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Psychiatry Psychiatry and Clinical Clinical Neurosciences Neurosciences 2015 2016; 70: 159–166

doi:10.1111/pcn.12371 doi:10.1111/pcn.12371

Regular Article

Effect of subchronic administration of agomelatine on brain energy metabolism and oxidative stress parameters in rats Aline Haas de Mello, MSc,1 Luana da Rosa Souza, BSc,1 Ana Carla Moreira Cereja, BSc,1 Rosiane de Bona Schraiber, BSc,1 Drielly Florentino, MSc,1 Maryane Modolon Martins, BSc,1 Fabricia Petronilho, PhD,1 João Quevedo, PhD2,3 and Gislaine Tezza Rezin, PhD1* 1 Laboratory of Clinical and Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Tubarão, 2Laboratory of Neuroscience, Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil, and 3Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, USA

Aims: The aim of this study was to investigate the effect of subchronic administration of agomelatine on energy metabolism, oxidative stress markers and antioxidant defense in the brains of rats. Methods: The animals received daily intraperitoneal injections of agomelatine (10, 30 or 50 mg/kg) or saline for 14 days. The prefrontal cortex, cerebellum, hippocampus, striatum and posterior cortex were analyzed. Results: The findings showed that complex I was activated in the prefrontal cortex, cerebellum and striatum and inhibited in the posterior cortex at the 10-mg/kg dose, and inhibited in all brain areas analyzed at the 30-mg/kg and 50-mg/kg doses. Complex II was activated in the posterior cortex at the 50-mg/kg dose. Complex IV was inhibited in the striatum and posterior cortex at the 10-mg/kg dose, inhibited in the striatum at the 30-mg/kg dose and activated in the hippocampus at the 50-mg/kg dose.

EVERAL STUDIES HAVE shown that major depression is associated with impairment of brain energy metabolism and with oxidative stress.1–7 Mitochondria provide most of the energy to cells and are involved in the regulation of free radicals.5,8 It has

S

*Correspondence: Gislaine Tezza Rezin, PhD, University of Southern Santa Catarina, Av. José Acácio Moreira, 787, Tubarão, 88704-900, SC, Brazil. Email: [email protected] Received 9 April 2015; revised 25 August 2015; accepted 5 November 2015.

Creatine kinase activity was inhibited in the striatum at the 10-mg/kg and 30-mg/kg doses. Lipid peroxidation and protein carbonylation levels were not changed after the administration of agomelatine. Superoxide dismutase activity was increased in the striatum at the 10-mg/kg dose, and catalase activity was inhibited in the cerebellum at the 10-mg/kg dose and increased in the posterior cortex at the 30-mg/kg dose.

Conclusions: Our results are consistent with other studies showing that some antidepressants may influence brain energy metabolism and oxidative stress parameters and expand knowledge about the effects of agomelatine in biochemical parameters in the brains of rats. Key words: agomelatine, creatine kinase, depression, mitochondrial respiratory chain, oxidative stress.

been demonstrated that the malfunctioning of the sequence of biochemical reactions involved in the production of adenosine triphosphate (ATP), known as mitochondrial dysfunction, is associated with the pathophysiology of major depression.2,9–11 Most of the cell energy is obtained via oxidative phosphorylation, a process that requires the action of multiple enzymatic complexes (complexes I, II, III and IV), called mitochondrial respiratory chain.8 Besides, creatine kinase also plays a role in the metabolism of high-energy consuming tissues, such as the brain, and serves as an alternative production system of ATP.12

