The antidepressant effects of rosiglitazone on rats with depression induced by neuropathic pain

Life Sciences 203 (2018) 315–322

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The antidepressant effects of rosiglitazone on rats with depression induced by neuropathic pain Jian Zonga,b, Xingzhi Liaoa, Bingxu Renb, Zhiping Wanga, a b

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Department of Anesthesiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China Department of Anesthesiology, the Forth People's Hospital of Wuxi, Wuxi, Jiangsu, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Rosiglitazone Depression Neuropathic pain

A growing number of studies reported that rosiglitazone (a PPARgamma agonist) could ameliorate the painful state and prevent stress-induced depression. However, whether rosiglitazone can prevent pain-induced depression is unclear. This study aimed to explore the antidepressant effects of rosiglitazone in L5 spinal nerve transection (SNT) induced neuropathic pain rats. In addition, AMPK inhibitor (Compound C) and autophagic antagonist (3-methyladenine, 3-MA) were applied to investigate the underlying therapeutic mechanisms. L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors were detected by paw pressure threshold test (PPT), open-field test (OFT), forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT). Rosiglitazone could ameliorate L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors and the effect could be reversed by Compound C or 3-MA. Compared with the sham group, the levels of BDNF, AMPK, Beclin-1 and LC3B in rats hippocampus significantly decreased in L5 SNT group. On the contrary, rosiglitazone administration significantly up-regulated the levels of AMPK, BDNF, Beclin-1 and LC3B in rats hippocampus. Compared with sham group, the levels of TNF-α, IL-1β, superoxide dismutase (SOD) and malondialdehyde (MDA) in rat hippocampus significantly increased in L5 SNT group. Besides, rosiglitazone administration significantly decreased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. Compared with rosiglitazone group, 3-MA administration, but not Compound C administration, significantly increased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. In conclusion, rosiglitazone can counteract down-regulation of AMPK and BDNF induced by L5 SNT rats in hippocampus, and activate autophagic pathway. These effects may contribute to the antidepressant effect of rosiglitazone on the rats with depression induced by L5 SNT.

1. Introduction Neuropathic pain is defined as pain caused by the disease of the somatosensory system. Nerve injury can produce many neurobiological events in the peripheral and central nervous systems, which are closely related to the production of chronic pain [26,42]. Neuropathic pain is a common chronic pain which is lack of effective treatment because the mechanisms of neuropathic pain still not understood clearly [21]. It affects quality of life, sleep, work, and decreases socialization. Epidemiological studies have demonstrated that some psychiatric disorders are more common among persons suffering from chronic than in the general population, such as anxiety, depression, substance use disorder, suicide, schizophrenia and dementia [43]. Clinically, depression is highly prevalent in individuals with chronic pain and further increases the risk of the development of chronic pain [1]. Rosiglitazone, an anti-diabetic drug in the thiazolidinedione class of drugs, functions as an insulin sensitizer, by binding to the peroxisome

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proliferator-activated receptor γ (PPARγ) in fat cells and making the cells more responsive to insulin [33,35]. A growing number of studies reported that rosiglitazone could ameliorate the painful state in the diabetic neuropathy [45], the spared nerve injury-induced neuropathy [32] and the tibial and sural nerve transaction-induced painful neuropathy [18,20]. Recently, a study performed by Cheng et al. [7] showed that rosiglitazone could prevent stress-induced depression, and its possible mechanism was associated with the regulation of neurotrophic factor-α1. Also, Sharma et al. [41] have demonstrated that rosiglitazone significantly reduced immobility time in the FST in db/db diabetic mice. Rosiglitazone administration could prevent the chronic unpredictable stress-induced depression by impairing glucose tolerance [36]. These results suggest that rosiglitazone has the potential function of antidepressant and analgesic. Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that plays a critical role in cellular energy homeostasis [15]. AMPK can activate hepatic fatty acid oxidation and

Corresponding author at: Department of Anesthesiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi 214023, Jiangsu, China. E-mail address: [email protected] (Z. Wang).

https://doi.org/10.1016/j.lfs.2018.04.057 Received 6 October 2017; Received in revised form 23 April 2018; Accepted 30 April 2018 Available online 03 May 2018 0024-3205/ © 2018 Elsevier Inc. All rights reserved.

