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ARTICLE Anti-depressant effect of hesperidin in diabetic rats Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by MCGILL UNIVERSITY on 11/21/14 For personal use only.

Salma A. El-Marasy, Heba M.I. Abdallah, Siham M. El-Shenawy, Aiman S. El-Khatib, Osama A. El-Shabrawy, and Sanaa A. Kenawy

Abstract: This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)−1, by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)−1·day−1, per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)−1·day−1, per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain. Key words: hesperidin, anti-depressant, forced swimming test, streptozotocin, fluoxetine. Résumé : Cette étude visait a` examiner le possible effet antidépresseur de l'hespéridine (Hsp) chez des rats dont le diabète a été induit par la streptozotocine (STZ). De plus, l'effet de l'Hsp sur l'hyperglycémie, le stress oxydant, l'inflammation, le facteur neurotrophique dérivé du cerveau (BDNF, brain derived neurotrophic factor) et les monoamines du cerveau chez les rats diabétiques, a aussi été évalué. L'hyperglycémie a été induite chez des rats Wistar par une seule dose de STZ (52.5 mg·(kg de masse corporelle)−1) administrée par voie i.p., a` l'exception du groupe normal qui a reçu le véhicule. Les rats souffrants d'hyperglycémie ont reçu de l'Hsp par voie orale (25,0, 50,0 ou 100,0 mg·(kg de masse corporelle)−1·jour−1) et de la fluoxétine (Flu) (5,0 mg·(kg de masse corporelle)−1·jour−1), 48 h après l'injection de STZ pendant 21 jours consécutifs. Le groupe normal et le groupe STZ contrôle ont reçu le véhicule de façon similaire. Des paramètres comportementaux et biochimiques ont alors été évalués. Le traitement a` l'Hsp renversait la prolongation de la période d'immobilité induite par la STZ lors d'un test de nage forcée, et il atténuait l'hyperglycémie, il diminuait le contenu en malonaldéhyde (MDA) et accroissait le contenu en glutathion réduit dans le cerveau, de même que le contenu en BDNF. L'Hsp atténuait les modifications neurochimiques induites par la STZ, ce qui se traduisait par un accroissement des contenus en monoamines dans le cerveau, notamment la norépinéphrine, la dopamine et la sérotonine. Tous ces effets de l'Hsp étaient similaires a` ceux observés avec l'antidépresseur bien connu, la Flu. Cette étude montre que l'effet antidépresseur exercé par l'Hsp chez les rats diabétiques peut faire intervenir en partie l'amélioration de l'hyperglycémie, ses activités anti-oxydantes et anti-inflammatoires, l'accroissement de la neurogenèse de même que la modification des contenus en monoamines dans le cerveau. [Traduit par la Rédaction] Mots-clés : hespéridine, antidépresseur, test de la nage forcée, streptozotocine, fluoxétine.

Introduction Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycaemia, which may result from defects in insulin secretion, or an impaired response to insulin, i.e., insulin resistance (American Diabetes Association 2010). According to the Diabetes Atlas of the International Diabetes Federation, by 2030 it is expected that about 552 million adults worldwide will be affected by this disease (Seshasai et al. 2011; Whiting et al. 2011). Clinical studies have reported that diabetic patients have a nearly 30% higher risk for depression than the general population, and depression is associated with worsened diabetes out-

comes (Champaneri et al. 2010). Experimentally, rats with diabetes induced with streptozotocin (STZ) showed depressive-like behavior when submitted to the forced swimming test (FST), which is a predictive animal model of depression (Gomez and Barros 2000). It has been documented that chronic hyperglycaemia promotes free radical accumulation that, in turn, results in inflammation and inflammatory-related responses (Li et al. 2014b). In fact, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-␣), have been reported to play a dual role, i.e., in the development of diabetes as well as depression (Tuttle et al. 2004; Luppino et al. 2010; Stuart and Baune 2012). Brain-derived neurotrophic factor (BDNF) is promi-

Received 21 July 2014. Accepted 17 September 2014. S.A. El-Marasy, H.M.I. Abdallah, S.M. El-Shenawy, and O.A. El-Shabrawy. Department of Pharmacology, National Research Centre, 12622 Cairo, Egypt. A.S. El-Khatib and S.A. Kenawy. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Corresponding author: Salma A. El-Marasy (e-mail: [email protected]). Can. J. Physiol. Pharmacol. 92: 945–952 (2014) dx.doi.org/10.1139/cjpp-2014-0281

Published at www.nrcresearchpress.com/cjpp on 19 September 2014.

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nent in the development, survival, and function of neurons; it improves glucose metabolism as well as insulin sensitivity (Yamanaka et al. 2007; Arentoft et al. 2009; Noble et al. 2011). Many studies have demonstrated the importance of neurotrophins, especially BDNF, in the pathophysiology of diabetes as well as depression (Réus et al. 2011; Taliaz et al. 2011). Diabetes mellitus is accompanied by alterations in brain monoaminergic neurotransmitters, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-HT), which can result in depression (Fang et al. 2014; Li et al. 2014a). Although classical anti-depressants are recommended as the first-choice drugs for treatment of depression associated with diabetes, through restoration of brain monoamines, mainly NE and 5-HT, animal and human studies have shown that they can interfere with blood glucose levels (Gomez and Barros 2000; Khoza et al. 2012). Thus, efforts have been directed towards the development of herbal and dietary supplements to be used as anti-depressants with fewer side effects (Yi et al. 2010; Hurley et al. 2013). Hesperidin (Hsp), a naturally occurring flavanone glycoside, is predominant in citrus fruits (Yang et al. 2012). Therapeutically useful properties of Hsp have been described, such as anti-diabetic (Ahmad et al. 2012), anti-oxidant (Yang et al. 2012), neuroprotective (Hwang and Yen 2008), and anti-cancer (Lee et al. 2010). Although it has been suggested that Hsp possesses anti-depressant like properties and may be a source of interest as a therapeutic agent for the treatment of depressive disorders (Souza et al. 2013), according to the author's knowledge, its anti-depressant activity in STZ-induced diabetes has not yet been elucidated. Therefore, our study attempted to investigate the possible antidepressant like effect of Hsp in STZ-induced diabetic rats using the FST. Additionally, the roles of hyperglycaemia, oxidative stress, inflammation, BDNF, and brain monoamines in the antidepressant-like activity of Hsp in diabetic rats were assessed. Fluoxetine (Flu) was used as the standard anti-depressant drug for comparison.