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Studies using animal models showed inhibition in activity of mitochondrial respiratory chain complexes in rat brains after chronic stress,1,2 and a study conducted with depressed patients showed that they have reduced glucose metabolism in some brain regions.13 Furthermore, the oxidative phosphorylation generates reactive oxygen species (ROS) and the electron transport chain in mitochondria is vulnerable to damage by these.5,14 ROS are controlled or eliminated by antioxidant systems,15 which consist of various enzymes and compounds that include superoxide dismutase (SOD) and catalase (CAT).16 The oxidative stress process refers to an imbalance between ROS production and antioxidant defenses, and leads to oxidation of biomolecules, such as lipids, proteins and DNA, with subsequent loss of their biological functions.17 The brain is considered more vulnerable to oxidative stress than other tissues because it metabolizes 20% of total body oxygen, and has limited antioxidant capacity.18 In this context, there is increasing evidence that oxidative stress may be associated with major depression.1,3,4,19 Hereupon, it is suggested that the impairment of energy metabolism and oxidative stress could participate in the therapeutic or side-effects of antidepressants.5 In this sense, it has already been shown that some antidepressants can increase energy metabolism and reduce damage caused by oxidative stress.6,12,20–26 However, many molecular mechanisms of some antidepressants have not yet been sufficiently clarified.5 Agomelatine is the first antidepressant agent with a non-monoaminergic action mechanism, which acts on the melatonin receptors.27 Agomelatine has shown to be effective, safe, and well tolerated, making it an option for patients who do not respond to conventional treatments based on monoaminergic theory.28 In addition, a study with cell culture conducted by Akpinar et al.29 pointed out that agomelatine has antioxidant activity. Therefore, considering that the effects of agomelatine related to brain energy metabolism and oxidative stress are little known, we evaluated the effect of subchronic administration of agomelatine on energy metabolism (activity of complexes of the mitochondrial respiratory chain and of creatine kinase), oxidative stress markers (lipid peroxidation and protein carbonylation) and antioxidant defense (SOD and CAT activities) in the brains of rats.

Psychiatry and Psychiatry Clinical Neurosciences 70: 159–166 and Clinical 2016; Neurosciences 2015

METHODS Animals Male Wistar rats (250–300 g) were obtained from the Central Animal House of UNISUL. Animals were housed in groups of six, had free access to chow and water, and were maintained on a 12-h light–dark cycle at 23 ± 1° C. The experiments followed the Guide for the Care and Use of Laboratory Animals (National Institutes of Health) and had the approval of the UNISUL Ethics Committee (protocol 12.003.4.06.IV). Moreover, all efforts were made to minimize animal suffering, as well as to reduce the number of animals.

Treatment Animals received daily intraperitoneal injections of agomelatine (10, 30 or 50 mg/kg) in 1.0 mL/kg volume for 14 days. The drug was dissolved in saline solution (vehicle). Control animals received the vehicle (1.0 mL/kg).

Tissue and homogenate preparation Twenty-four hours after the last injection, the animals were killed by decapitation. The brain was removed and the prefrontal cortex, hippocampus, striatum, cerebellum and posterior cortex were isolated. To measure the activity of mitochondrial respiratory chain enzymes and of creatine kinase, the samples were homogenized in sucrose, ethylenediaminetetraacetic acid, trizma base and heparin (SETH) buffer and the homogenates were centrifuged at 3000 r.p.m. for 10 min. To measure the oxidative damage in lipids, the samples were homogenized in phosphate buffer and the homogenates were centrifuged at 2500 r.p.m. for 10 min. To measure the oxidative damage to proteins, the samples were homogenized in phosphate buffer and the homogenates were centrifuged at 14 000 r.p.m. for 15 min. To measure SOD activity, the samples were homogenized in glycine buffer and the homogenates were centrifuged at 3000 r.p.m. for 10 min. To measure CAT activity, the samples were homogenized in phosphate buffer and the homogenates were centrifuged at 3000 r.p.m. for 10 min. After homogenization, the supernatants were stored at −70°C until they were used for biochemical analyses. Protein content was determined by the method

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described by Lowry and colleagues30 using bovine serum albumin as standard.