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controlled (2 ± 1°C) room at 8:00–9:00 a.m. Rats were placed individually beneath an inverted ventilated Plexiglas cage with a metalmesh floor allowing access to the plantar surface of hind paw. The electronic esthesiometer pressure was applied on the plantar region of the right hind paw until the rat withdrew it. The paw withdrawal threshold (PWT) was calculated as the mean of five independent measurements.

ketogenesis, inhibit synthesis, lipogenesis, and triglyceride synthesis, and modulate insulin secretion by pancreatic β-cells ([15,17,23,34]. A previous study demonstrated that paroxetine, an antidepressant agent, dose dependently increased mitochondrial biogenesis, which involved the AMPK-PPARγ coactivator-1α pathway [48]. In addition, paroxetine-induced AMPK activation increased glucose uptake and ATP production. These neuronal metabolic-enhancing effects of paroxetine could be suppressed by compound C, an AMPK inhibitor [19]. Moreover, Xu et al. reported the activation of AMPK in rat hippocampus contributed to the mechanisms of ketamine exerting rapid antidepressant effect [48]. Additionally, Mao et al. [30] have demonstrated that AMPK could activate autophagy by phosphorylating unc-51 like autophagy activating kinase 1 (ULK1). Recently, a study used distinct antidepressants to observe its effects on the autophagic pathway in neural cells and showed a promoting effect [53]. Collectively, these results indicate that the activation of AMPK and autophagic pathway are probably implicated in the antidepressant action. However, whether the antidepressant effect of rosiglitazone requires AMPK-autophagic activation has still not been reported. The present study aimed to investigate the antidepressant effects of rosiglitazone in L5 spinal nerve transection (SNT) induced neuropathic pain rats. In addition, AMPK inhibitor (Compound C) and autophagic antagonist (3-methyladenine, 3-MA) were applied to observe their effects on the antidepressant action of rosiglitazone, since AMPK and autophagic pathway are probably implicated in its underlying therapeutic mechanisms.

2.3. Open-field test (OFT) Locomotor activity of rats was measured by OFT, which was performed as previously described [49]. The open-field consisted of an arena of 100 × 100 cm square floor surrounded by 30 cm high wall. The floor of the arena was divided into 25 equal squares. Twenty-four hours after the last drug or vehicle administration (between 7:00–8:00 a.m. at day 15 after L5 SNT operation), rats were placed in the center of the square, and the number of crossings and rearings were recorded. 2.4. Forced swimming test (FST) FST was performed between 9:00–15:00, after the OFT. FST was performed as previously described [2]. The rats in FST could not touch the bottom of the tank. The volume of the tank was 60 cm tall, 30 cm in diameter, and was filled with water in a depth of 35 cm. Rats were placed in the water for 5 min individually, and the immobility time of rats was recorded by the same observer. Each rat was judged to be immobile when it ceased struggling and remained floating motionless in the water, making only those movements necessary to keep its head above water. Water in the tank was changed after the test of every rat.