Materials and methods Animals Male albino Wistar rats weighing 290–320 g were used throughout the experiment. They were obtained from the animal house colony of the National Research Centre (Dokki, Cairo, Egypt) and were housed for at least one week in the laboratory room prior to testing under standard housing conditions. Animals were fed standard laboratory pellets with water ad libitum. All animal procedures were performed in accordance with the Ethics Committee of the National Research Centre, Egypt (registration number 13/022). Drugs and chemicals Streptozotocin was purchased from Sigma–Aldrich (Missouri, USA), fluoxetine hydrochloride (Flu) was provided by Amoun Pharmaceutical Industries (Cairo, Egypt). Hesperidin (Hsp) was purchased from Sigma–Aldrich. All other reagents used in the experiments were of analytical grade and of the highest purity. Induction of diabetes Rats were fasted overnight and then hyperglycaemia was induced with a single intraperitoneal injection of STZ (52.5 mg·(kg body mass)−1) that was freshly dissolved in 0.1 mol·L−1 citrate buffer (pH 4.5) (Barrière et al. 2012). After the STZ injection, the treated rats received a 5% glucose solution instead of drinking water for 24 h to reduce death due to hypoglycemic shock. Forty-eight hours after the STZ injection, blood samples were taken from the tail vein, and blood glucose levels were measured with a portable glucometer. Only rats with fasting blood glucose levels ≥250 mg·dL−1 were selected as the hyperglycaemic animals to be used for further experimentation.

Can. J. Physiol. Pharmacol. Vol. 92, 2014

Drug treatments Rats were weighed and randomly allocated to 6 groups (8 rats in each) as follows: group I rats received distilled water and served as the normal group; group II was the hyperglycaemic control group; groups III–V comprised hyperglycaemic rats that were orally treated with Hsp (25.0, 50.0, and 100.0 mg·(kg body mass)−1·day−1), respectively; group IV rats were orally treated with Flu (5.0 mg·kg−1·day−1) for 21 consecutive days. Treatment started 48 h after STZ administration. Normal and hyperglycaemic control rats similarly received the vehicle. The selection of the doses of Hsp was based on the previously published data of Raza et al. (2011). The dose of Flu was selected according to the previously published data of Vidal et al. (2009). Body mass changes Each rat was weighed at the beginning of the experiment (initial body mass) and 24 h following the last treatment (final body mass). The percent change in body mass was calculated as follows: % change in body mass ⫽

mass ⫺ initial body mass 共 final bodyInitial 兲 × 100 body mass

Determination of blood glucose levels Blood glucose levels were measured with a portable glucometer (OKmeter, OK Biotech) 24 h following the last treatment. Blood samples were withdrawn from the rats using the tail vein puncture method, and a drop of blood was placed on the glucometer strip loaded in the apparatus for blood glucose determination. Results are expressed in milligrams of glucose per decilitre of blood. Behavioral tests Locomotor activity test Spontaneous locomotor activity of the rats was measured by using a grid floor activity cage (Model No. 7430, Ugo-Basile, Comerio, Italy) to detect the rat's movements. Movements by the rat that interrupted infrared beams were automatically detected, and the beam-interruption information was processed by the activity cage software to provide counts of horizontal movements. Before STZ injection, rats were acclimated to the test room for 1 h. Then, each rat was placed individually into the activity cage for a 10 min session and the basal activity counts were recorded. At the end of the session, each rat was gently removed from the activity cage, and then returned to their home cage. The arena was wiped out with a 70% (v/v) alcohol solution in distilled water between sessions to prevent olfactory cues. Twenty-four hours after the last administration of the test drugs, each rat was then re-exposed to the activity apparatus for a 10 min test session and the final activity counts were recorded (Thome et al. 2001). Percent of basal activity counts was calculated as follows: % of basal activity counts ⫽ (final activity counts/basal activity counts) × 100

Forced swimming test The FST was designed as described by Porsolt et al. (1978) and modified by Cryan et al. (2002a, 2002b) and Estrada-Camarena et al. (2006). A vertical plexiglas cylinder, 46 cm high and 20 cm wide was filled with tap water (23–25 °C) to a depth of 30 cm, so that rats could not support themselves by touching the bottom with their paws or tail. After 23 days of STZ injection animals were submitted to the FST. Two swimming sessions were conducted by placing each rat in the plexiglas cylinder filled with water. In the pre-test session, the rat was forced to swim for a 10 min period. After the pre-test session, the rat was removed from the cylinder, dried with a towel, and then returned to its home cage. The water in the cylinder was replaced after each test. Twenty-four hours later, the rat was re-exposed to the same experimental conditions for 5 min. Published by NRC Research Press

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The test session was video recorded via a camera positioned above the cylinder for subsequent analysis (Kang et al. 2005). Immobility duration was recorded. The rat was judged to be immobile whenever it stopped all active behavior and remained floating in the water with minimal movements, and with its head just above the water. Brain homogenate preparation Rats were euthanized by decapitation 1 h following the FST. The whole brain was carefully excised, dissected through the midline into the 2 hemispheres (right and left), immediately weighed to avoid any effects from drying, and stored at −80 °C. The right hemisphere of each brain was homogenized (MPW-120; Medical Instruments) in 20% (w/v) ice-cold phosphate buffer. Then, the homogenate was centrifuged using a cooling centrifuge (2k15; Sigma/Laborzentrifugen) at 1538g for 5 min and the resulting supernatant was used for determining the brain contents of malondialdhyde (MDA), reduced glutathione (GSH), interleukin 6 (IL-6), and BDNF. The left hemisphere of each brain was homogenized in 75% (v/v) HPLC grade methanol (Doummar & Sons, Adra, Syria). Then the homogenate was centrifuged using cooling centrifuge at 2403g for 10 min, and the resulting supernatant was used for determination of brain levels of NE, DA, and 5-HT. Determination of lipid peroxidation in the brain Lipid peroxidation was assayed by measuring brain levels of MDA according to the method of Ruiz-Larrea et al. (1994). The supernatant was read spectrophotometrically at 532 nm, and the brain content is expressed in nanomoles of MDA per milligram of brain tissue. Determination of GSH in the brain The brain levels of GSH were determined according to the method described by Ellman (1959). Calculation of GSH was based on a standard glutathione curve and is expressed in micromoles of GSH per gram of brain tissue. Determination of IL-6 in the brain IL-6 levels in the rat brain were estimated using a rat-specific immunoassay kit (Rat IL-6 ELISA) from Glory Science (Del Rio, Texas, USA) according to the manufacturer's protocol. The intensity of the colored product was directly proportional to the concentration of rat IL-6, as evaluated using a microplate reader (Biotech ELx800; Biotech Instruments) set at 450 nm. The sample concentration was determined against a standard curve and is expressed in nanograms of IL-6 per gram of brain tissue. Determination of BDNF in the brain BDNF levels were estimated using a rat-specific immunoassay kit (Rat BDNF ELISA) from Glory Science, according to the manufacturer's protocol. The intensity of the colored product was directly proportional to the concentration of rat BDNF, as determined using a microplate reader (Biotech ELx800) set at 450 nm. The sample concentration was determined against a standard curve and is expressed in nanograms of BDNF per gram of brain tissue. Determination of monoamines in the brain Brain monoamines, namely, NE, DA, and, 5-HT, were estimated using HPLC (Agilent 1200 series; Agilent Technologies, California, USA) according to method described by Pagel et al. (2000). Brain levels of monoamines are expressed in micrograms of monoamine per gram of brain tissue, and were calculated as follows: Monoamine content (␮g · (g brain tissue)⫺1) ⫽ AT /AS × CS × dilution factor