thiobarbituric acid reactive substances, as described by Draper and Hadley.35 Samples were mixed with trichloroacetic and thiobarbituric acids. Subsequently, the samples were incubated in a water bath at 100° C for 30 min. The levels of malondialdehyde and equivalents were determined by absorbance at 532 nm. The oxidative damage to proteins (protein carbonylation) was assessed according to Levine et al.,36 by quantification of carbonyl groups based on the reaction with dinitrophenylhydrazine (DNPH). Proteins are precipitated by the addition of trichloroacetic acid and dissolved in DNPH. The absorbance was evaluated in a spectrophotometer at 370 nm. SOD activity was assayed by measuring the inhibition of adrenaline auto-oxidation, according to Bannister and Calabrese,37 by measuring the speed of adrenochrome formation, determined spectrophotometrically at 480 nm in a reaction medium containing glycine-NaOH and adrenaline. CAT activity was determined by measuring the rate of decrease in absorbance of hydrogen peroxide, as described by Aebi.38 A sample aliquot was added to a substrate mixture containing hydrogen peroxide and phosphate buffer. Initial and final absorbances were recorded at 240 nm after 1 and 6 min, respectively.

Activities of mitochondrial respiratory chain enzymes Complex I activity was evaluated according to Cassina and Radi31 by the determination of the rate of nicotinamide adenine dinucleotide (NADH)dependent ferricyanide reduction. The sample was added to an incubation medium containing potassium phosphate buffer, ferricyanide, NADH and rotenone. Spectrophotometric reading was performed for 3 min, at 420 nm. Complex II activity was determined by the method described by Fischer et al.,32 measured by following the decrease in absorbance due to the reduction of 2.6-dichloroindophenol (DCIP). The sample was added to an incubation medium containing potassium phosphate buffer, sodium succinate and DCIP. Incubation was carried out for 20 min at 30°C in a water bath. After incubation, sodium azide, rotenone and DCIP were added to samples, and spectrophotometric reading was performed for 5 min, at 600 nm. Complex IV activity was assayed according to Rustin et al.,33 measured by following the decrease in absorbance due to the oxidation of previously reduced cytochrome c. The sample was added to an incubation medium containing potassium phosphate buffer, lauryl maltoside and cytochrome c. After that, the reading was carried out in a spectrophotometer for 10 min, at 550 nm.

Creatine kinase activity Creatine kinase activity was estimated according to Hughes.34 The sample was added to an incubation medium containing lauryl maltoside, tris buffer and phosphocreatine. After this, samples were placed in a water bath at 37°C. After 15 min, adenosine diphosphate was added and samples were placed again in a water bath for 10 min. Thereafter, p-hydroxymercuribenzoic acid, alpha-naphthol, diacetyl and distilled water were added to samples, which were placed in a water bath again for 20 min. Finally, the creatine formed was measured in a spectrophotometer at 540 nm.

Oxidative stress parameters The oxidative damage to lipids (lipid peroxidation) was determined based on the formation of

Statistical analysis Data were presented as mean ± SD and were analyzed by one-way analysis of variance (ANOVA) followed by Tukey’s test when F was significant. All analyses were performed using SPSS (SPSS, Chicago, IL, USA). Differences were considered significant when P < 0.05.

RESULTS In the present study, we evaluated the activity of complexes I, II, and IV of the mitochondrial respiratory chain, creatine kinase activity, lipid peroxidation, protein carbonylation, SOD and CAT activities in the brains of rats after subchronic administration of agomelatine (10, 30 or 50 mg/kg for 14 days). Our findings revealed that complex I activity was activated in the prefrontal cortex, cerebellum and striatum at the 10-mg/kg dose, inhibited in the posterior cortex at the 10-mg/kg dose and inhibited in the prefrontal cortex, cerebellum, hippocampus, striatum and posterior cortex at the 30-mg/kg and 50-mg/kg doses (Fig. 1a). Complex II activity was activated in the posterior cortex at the 50-mg/kg dose (Fig. 1b). Complex IV activity was inhibited in the striatum and

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Figure 1. Energy metabolism after subchronic administration of agomelatine in the prefrontal cortex, cerebellum, hippocampus, striatum and posterior cortex of rats. Values are expressed as mean ± SD (n = 6). *Different from saline; P < 0.05 (one-way analysis of variance followed by Tukey’s test). ( ) Saline; ( ) 10 mg/kg agomelatine; ( ) 30 mg/kg agomelatine; ( ) 50 mg/kg agomelatine.