2. Materials and methods 2.1. Animals and study groups

2.5. Sucrose preference test (SPT)

Animals were group housed in cages and were maintained in standard laboratory condition with alternating light–dark cycle of 12 h each. A total number of 72 Sprague-Dawley rats (200–250 g) were purchased from Shanghai Animal Center, Shanghai, China. Each cage has six rats, and the food, water were free and kept in a 12 h light/dark cycle (lights on at 08:00 AM). Animal care was in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and was approved by the Animal Use and Protection Committee of Nanjing Medical University. 72 rats were equally randomized into 6 groups (n = 12):sham-operation with vehicle (sham group); L5 SNT with vehicle 2 ml/kg (L5 SNT group) or rosiglitazone 20 mg/kg p.o. for consecutive 7 d. (L5 SNT + RO group); L5 SNT with rosiglitazone 20 mg/kg p.o. and Compound C 1 mg/kg i.p. for consecutive 7 d (L5 SNT + RO + ComC group); L5 SNT with rosiglitazone 20 mg/kg p.o. and 2 μL 3-MA i.p. for consecutive 7 d (L5 SNT + RO + 3-MA group); L5 SNT with morphine 10 mg/kg p.o. for consecutive7 d. (M group). Rats were anesthetized with sodium pentobarbital (50 mg/kg). L5 SNT was performed as previously described ([21,51]. Briefly, the right leg was shaved, a small incision to the skin overlaying L5-S1 was made, the L5 spinal nerve was exposed and identified after the muscles and the adhering tissue were separated and removed carefully. The L5 spinal nerve was transected, then ligated with a 3–0 silk thread tightly, and closed the wound. The sham operation was performed in the same manner until the L5 spinal nerve was only exposed without ligation or transaction. The drugs were administered at the day7 to day 14 after operation daily at 7:00–8:00 a.m.

SPT was performed between 12:00–24:00 (day 15 after L5SNT operation). The SPT procedure was performed as described below according to previous studies ([8,22]. Firstly, the rats were acclimatized to sucrose and water for 2 days. A bottle of 1% sucrose solution and a bottle of tap water were presented at random positions to each rat. For testing, on day 3, rats were deprived by food and water for 4 h. For testing, two bottles, one containing 1% sucrose solution and the other containing tap water were weighed and presented to each rat for 4 h. The position of the two bottles was set randomly. The sucrose preference was calculated using the following formula: Sucrose preference = sucrose consumption (g)/water consumption (g) + sucrose consumption (g) × 100%. 2.6. Tail suspension test (TST) TST was conducted between 9:00–15:00 on the next day after FST as previously described [12]. Briefly, individual rats were acoustically and visually isolated, and suspended about 50 cm above the floor by placing adhesive tape. Each rat was suspended for total 6 min, of which the duration of immobility was recorded at the last 5 min. Rats were considered as immobile when they were passively suspended and remained completely motionless. Animals were sacrificed after TST immediately. 2.7. Western blot Animals were sacrificed immediately by overdose of sodium pentobarbital of 70 mg/kg. Whole hippocampus tissues were harvested and homogenized in RIPA buffer (Beyotime P0013C, Haimen, Jiangsu, China) plus protease inhibitors. Protein concentrations were determined by using BCA method assay kit (Beyotime P0012S, Haimen, Jiangsu, China). After that, samples were centrifuged at 3000G at 4 °C for 30 min to obtain the supernatants. Then supernatants was stored in −70 °C refrigerator for the following experiments. Equal sample

2.2. Paw pressure threshold test (PPT) The test was performed on 1 day before operation and every days after operation until the animals were sacrificed. After 30 min habituation in the test room, PPT was performed as previously described [6,20]. It was measured by an Electro Von Frey Anesthesiometer (Model 2390 CE, IITC Life Science, Inc.) in a quiet temperature316

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contain 50 μg proteins was electrophoresed on a 12% SDS-polyacrylamide gradient gel and transferred onto nitrocellulose membranes (Millipore). After blocking nonspecific binding with 5% fat-free milk for 30 min, the membranes were incubated the primary antibodies: rabbit anti- BDNF (1:200 Santa Cruz, Inc. USA);rabbit anti-AMPKα (1:1000, Cell Signaling Technology, Inc. Danvers, MA, USA); rabbit anti-Beclin-1 (1:1000, Cell Signaling Technology, Inc. Danvers, MA, USA); rabbit anti-LC3B (1:1000, Cell Signaling Technology, Inc. Danvers, MA, USA) at 4 °C overnight. Washed with rinse buffer, the membranes were incubated with 1:1000 diluted HRP-conjugated goat anti-rabbit IgG (Santa Cruz) for 2 h at room temperature (RT), followed by developing with enhanced chemiluminescence reagents (Amershame). In addition, β-actin was used as a loading control. The optical densities were analyzed by using ImageMasterTM2D Platinum (Version 5.0, Amersham Biosciences, Piscataway, NJ).