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where: AT = area under the curve for the sample, AS = area under the curve for the standard, CS = concentration of the standard (␮g·mL−1), and the dilution factor = 10. Statistical analysis Data concerning the locomotor activity test, FST, and biochemical analysis are presented as the mean ± SEM for 8 rats per group in the behavioral tests and 6 rats per group in the biochemical tests. Comparisons between more than 2 groups in the locomotor activity test were carried out using 2-way analysis of variance (ANOVA) followed by Tukey's multiple comparisons test. Comparisons between more than 2 groups in the FST and biochemical analyses were carried out using one-way ANOVA followed by Tukey's multiple comparisons test, except for the comparison of monoamine content between more than 2 groups, which was carried out using the least significant difference (LSD) multiple comparisons test. All analyses utilized GraphPad Prism 6.0 statistical package for Windows (GraphPad, San Diego, Calif.). Statistical significance was set at p < 0.05.

Results Figure 1 shows that the induction of diabetes with a single i.p. dose of STZ (52.5 mg·kg−1) was associated with a significant loss in body mass (ca. 31.51%) 24 days after STZ administration, whereas normal rats showed a significant gain in body mass (ca. 6.75%). Oral administration of 25.0 mg Hsp·kg−1 after 48 h of STZ injection for 21 successive days produced a significant gain in body mass (ca. 8.25%); 50.0 mg Hsp·kg−1·day−1 reduced the loss of body mass by ca. 19.41%; and 100.0 mg Hsp·kg−1·day−1 produced a significant loss in body mass by 30.68%. In the same manner, Flu (5.0 mg·kg−1·day−1 also significantly reduced body mass loss (ca. 20.17%). STZ-induced diabetic rats had significantly elevated blood glucose levels, 582.0 mg·dL−1, whereas blood glucose levels in the normal group were 99.25 mg·dL−1. Oral administration of Hsp (25.0, 50.0, or 100.0 mg·kg−1·day−1) produced a significant decrease in blood glucose levels (to 20.73%, 62.74%, and 63.35% of the STZ control group values, respectively). Similarly, oral administration of Flu (5.0 mg·kg−1·day−1) significantly reduced blood glucose levels (to 53.26% of the STZ control group values; Fig. 2). Although normal, diabetic, and Hsp- or Flu-treated rats showed a significant reduction in their final locomotor activity with respect to their correspondent basal activity, there was no significant difference in the final locomotor activity, or in the percent basal activity counts in any of the groups as compared with the normal rats (Table 1; Fig. 3). Results depicted in Fig. 4 indicate that immobility duration for the diabetic rats increased significantly (to 141.96 s) compared with the normal group (72.46 s). Oral administration of Hsp in the 3 doses of 25.0, 50.0, and 100.0 mg·kg−1·day−1 significantly decreased immobility duration to 29.99%, 45.72%, and 48.35% of the STZ control group, respectively. Similar results were obtained with the administration of Flu (5.0 mg·kg−1), as it significantly decreased immobility duration to 49.70% of the STZ control group values. As shown in Table 2, diabetic rats had significantly increased brain levels of MDA (62.51 nmol·(mg brain tissue)−1) compared with the normal group (42.19 nmol·(mg brain tissue)−1). Oral administration of 25.0 mg Hsp·kg−1·day−1 significantly decreased brain levels of MDA to 40.67% and 60.25% of the STZ control group and normal group values, respectively; 50.0 and 100.0 mg·Hsp·kg−1·day−1 reduced MDA levels to 78.48% and 78.31% of the STZ control group values, respectively. Also, Flu (5.0 mg·kg−1·day−1) significantly reduced brain levels of MDA to 65.22% of the STZ control group. Regarding brain levels of GSH, a significant depletion (to 3.47 ␮mol·(g brain tissue)−1) in the brain levels of GSH was observed in diabetic rats, compared with the normal group (3.83 ␮mol·(g brain tissue)−1). Oral administration of 25.0 or 50.0 mg Hsp·kg−1·day−1 significantly restored brain levels of Published by NRC Research Press

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Fig. 1. Effect of hesperidin (Hsp) on the body mass of streptozotocin (STZ)-induced diabetic male Wistar rats. Results are the mean ± SEM for individual change in body mass (%) (n = 8 rats per group). Statistical analyses were carried out using one-way ANOVA followed by Tukey's multiple comparison test; *, p < 0.05 compared with the normal group; †, p < 0.05 compared with the STZ control group. Flu, fluoxetine.

Fig. 2. Effect of hesperidin (Hsp) on the blood glucose levels of streptozotocin (STZ)-induced diabetic male Wistar rats. Results are the mean ± SEM (n = 8 rats per group). Statistical analyses were carried out using one-way ANOVA followed by Tukey's multiple comparison test; *, p < 0.05 compared with the normal group; †, p < 0.05 compared with the STZ control group. Flu, fluoxetine.

Table 1. Effect of hesperidin (Hsp) on spontaneous locomotor activity of streptozotocin (STZ)-induced diabetic rats submitted to locomotor activity test. Locomotor activity (count) Treatment (mg·(kg body mass)−1)

Basal

Final

Normal Control STZ (52.5) STZ+Hsp (25.0) STZ+Hsp (50.0) STZ+Hsp (100.0) STZ+Flu (5.0)

200.13±23.36 177.14±16.54 168.86±23.61 207.79±17.37 190.75±23.19 163.21±22.02

82.00*±11.35 39.64*±7.92 60.43*±9.84 49.64*±7.41 59.75*±12.05 65.86*±12.16

Note: Results are the mean ± SEM (n = 8 male albino Wistar rats per group). Statistical analyses were carried out using 2-way ANOVA followed by Tukey's multiple comparison test; *, p < 0.05 compared with the corresponding basal values for the group.