posterior cortex at the 10-mg/kg dose, inhibited in the striatum at the 30-mg/kg dose and activated in the hippocampus at the 50-mg/kg dose (Fig. 1c). Moreover, creatine kinase activity was inhibited in the striatum at the 10-mg/kg and 30-mg/kg doses (Fig. 1d). The results also showed that lipid peroxidation and protein carbonylation levels showed no statistically significant changes after subchronic administration of agomelatine (Fig. 2a,b, respectively). However, SOD activity was increased in the striatum at the 10-mg/kg dose (Fig. 2c), and CAT activity was inhibited in the cerebellum at the 10-mg/kg dose and increased in the posterior cortex at the 30-mg/kg dose (Fig. 2d).

DISCUSSION This study evaluated the effect of subchronic administration of agomelatine (10, 30 or 50 mg/kg) on energy metabolism and oxidative stress parameters in the brains of rats. Papp et al.39 showed that

agomelatine (10 and 50 mg/kg) reversed the reduction in sucrose consumption induced by chronic mild stress in rats, demonstrating antidepressant-like activity in these doses. El Yacoubi et al.40 demonstrated that agomelatine (50 mg/kg) significantly reduced immobility duration in the tail suspension test in a genetic model of depression, and both agomelatine doses (10 and 50 mg/kg) significantly increased the sucrose preference, indicating that agomelatine has antidepressant properties in these doses.40 Our findings showed that, in most brain structures, complex I of mitochondrial respiratory chain was activated at the lowest dose and inhibited at the highest doses. The activation of complex I with the lowest dose may be an effect in attempt to guarantee adequate production of ATP via oxidative phosphorylation. In contrast, the highest doses may have had toxic effects on complex I, compromising the activity. Complex II was activated only in the posterior cortex at the highest dose. Complex II was probably less affected because complex I is the main entrance of electrons and may be more susceptible to alterations.

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Psychiatry and and Clinical Clinical Neurosciences Neurosciences 2015 2016; 70: 159–166 Psychiatry

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Figure 2. Oxidative stress parameters after subchronic administration of agomelatine in the prefrontal cortex, cerebellum, hippocampus, striatum and posterior cortex of rats. Values are expressed as mean ± SD (n = 6). *Different from saline; P < 0.05 (one-way analysis of variance followed by Tukey’s test). ( ) Saline; ( ) 10 mg/kg agomelatine; ( ) 30 mg/kg agomelatine; ( ) 50 mg/kg agomelatine. CAT, catalase; MDA, malondialdehyde; SOD superoxide dismutase.

Another option is that agomelatine may have more affinity with complex I receptors and thus cause more changes in this enzyme. Complex IV was inhibited in some structures at the lower doses and activated in the hippocampus at the highest dose. These alterations may be due to an adaptation mechanism after the effects of agomelatine in complex I. The creatine kinase activity was inhibited in the striatum at the lower doses. This inhibition may be due to an imbalance of the mitochondrial respiratory chain, which may lead to ROS production, thus damaging creatine kinase structure. Studies have shown that major depression is associated with impairments in brain energy metabolism.1,2,13 Mitochondrial dysfunction causes an increased production of ROS,14,41 and the excess of ROS can cause more damage in mitochondria, undermining the ability of mitochondria to meet cell energy demand and may lead to the production of even more ROS.42 Drugs used to treat major depression could boost energy metabolism and thus reduce damage caused

by oxidative stress.10 In this context, several studies have shown that some antidepressants may improve energy metabolism.5,12,20–22 Assis et al.20 demonstrated that ketamine and imipramine increased creatine kinase activity in the rat brain. Santos and colleagues12 showed that chronic administration of paroxetine also increased creatine kinase activity in the rat brain. Scaini et al.21 demonstrated that paroxetine, nortriptyline and venlafaxine caused an increase in activity of some complexes of the mitochondrial respiratory chain in the brains of rats. Ferreira et al.22 showed that bupropion increased some enzymes of brain energy metabolism in rats. In addition, some studies have demonstrated that antidepressants can inhibit cerebral energy metabolism.43–45 Agostinho et al.43 showed that fluoxetine inhibited the creatine kinase activity in the rat brain. Hroudova and Fisar44 studied in vitro effects of eight different antidepressants on the mitochondrial respiratory chain, and showed that most of them inhibited the activity of complexes (complex I and IV were most affected). Gonçalves et al.45 showed