Fig. 1. Effects of rosiglitazone in the Paw pressure Threshold test in L5 SNT rat model, Sham group vs L5 SNT group ***P < 0.001; L5 SNT + RO group vs L5 SNT group, ##P < 0.01 ###P < 0.001. (B) Effects of Compound C and 3-MA in the Paw pressure Threshold test in L5 SNT rat model, L5 SNT + RO group vs L5 SNT + RO + ComC group, **P < 0.01 ***P < 0.001; L5 SNT + RO group vs L5 SNT + RO + 3MA group, ##P < 0.01 ###P < 0.001. n = 12.

2.8. Levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β measurement TNF-α and IL-1β levels were determined by using ELISA kits (Beyotime Biotechnology). The procedure was according to the manual. The standard curve demonstrated a direct relationship between Optical Density (OD) and test concentrations. Total protein were measured by Lowry's method using bovine serum albumin as a standard.

(p < 0.001)(Fig. 2 A,B). Behavioral tests of depression including FST, TST and SPT showed that L5 SNT could significantly increase the immobility time (P < 0.001) of FST and TST, and significantly decreased the percentage of sucrose preference (P < 0.001)(Fig. 2 C, D,E). 3.2. Effects of rosiglitazone and morphine on the behavioral performance in L5 SNT rats model

2.9. Superoxide dismutase (SOD) and malondialdehyde (MDA) measurement

Rosiglitazone orally treated at the doses 20 mg/kg/d or morphine orally treated at the doses 10 mg/kg/d respectively for consecutive 7 days, significantly increased PPT (P < 0.001) of L5 SNT rats (Fig. 1,B)·Tests of depressive-like behavior showed that the scores of crossings and rearings in the OFT, the percentage of sucrose preference significantly increased after administration of rosiglitazone in L5 SNT rats (P < 0.001)(Fig. 2 A,B,E), Rosiglitazone administration significantly decreased immobility time of FST and TST of L5 SNT rats (P < 0.001) compared with L5 SNT group (Fig. 2 C,D). But morphine had no benefit change in the depression-like behavior test (Fig. 2). The rats in Compound C group and 3-MA group were co-administrated with Compound C or 3-MA, the benefit change induced by rosiglitazone was counteracted (P < 0.001)(Fig. 2 A,B,C,D,E).

The activity of SOD was measured by testing the ability of pyrogallol to perform automatic oxidation. When SOD was present, the self-oxidation inhibition of the compound occurred and the enzyme activity could be measured indirectly using a temperature-controlled dual-beam spectrophotometer with an absorbance of 420 nm. The 50% inhibition of pyrogallol autoxidation was defined as 1 U SOD. To test the MDA level, the sample was mixed with 1 ml of 10% trichloroacetic acid and 1 ml of 0.67% thiobarbituric acid and then heated in a boiling water bath for 30 min. The malondialdehyde equivalent was determined in the tissues and granules of the rats' brain at absorbance of 532 nm using a spectrophotometer. 2.10. Statistical analysis

3.3. Effects of rosiglitazone on the expression of AMPK, BDNF, Beclin-1 and LC3B, in hippocampus in L5 SNT rats model

The data are expressed as mean ± SD. Statistical analysis was performed using Social Science Statistics (SPSS) version 19.0 (SPSS, Inc., Chicago, IL, USA). Comparison among groups was performed by one-way analysis of variance (ANOVA). The post hoc analyses were performed using Fisher's least significant difference tests. P < 0.05 was considered statistically significant.

One-way ANOVA test showed that significant changes of BDNF [F = 15.1, P < 0.001],AMPK [F (2,15) = 17.89, P < 0.001], Beclin1[F (2,15) = 30.91, P < 0.001], LC3B[F (2,15) = 25.72, P < 0.001], among these three groups. Compared with the sham group, L5 SNT group significantly decreased the levels of BDNF,AMPK, Beclin-1 and LC3B in rats hippocampus (P < 0.001). On the contrary, rosiglitazone administration significantly up-regulated levels of AMPK, BDNF,Beclin1 and LC3B in rats hippocampus (P < 0.001) compared with the L5 SNT group (Fig. 3 A,B,C,D). (2,15)