GSH (to 109.51% and 107.78% of the STZ control group values, respectively), and similar results were obtained with orally administered Flu (5.0 mg·kg−1·day−1), which restored brain levels of GSH to 112.10% of the STZ control group; however, 100.0 mg Hsp·kg−1·day−1 produced brain levels of GSH similar to the STZ control group values (decreased levels) (Table 2). The effect of Hsp on brain levels of IL-6 in diabetic rats is shown in Table 2. Brain levels of IL-6 were significantly elevated in the diabetic rats (75.84 ng·(g brain tissue)−1) compared with the normal rats (54.76 ng·(g brain tissue)−1). Oral administration of 25.0, 50.0, and 100.0 mg Hsp·kg−1·day−1 restored brain levels of IL-6 to 64.94%, 73.19%, and 57.49% of the STZ control group values, respec-

Fig. 3. Effect of hesperidin (Hsp) on the spontaneous locomotor activity of streptozotocin (STZ)-induced diabetic male Wistar rats submitted to a locomotor activity test. Results are the mean ± SEM of individual basal activity counts (%) (n = 8 rats per group). Statistical analyses were carried out using one-way ANOVA followed by Tukey's multiple comparison test; values for p < 0.05 were considered statistically significant. Flu, fluoxetine.

Fig. 4. Effect of hesperidin (Hsp) on the immobility duration of streptozotocin (STZ)-induced diabetic male Wistar rats submitted to the forced swimming test. Results are the mean ± SEM (n = 8 rats per group). Statistical analyses were carried out using one-way ANOVA followed by Tukey’s multiple comparison test; *, p < 0.05 compared with the normal group; †, p < 0.05 compared with the STZ control group.

tively. Similarly, oral administration of Flu (5.0 mg·kg−1·day−1) restored brain levels of IL-6 to 72.01% of the STZ control group values. Regarding brain levels of BDNF, the diabetic rats had significantly reduced levels (43.37 ng·(g brain tissue)−1) compared with the normal rats (61.17 ng·(g brain tissue)−1). Oral administration of 25.0, 50.0, and 100.0 mg Hsp·kg−1·day−1 significantly elevated BDNF levels (to 135.44%, 136.50%, and 137.21%, respectively, of the STZ control group values). The results were similar with Flu (5.0 mg·kg−1·day−1), as it restored BDNF levels to 144.71% of the STZ control group values (Table 2). As demonstrated in Table 3, the diabetic rats had significantly decreased brain levels of NE, DA, and 5-HT (0.76, 1.19, and 0.32 ␮g·(g tissue)−1, respectively) compared with the values for the normal rats (0.91, 1.34, and 0.50 ␮g·(g tissue)−1, respectively). Oral administration of 25.0 mg Hsp·kg−1·day−1 significantly elevated brain levels of NE to 123.68% of the STZ control group values; 50.0 mg Hsp·kg−1·day−1 slightly increased brain levels of NE, but the increase was not statistically significant when compared with the STZ control group values; 100.0 mg Hsp·kg−1·day−1 increased brain levels of NE to 125.00% of the STZ control group values. Similar results were obtained with orally administered Flu (5.0 mg·kg−1·day−1), which significantly elevated the brain levels of NE to 131.58% of the STZ control group values. Oral administration of 25.0, 50.0, or 100.0 mg Hsp·kg−1·day−1 significantly restored brain levels of DA to 116.81%, 109.24%, and 112.61% of the normal group, respectively. Similarly, orally administered Flu (5.0 mg·kg−1·day−1) normalized the brain levels of DA to 109.24% of the STZ control group Published by NRC Research Press

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Table 2. Effect of hesperidin (Hsp) on the brain contents of malondialdehyde (MDA), reduced glutathione (GSH), interleukin-6 (IL-6), and brain derived neurotrophic factor (BDNF) of streptozotocin (STZ)-induced diabetic rats. Treatment (mg·(kg body mass)−1)

MDA (nmol·(mg brain tissue)−1)

GSH (␮mol·(g brain tissue)−1)

IL-6 (ng·(g brain tissue)−1)

BDNF (ng·(g brain tissue)−1)

Normal STZ control (52.5) STZ+Hsp (25.0) STZ+Hsp (50.0) STZ+Hsp (100.0) STZ+Flu (5.0)

42.19±1.66† 62.51±1.42* 25.42±0.84*† 49.06±0.86† 48.95±1.56† 40.77±2.44†

3.83±0.04† 3.47±0.04* 3.80±0.01† 3.74±0.07† 3.51±0.02* 3.89±0.04†

54.76±0.56† 75.84±1.95* 49.25±3.47† 55.51±4.89† 43.60±0.90† 54.61±4.14†

61.17±0.54† 43.37±0.28* 58.74±0.28† 59.20±2.79† 59.51±2.05† 62.76±3.54†

Note: Results are the mean ± SEM (n = 6 male albino Wistar rats per group). Statistical analyses were carried out using one-way ANOVA followed by Tukey's multiple comparison test; *, p < 0.05 compared with the normal group; †, p < 0.05 compared with the STZ control group.

Table 3. Effect of hesperidin (Hsp) on brain monoamines content of streptozotocin (STZ)-induced diabetic rats. Brain monoamines (␮g·(g brain tissue)−1) Treatment (mg·(kg body mass)−1) Normal Control STZ (52.5) STZ+Hsp (25.0) STZ+Hsp (50.0) STZ+Hsp (100.0) STZ+Flu (5.0)

Norepinephrine †

0.91±0.02 0.76±0.03* 0.94±0.06† 0.82 ± 0.01 0.95±0.07† 1.00±0.07†

Dopamine †

1.34±0.04 1.19±0.02* 1.39±0.08† 1.30±0.01† 1.34±0.02† 1.30±0.02†

Serotonin 0.50±0.01† 0.32±0.01* 0.47±0.05† 0.54±0.05† 0.53±0.04† 0.50±0.05†

Note: Results are the mean ± SEM (n = 6 male albino Wistar rats per group). Statistical analyses were carried out using one-way ANOVA followed by Least Significant Difference multiple comparison test; *, p < 0.05 compared with the normal group; †, p < 0.05 compared with the STZ control group.

values. Oral administration of 25.0, 50.0, or 100.0 mg Hsp·kg−1·day−1 significantly elevated brain levels of 5-HT to 146.88%, 168.75%, and 165.63% of the STZ control group values, respectively. Also, orally administered Flu (5.0 mg·kg−1·day−1) restored brain serotonin contents to 156.25% of the STZ control group values.