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that chronic administration of escitalopram decreased the activities of some complexes of the mitochondrial respiratory chain in the rat brain. Our results also revealed that oxidative stress markers (lipid peroxidation and protein carbonylation levels) have not changed significantly after subchronic administration of agomelatine. Since lipid peroxidation and protein carbonylation indicate oxidative damage to lipids and proteins, respectively, our results showed that agomelatine did not affect this parameter, but in an animal model of depression this result can be different. Furthermore, Réus et al.46 showed that imipramine and harmine reduced lipid and protein oxidation in the prefrontal cortex and hippocampus of rats. Analyses of antioxidant defense showed that SOD activity was increased in the striatum at the lowest dose, whereas the CAT activity was decreased in the cerebellum at the lowest dose and increased in the posterior cortex at the 30-mg/kg dose. Increasing evidence suggests that some antidepressants could have antioxidant properties.6,25,26 An in vitro study conducted by Kolla et al.47 showed that amitriptyline and fluoxetine were associated with increased SOD activity, suggesting that the neuroprotective actions of some antidepressants include the upregulation of SOD activity. Réus et al.46 showed an increase in SOD and CAT activities in the prefrontal cortex and hippocampus of rats after treatment with imipramine and harmine. Abdel-Wahab and Salama24 showed that venlafaxine has antioxidant properties by enhancing the antioxidant defenses and attenuation of oxidative stress in mice. In the serum of patients with major depression, initial lower concentrations of SOD were increased after 8 weeks with antidepressant treatment.26 Cumurcu et al.23 assessed the effect of sertraline, paroxetine and escitalopram for 3 months in depressed patients and showed that these agents increased total antioxidant capacity and decreased total oxidant status and oxidative stress index. There are few studies evaluating these effects of agomelatine. In a study with neuronal cells exposed in cell culture conducted by Akpinar et al.,29 the lipid peroxidation levels were significantly lower in the agomelatine group. In addition, the same study showed that glutathione and glutathione peroxidase values were significantly higher in the agomelatine group, showing an antioxidant role of agomelatine in neurons.29 Therefore, given that antioxidants can protect against neuronal damage caused by oxidative stress,

and consequently may contribute to the remission of depressive symptoms, the increase in activity of SOD and of CAT in the posterior cortex and striatum after agomelatine administration shows that maybe this can be a beneficial effect of this agent in the treatment of major depression. In this context, Behr et al.25 showed evidence that the recovery from a major depressive episode may be associated with normalization of antioxidant potential induced by antidepressants. These authors examined the preclinical and clinical literature on oxidative/antioxidant effects of antidepressant agents and concluded that most data support that antidepressants exert antioxidant effects (agomelatine was not studied in this review).25 Furthermore, our findings show that agomelatine alters energy metabolism and antioxidant defense in different brain structures. Regarding the energy metabolism, we found that, in general, complex I, the main entrance of electrons in the mitochondrial respiratory chain, was the most affected. Therefore, we suppose that some adaptation mechanism was activated during electron transport after exposure to agomelatine. Moreover, we still cannot explain why certain brain structures are most affected by agomelatine or because CAT activity presented an inhibition in the cerebellum whereas CAT and SOD activity had an increase in the posterior cortex and striatum. We suggest a relation between brain structures and amount of melatonin receptors in each region, as this is the location of action of agomelatine. In conclusion, our findings are consistent with other studies that suggest that some antidepressants can modulate energy metabolism and oxidative stress parameters in the brain and expand knowledge about the effects of the first non-monoaminergic antidepressant in these biochemical parameters.

ACKNOWLEDGMENTS This research was supported by UNISUL.

DISCLOSURE STATEMENT The authors declare no conflict of interest.

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