al., 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 angiotensin-converting 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, Tota et al., 2012b).

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.

Section snippets

Animals

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

Results

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, p < 0.0001) (Fig. 1), suggesting significant effects on short-term 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

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

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 here a significant correlation between these memory related behavioral parameters and the

Acknowledgments

Ciobica Alin is supported by a POSDRU grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi.

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