Discussion This study imparts new information on the anti-depressant effects of Hsp (25.0, 50.0, and 100.0 mg·kg−1), which was similar to Flu in STZ-induced diabetic rats. To the authors' knowledge, this is the first study to address the involvement of hyperglycaemia, oxidative stress biomarkers, pro-inflammmatory cytokines such as IL-6 and BDNF as well as brain monoamines in the antidepressant effect of Hsp in STZ-induced diabetic rats. STZ-induced diabetes is a well-established animal model of type 1 diabetes that results in marked hyperglycaemia, probably through the destruction of pancreatic ␤-cells and lack of insulin secretion (Ho et al. 2012). In our study, Hsp ameliorated STZ-induced hyperglycaemia in a manner similar to that of Flu. This finding is in line with the previous studies of Mahmoud et al. (2012) and Shi et al. (2012), and indicates that the anti-depressant effect of Hsp may be, in part, due to its attenuation of hyperglycaemia in diabetic rats. In our study, Hsp at a dose of 25.0 mg·kg−1 showed the most significant effects on hyperglycaemia and therefore on body mass than other doses, indicating a general health improvement. This finding is in accordance with those of Balakrishnan and Menon (2006), who showed that 25.0 mg·kg−1 was the most effective dose for the reversal of nicotine-induced toxicity in rats. STZ-induced diabetic rats showed increased immobility duration in the FST by comparison with the normal rats. This finding is in accordance with a previous study by Gupta et al. (2014), and indicates the development of depressive-like behavior resulting from diabetes. In our study, Hsp effectively reversed STZ-induced prolongation of immobility duration in the FST. This effect was similar to that

produced by the standard anti-depressant drug Flu, and indicates the anti-depressant effect of Hsp in diabetic rats. This finding is in agreement with a previous study by Filho et al. (2013), who demonstrated anti-depressant-like activity of Hsp in a mouse FST. In this work, although diabetic rats showed a significant reduction in their final locomotor activity with respect to their correspondent basal activity, both Hsp- and Flu-treated rats showed the same effect, which may have resulted from the rats' habituation to the activity cage. Since no significant difference is obtained for percent change in basal activity counts among the various groups of rats, therefore the effect of STZ and Hsp on immobility duration in the FST was independent of changes in locomotor activity. It is well-established that experimental animal models of diabetes are accompanied by oxidative stress due to the overproduction of reactive oxygen species (ROS) and the decreased efficiency of anti-oxidant defense mechanisms resulting from chronic hyperglycaemia (Wayhs et al. 2010). In agreement with prior studies (Ates et al. 2007; de Morais et al. 2014), this study shows that STZ-induced diabetic rats have increased brain levels of MDA (which is an end-product of lipid peroxidation), and reduced brain levels of non-enzymatic endogenous anti-oxidants, namely GSH, owing to increased levels of ROS and lipid peroxides, when compared with the normal rats. This suggests that STZ-induced oxidative stress resulting from chronic hyperglycaemia may account for the depressive behavior in diabetic rats. Treatment with Hsp in this study reversed STZ-associated oxidative stress resulting from chronic hyperglycaemia, as it restored brain levels of MDA and GSH, similar to that of the Flu-treated rats. This finding is in line with prior studies of Ibrahim (2008) and Mahmoud et al. (2012), who demonstrated the anti-oxidant activity of Hsp in diabetic rats. The low dose of Hsp more significantly reduced lipid peroxidation than other doses. The current finding is in agreement with a prior study that showed the low dose of Hsp (25.0 mg·kg−1) was the most effective for the reversal of nicotineinduced lipid peroxidation in rats (Balakrishnan and Menon 2006). Thus, this finding indicates that the anti-oxidant activity of Hsp may play a role in its anti-depressant effect in diabetic rats. Moreover, the ameliorating effect of Hsp on hyperglycaemia may have mediated its anti-oxidant activity in the diabetic rats. It has been demonstrated that there is a strong association between free radical accumulation resulting from hyperglycaemia and the evolution of pro-inflammatory cytokines such as IL-6 in diabetic rats (Ugochukwu et al. 2006). In this manner, our study shows that STZ-induced diabetic rats had elevated brain levels of IL-6 compared with the normal rats. This implies that proinflammatory mediators accessing the central nervous system may lead to the depression associated with diabetes. Hsp significantly decreased brain levels of IL-6 to a level similar to that observed in Flu-treated diabetic rats. This suggests that Hsp exerted its anti-depressant effect via its anti-inflammatory activity, mediated through its anti-oxidant effects. Previous studies have reported that Hsp attenuated pro-inflammatory cytokines Published by NRC Research Press

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such as (TNF-␣ and IL-1␤) in STZ-induced diabetic neuropathic pain in rats (Visnagri et al. 2014). Moreover, a previous experimental study revealed that Hsp decreased serum levels of pro-inflammatory cytokines such as TNF-␣ and IL-6 in diabetic rats (Mahmoud et al. 2012). In our study, Flu, which is a selective serotonin reuptake inhibitor, administered orally at a dose of 5.0 mg·kg−1·day−1 for 21 days reduced hyperglycaemia, oxidative stress, and inflammation in STZ-induced diabetic rats. In accordance with this finding, Tembhurne and Sakarkar (2011) have revealed that a 9 week treatment with Flu (20.0 mg·kg−1, per oral) decreased the glycaemic index and protected STZ-induced diabetic rats from diabetic neuropathy. Moreover, clinical studies have reported the effectiveness of Flu in reducing the severity of depression as well as hyperglycaemia in diabetic patients, leading to better glycaemic control (Goodnick 2001; Khazaie et al. 2011). However, more preclinical and clinical studies are still needed to investigate the effectiveness of long-term administration of Flu, and its underlying mechanisms on glucose–insulin homeostasis in diabetics suffering from depression. STZ-induced diabetic rats in this study showed reduced brain levels of BDNF by comparison with the normal rats. This finding is in agreement with previous studies (Guo et al. 2010; Navaratna et al. 2011). Moreover, reduced neurogenesis and lower BDNF levels are observed in animal models of depression (Hurley et al. 2013; Liu et al. 2014). Thus, the findings from our study indicate that impaired neurogenesis may mediate the development of depression in diabetic rats. Hsp restored BDNF content to levels similar to those in Flutreated diabetic rats. This results from our study agree with those of Donato et al. (2014), who demonstrated that chronic treatment with Hsp elevated BDNF in the hippocampus of mice. Since BDNF has been directly implicated in cell survival, neurogenesis (Post 2007; Zhao et al. 2008), and changes to hippocampal neurogenesis (Banasr et al. 2011), it may be that the anti-depressant effect of Hsp is mediated through enhanced neurogenesis in diabetic rats. In this study, STZ-induced diabetic rats exhibited low brain levels of monoamines, namely, NE, 5-HT, and DA, when compared with the normal rats. This finding is consistent with previous reports (Kino et al. 2004; Yamato et al. 2004), and indicates that depression may result from impairment of monoaminergic functions in diabetic rats. In our study, Hsp restored brain levels of monoamines in a manner similar to that of Flu. Taking into consideration that deficiency in brain monoamines is closely related to depression (Nutt 2002; Blier and El Mansari 2013), the anti-depressant effect of Hsp may be through modulation of brain levels of monoamines in diabetic rats. Moreover, Hsp-mediated increase in brain monoamines may be through altered metabolism, increased release, or reuptake of monoamines. Prior studies have reported that Hsp protected against reductions in DA and its metabolites in 6-hydroxydopamine-induced Parkinson's disease in rats (Antunes et al. 2014). Souza et al. (2013) revealed that the anti-depressant effect of Hsp was dependent on an interaction with the serotonergic 5-HT1A receptors. Since Kozisek et al. (2008) reported that BDNF promotes the function, survival, and regrowth of serotonergic and noradrenergic neurons, Hsp effects on brain monoamines may be mediated by the amelioration of BDNF content. It has been demonstrated that pro-inflammatory cytokines influence the synthesis, release, and re-uptake of brain monoamines, resulting in depression (Miller et al. 2009, 2013). This suggests that Hsp attenuation of brain monoamine levels may be via its anti-inflammatory activity. Obviously, more studies are needed to elucidate the exact mechanism underlying Hsp-mediated increases in brain levels of NE, DA, and 5-HT in diabetic rats. We have concluded that Hsp exerted its anti-depressant effect in STZ-induced diabetic rats, at least in part, via its modulatory

Can. J. Physiol. Pharmacol. Vol. 92, 2014

effect on hyperglycaemia, its anti-oxidant and anti-inflammatory activities, alteration of BDNF levels, and activation of the brain's monoaminergic system. More pre-clinical studies are needed to elucidate other mechanisms that may be involved in the antidepressant effect of Hsp. Clinical studies are warranted to assess the applicability of Hsp as therapeutic agent for the treatment of depressive disorders in diabetic patients. Conflicts of interests: The authors declare that there were no conflicts of interest associated with this work.

Acknowledgements The authors gratefully acknowledge the financial assistance provided by the National Research Centre, Cairo, Egypt.

References Ahmad, S.T., Arjumand, W., Nafees, S., Seth, A., Ali, N., Rashid, S., et al. 2012. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation. Toxicol. Lett. 208(2): 149–161. doi:10.1016/j.toxlet.2011.10.023. PMID:22093918. American Diabetes Association. 2010. Diagnosis and classification of diabetes mellitus. Diabetes Care, 33(Suppl. 1): S62–S69. doi:10.2337/diacare.27.2007.S5. Antunes, M.S., Goes, A.R., Boeira, S.P., Prigol, M., and Jesse, C.R. 2014. Protective effect of hesperidin in a model of Parkinson's disease induced by 6-hydroxydopamine in aged mice. Nutrition. In press. doi:10.1016/j.nut.2014. 03.024. Arentoft, A., Sweat, V., Starr, V., Oliver, S., Hassenstab, J., Bruehl, H., et al. 2009. Plasma BDNF is reduced among middle-aged and elderly women with impaired insulin function: evidence of a compensatory mechanism. Brain Cogn. 71(2): 147–152. doi:10.1016/j.bandc.2009.04.009. PMID:19481324. Ates, O., Cayli, S.R., Yucel, N., Altinoz, E., Kocak, A., Durak, M.A., et al. 2007. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J. Clin. Neurosci. 14(3): 256–260. doi:10.1016/j.jocn.2005.12.010. PMID:17258134. Balakrishnan, A., and Menon, V.P. 2006. Role of hesperidin on nicotine toxicity. Int. J. Pharmacol. 2(6): 664–669. doi:10.3923/ijp.2006.664.669. Banasr, M., Dwyer, J.M., and Duman, R.S. 2011. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr. Opin. Cell Biol. 23(6): 730– 737. doi:10.1016/j.ceb.2011.09.002. PMID:21996102. Barrière, D.A., Rieusset, J., Chanteranne, D., Busserolles, J., Chauvin, M.A., Chapuis, L., et al. 2012. Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization. Pain, 153(3): 553– 561. doi:10.1016/j.pain.2011.11.019. PMID:22177224. Blier, P., and El Mansari, M. 2013. Serotonin and beyond: therapeutics for major depression. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368(1615): 20120536. doi: 10.1098/rstb.2012.0536. PMID:23440470. Champaneri, S., Wand, G.S., Malhotra, S.S., Casagrande, S.S., and Golden, S.H. 2010. Biological basis of depression in adults with diabetes. Curr. Diab. Rep. 10(6): 396–405. doi:10.1007/s11892-010-0148-9. PMID:20878274. Cryan, J.F., Markou, A., and Lucki, I. 2002a. Assessing anti-depressant activity in rodents: recent developments and future needs. Trends Pharmacol. Sci. 23(5): 238–245. doi:10.1016/S0165-6147(02)02017-5. PMID:12008002. Cryan, J.F., Page, M.E., and Lucki, I. 2002b. Noradrenergic lesions differentially alter the anti-depressant-like effects of reboxetine in a modified forced swim test. Eur. J. Pharmacol. 436(3): 197–205. doi:10.1016/S0014-2999(01)01628-4. PMID:11858799. de Morais, H., de Souza, C.P., da Silva, L.M., Ferreira, D.M., Werner, M.F., Andreatini, R., et al. 2014. Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocindiabetic rats. Behav. Brain Res. 258: 52–64. doi:10.1016/j.bbr.2013.10.011. PMID:24140504. Donato, F., de Gomes, M.G., Goes, A.T., Filho, C.B., Del Fabbro, L., Antunes, M.S., et al. 2014. Hesperidin exerts anti-depressant-like effects in acute and chronic treatments in mice: possible role of L-arginine–NO–cGMP pathway and BDNF levels. Brain Res. Bull. 104: 19–26. doi:10.1016/j.brainresbull.2014.03. 004. PMID:24709058. Ellman, G.L. 1959. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 82(1): 70– 77. doi:10.1016/0003-9861(59)90090-6. PMID:13650640. Estrada-Camarena, E., Fernandez-Guasti, A., and Lopez-Rubalcava, C. 2006. Participation of the 5-HT1A receptor in the anti-depressant-like effect of estrogens in the forced swimming test. Neuropsychopharmacology, 31(2): 247– 255. doi:10.1038/sj.npp.1300821. PMID:16012533. Fang, P., Min, W., Sun, Y., Guo, L., Shi, M., Bo, P., et al. 2014. The potential anti-depressant and antidiabetic effects of galanin system. Pharmacol. Biochem. Behav. 120: 82–87. doi:10.1016/j.pbb.2014.02.018. PMID:24582894. Filho, C.B., Del Fabbro, L., de Gomes, M.G., Goes, A.T., Souza, L.C., Boeira, S.P., et al. 2013. Kappa-opioid receptors mediate the anti-depressant-like activity of hesperidin in the mouse forced swimming test. Eur. J. Pharmacol. 698(1–3): 286–291. doi:10.1016/j.ejphar.2012.11.003. PMID:23178563. Gomez, R., and Barros, H.M. 2000. Ethopharmacology of the anti-depressant Published by NRC Research Press

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by MCGILL UNIVERSITY on 11/21/14 For personal use only.

El-Marasy et al.

effect of clonazepam in diabetic rats. Pharmacol. Biochem. Behav. 66(2): 329–335. doi:10.1016/S0091-3057(00)00221-5. PMID:10880686. Goodnick, P.J. 2001. Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann. Clin. Psychiatry, 13(1): 31–41. doi:10.3109/10401230109147127. PMID:11465683. Guo, J., Yu, C., Li, H., Liu, F., Feng, R., Wang, H., et al. 2010. Impaired neural stem/progenitor cell proliferation in streptozotocin-induced and spontaneous diabetic mice. Neurosci. Res. 68(4): 329–336. doi:10.1016/j.neures.2010.08. 012. PMID:20832431. Gupta, D., Kurhe, Y., and Radhakrishnan, M. 2014. Anti-depressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system. Physiol. Behav. 129: 73–78. doi:10.1016/j.physbeh.2014.02.036. PMID:24582678. Ho, N., Balu, D.T., Hilario, M.R., Blendy, J.A., and Lucki, I. 2012. Depressive phenotypes evoked by experimental diabetes are reversed by insulin. Physiol. Behav. 105(3): 702–708. doi:10.1016/j.physbeh.2011.09.003. PMID:21945451. Hurley, L.L., Akinfiresoye, L., Nwulia, E., Kamiya, A., Kulkarni, A.A., and Tizabi, Y. 2013. Anti-depressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav. Brain Res. 239: 27–30. doi:10.1016/j.bbr.2012.10.049. PMID:23142609. Hwang, S.L., and Yen, G.C. 2008. Neuroprotective effects of the citrus flavanones against H2O2-induced cytotoxicity in PC12 cells. J. Agric. Food Chem. 56(3): 859–864. doi:10.1021/jf072826r. PMID:18189359. Ibrahim, S.S. 2008. Protective effect of hesperidin, a citrus bioflavonoid, on diabetes-induced brain damage in rats. J. Appl. Sci. Res. 4(1): 84–95. Kang, M., Shin, D., Oh, J.W., Cho, C., Lee, H.J., Yoon, D.W., et al. 2005. The anti-depressant effect of Nelumbinis semen on rats under chronic mild stress induced depression-like symptoms. Am. J. Chin. Med. 33(2): 205–213. doi:10. 1142/S0192415X05002874. PMID:15974480. Khazaie, H., Rahimi, M., Tatari, F., Rezaei, M., Najafi, F., and Tahmasian, M. 2011. Treatment of depression in type 2 diabetes with fluoxetine or citalopram? Neurosciences (Riyadh), 16(1): 42–45. PMID:21206443. Khoza, S., Barner, J.C., Bohman, T.M., Rascati, K., Lawson, K., and Wilson, J.P. 2012. Use of anti-depressant agents and the risk of type 2 diabetes. Eur. J. Clin. Pharmacol. 68(9): 1295–1302. doi:10.1007/s00228-011-1168-3. PMID:22120432. Kino, M., Yamato, T., and Aomine, M. 2004. Simultaneous measurement of nitric oxide, blood glucose, and monoamines in the hippocampus of diabetic rat: an in vivo microdialysis study. Neurochem. Int. 44(2): 65–73. doi:10.1016/S01970186(03)00125-6. PMID:12971908. Kozisek, M.E., Middlemas, D., and Bylund, D.B. 2008. Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of anti-depressant therapies. Pharmacol. Ther. 117(1): 30–51. doi:10. 1016/j.pharmthera.2007.07.001. PMID:17949819. Lee, K.H., Yeh, M.H., Kao, S.T., Hung, C.M., Liu, C.J., Huang, Y.Y., et al. 2010. The inhibitory effect of hesperidin on tumor cell invasiveness occurs via suppression of activator protein 1 and nuclear factor-kappaB in human hepatocellular carcinoma cells. Toxicol. Lett. 194(1–2): 42–49. doi:10.1016/j.toxlet.2010.01. 021. PMID:20138977. Li, H., Zuo, Y.M., Lei, Y.H., Xu, R.J., and Wang, Y. 2014a. Modeling of diabetes mellitus-related depression. J. Neurophysiol. 46(1): 71–78. doi:10.1007/s11062014-9408-7. Li, J., Huang, M., and Shen, X. 2014b. The association of oxidative stress and pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. J. Diabetes Complications, 28(5): 662–666. doi:10.1016/j.jdiacomp.2014.06.008. PMID:25044235. Liu, D., Xie, K., Yang, X., Gu, J., Ge, L., Wang, X., et al. 2014. Resveratrol reverses the effects of chronic unpredictable mild stress on behavior, serum corticosterone levels and BDNF expression in rats. Behav. Brain Res. 264: 9–16. doi:10.1016/j.bbr.2014.01.039. PMID:24503118. Luppino, F.S., de Wit, L.M., Bouvy, P.F., Stijnen, T., Cuijpers, P., Penninx, B.W., et al. 2010. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry, 67(3): 220–229. doi:10.1001/archgenpsychiatry.2010.2. PMID:20194822. Mahmoud, A.M., Ashour, M.B., Abdel-Moneim, A., and Ahmed, O.M. 2012. Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J. Diabetes Complications, 26(6): 483–490. doi:10.1016/j. jdiacomp.2012.06.001. PMID:22809898. Miller, A.H., Maletic, V., and Raison, C.L. 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry, 65(9): 732–741. doi:10.1016/j.biopsych.2008.11.029. PMID:19150053. Miller, A.H., Haroon, E., Raison, C.L., and Felger, J.C. 2013. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress. Anxiety, 30(4): 297–306. doi:10.1002/da.22084. PMID:23468190. Navaratna, D., Guo, S.Z., Hayakawa, K., Wang, X., Gerhardinger, C., and Lo, E.H. 2011. Decreased cerebrovascular brain-derived neurotrophic factor-mediated neuroprotection in the diabetic brain. Diabetes, 60(6): 1789–1796. doi:10.2337/ db10-1371. PMID:21562076. Noble, E.E., Billington, C.J., Kotz, C.M., and Wang, C. 2011. The lighter side of BDNF. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300(5): R1053–R1069. doi:10.1152/ajpregu.00776.2010. PMID:21346243. Nutt, D.J. 2002. The neuropharmacology of serotonin and noradrenaline in

951

depression. Int. Clin. Psychopharmacol. 17(Suppl. 1): S1–S12. doi:10.1097/ 00004850-200206001-00002. PMID:12369606. Pagel, P., Blome, J., and Wolf, H.U. 2000. High-performance liquid chromatographic separation and measurement of various biogenic compounds possibly involved in the pathomechanism of Parkinson's disease. J. Chromatogr. B Biomed. Sci. Appl. 746(2): 297–304. doi:10.1016/S0378-4347(00)00348-0. PMID: 11076082. Porsolt, R.D., Anton, G., Blavet, N., and Jalfre, M. 1978. Behavioural despair in rats: a new model sensitive to anti-depressant treatments. Eur. J. Pharmacol. 47(4): 379–391. doi:10.1016/0014-2999(78)90118-8. PMID:204499. Post, R.M. 2007. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J. Psychiatr. Res. 41(12): 979–990. doi:10.1016/j. jpsychires.2006.09.009. PMID:17239400. Raza, S.S., Khan, M.M., Ahmad, A., Ashafaq, M., Khuwaja, G., Tabassum, R., et al. 2011. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res. 1420: 93–105. doi:10.1016/j.brainres.2011.08.047. PMID:21959178. Réus, G.Z., Stringari, R.B., Ribeiro, K.F., Ferraro, A.K., Vitto, M.F., Cesconetto, P., et al. 2011. Ketamine plus imipramine treatment induces anti-depressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav. Brain Res. 221(1): 166–171. doi:10.1016/j. bbr.2011.02.024. PMID:21397634. Ruiz-Larrea, M.B., Leal, A.M., Liza, M., Lacort, M., and de Groot, H. 1994. Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids, 59(6): 383–388. doi:10.1016/0039128X(94)90006-X. PMID:7940617. Seshasai, S.R., Kaptoge, S., Thompson, A., Di Angelantonio, E., Gao, P., Sarwar, N., et al. 2011. Diabetes mellitus, fasting glucose, and risk of causespecific death. N. Engl. J. Med. 364(9): 829–841. doi:10.1056/NEJMoa1008862. PMID:21366474. Shi, X., Liao, S., Mi, H., Guo, C., Qi, D., Li, F., et al. 2012. Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules, 17(11): 12868–12881. doi:10.3390/molecules171112868. PMID:23117428. Souza, L.C., de Gomes, M.G., Goes, A.T., Del Fabbro, L., Filho, C.B., Boeira, S.P., et al. 2013. Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the anti-depressant-like effect caused by hesperidin in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry, 40: 103–109. doi:10.1016/j.pnpbp. 2012.09.003. PMID:22996046. Stuart, M.J., and Baune, B.T. 2012. Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine co-morbidity. Neurosci. Biobehav. Rev. 36(1): 658–676. doi:10.1016/j.neubiorev.2011.10.001. PMID:22020230. Taliaz, D., Loya, A., Gersner, R., Haramati, S., Chen, A., and Zangen, A. 2011. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J. Neurosci. 31(12): 4475–4483. doi:10.1523/JNEUROSCI.572510.2011. PMID:21430148. Tembhurne, S.V., and Sakarkar, D.M. 2011. Effect of fluoxetine on an experimental model of diabetes-induced neuropathic pain perception in the rat. Indian J. Pharm. Sci. 73(6): 621–625. doi:10.4103/0250-474X.100235. PMID:23112395. Thome, J., Pesold, B., Baader, M., Hu, M., Gewirtz, J.C., Duman, R.S., et al. 2001. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol. Psychiatry, 50(10): 809–812. doi:10.1016/S0006-3223(01) 01229-X. PMID:11720700. Tuttle, H.A., Davis-Gorman, G., Goldman, S., Copeland, J.G., and McDonagh, P.F. 2004. Proinflammatory cytokines are increased in type 2 diabetic women with cardiovascular disease. J. Diabetes Complications, 18(6): 343–351. doi:10. 1016/S1056-8727(03)00088-6. PMID:15531184. Ugochukwu, N.H., Mukes, J.D., and Figgers, C.L. 2006. Ameliorative effects of dietary caloric restriction on oxidative stress and inflammation in the brain of streptozotocin-induced diabetic rats. Clin. Chim. Acta, 370(1–2): 165–173. doi:10.1016/j.cca.2006.02.003. PMID:16546151. Vidal, R., Valdizan, E.M., Mostany, R., Pazos, A., and Castro, E. 2009. Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptordependent signalling and functionality in rat brain. J. Neurochem. 110(3): 1120–1127. doi:10.1111/j.1471-4159.2009.06210.x. PMID:19522734. Visnagri, A., Kandhare, A.D., Chakravarty, S., Ghosh, P., and Bodhankar, S.L. 2014. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharm. Biol. 52(7): 814–828. doi:10.3109/13880209.2013.870584. PMID:24559476. Wayhs, C.A., Manfredini, V., Sitta, A., Deon, M., Ribas, G., Vanzin, C., et al. 2010. Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect. Metab. Brain Dis. 25(3): 297–304. doi:10.1007/s11011-010-9211-0. PMID: 20838862. Whiting, D.R., Guariguata, L., Weil, C., and Shaw, J. 2011. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract. 94(3): 311–321. doi:10.1016/j.diabres.2011.10.029. PMID:22079683. Yamanaka, M., Tsuchida, A., Nakagawa, T., Nonomura, T., Ono-Kishino, M., Sugaru, E., et al. 2007. Brain-derived neurotrophic factor enhances glucose utilization in peripheral tissues of diabetic mice. Diabetes Obes. Metab. 9(1): 59–64. doi:10.1111/j.1463-1326.2006.00572.x. PMID:17199719. Yamato, T., Misumi, Y., Yamasaki, S., Kino, M., and Aomine, M. 2004. Diabetes mellitus decreases hippocampal release of neurotransmitters: an in vivo Published by NRC Research Press

952

Yi, L.T., Li, C.F., Zhan, X., Cui, C.C., Xiao, F., Zhou, L.P., et al. 2010. Involvement of monoaminergic system in the anti-depressant-like effect of the flavonoid naringenin in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry, 34(7): 1223–1228. doi:10.1016/j.pnpbp.2010.06.024. PMID:20603175. Zhao, C., Deng, W., and Gage, F.H. 2008. Mechanisms and functional implications of adult neurogenesis. Cell, 132(4): 645–660. doi:10.1016/j.cell.2008.01. 033. PMID:18295581.

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microdialysis study of awake, freely moving rats. Diabetes Nutr. Metab. 17(3): 128–136. PMID:15334789. Yang, H.L., Chen, S.C., Senthil Kumar, K.J., Yu, K.N., Lee Chao, P.D., Tsai, S.Y., et al. 2012. Anti-oxidant and anti-inflammatory potential of hesperetin metabolites obtained from hesperetin-administered rat serum: an ex vivo approach. J. Agric. Food Chem. 60(1): 522–532. doi:10.1021/jf2040675. PMID: 22098419.

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