3. Results 3.1. L5 SNT-induced neuropathic pain symptoms and depressive likebehaviors PPTof rats in L5 SNT group significantly decreased on days 4, 6,8,10,12, 14 after L5 SNT compared with sham group (P < 0.001). Compared with L5 SNT group,PPT was significantly increased on days 8,10,12,14 after first administration of Rosiglitazone and morphine (P < 0.001). Co-administration of ComC and 3MA significantly decreased PPT compared with RO group and M group (P < 0.001) (Fig. 1).There were significant differences of crossings [F (5, 66) = 73.75, P < 0.001],and rearings[F (5, 66) = 65.65, P < 0.001], FST[F (5, 66) = 40.93, P < 0.001], TST[F (5, 66) = 71.68, P < 0.001], and SPT[F (5, 66) = 76.66, P < 0.001] among these 6 groups (n = 12). In the OFT, the scores of crossings and rearings of L5 SNT group significantly decreased compared with sham group

3.4. Effects of compound C and 3-MA on the pro-inflammatory cytokines and oxidative responses in L5 SNT rats model Mounting studies showed that excessive expression of pro-inflammatory cytokines and oxidative responses were both implicated in the pathogenesis of depression [4,5,13,38]. Our results demonstrated that significantly statistical differences in TNF-α [F (4,25) = 358.4, P < 0.001], IL-1β[F (4,25) = 115.3, P < 0.001], SOD[F (4,25) = 358.4, P < 0.001] and MDA[F (4,25) = 121.9, P < 0.001] in rats hippocampus among groups. Compared with sham group, the levels of TNFα, IL-1β, SOD and MDA in rat hippocampus of L5 SNT group 317

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Fig. 2. Effects of rosiglitazone, morphine,Compound C and 3MA on the crossings (A) and rearings (B) in the open-field test in L5 SNT rat model,the immobility time in the FST (C) and TST (D), and SPT (E) in L5 SNT rat model. ***P < 0.001. n = 12.

animal models [5,7,18,32,41]. In our study, L5 spinal nerve transection (SNT) induced a significant decrease in PPT which indicated the induction of peripheral neuropathic pain. Rosiglitazone orally treated at a dose of 20 mg/kg/d for consecutive 7 d could attenuate this decrease. Furthermore, our results also demonstrated that rosiglitazone treatment significantly attenuated L5 SNT -induced down-regulation of AMPK, BDNF, Beclin-1, LC3B. Additionally, we also observed that rosiglitazone significantly decreased the L5 SNT -elicited excessive expression of proinflammatory and oxidative cytokines including TNF-α, IL-1β, SOD and MDA. These beneficial effects could be counteracted by Compound C (AMPK antagonist) and 3-MA (autophagic inhibitor). Through the behavioral tests we found that the crossings and rearings of OFT, the percentage of the sucrose preference significantly

significantly increased (P < 0.001). Besides, rosiglitazone treatment significantly decreased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus compared with L5 SNT group (P < 0.001). Compared with rosiglitazone group, 3-MA administration, but not Compound C administration, the levels of TNF-α, IL-1β, SOD and MDA in hippocampus significantly increased (P < 0.001).(Fig. 4 A,B,C,D). 4. Discussion Clinically, rosiglitazone, a PPARγ agonist, was used to treat diabetes through increasing insulin sensitivity and prompting glucose consumption [4]. Increasing evidences show that rosiglitazone exhibits therapeutic effects for neuropathic pain and depressive symptoms in 318

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Fig. 3. Western bolt bands (A),The expression of AMPK (B), BDNF(C),Beclin-1 (D) and LC3B (E) in rat hippocampus after rosiglitazone treatment in L5 SNT rat model. ***P < 0.001. n = 12.

action is similar to a previous study using rosiglitazone orally at a dose of 17 mg/kg/d for consecutive 5 d in a mouse model [13]. Although its therapeutic mechanisms have yet been clearly elucidated, a previous study by Ahmed et al. [13],the research suggested that rosiglitazone exhibited a markedly anti-depressant-like action in behavioral models and this effect may be attributed to the reduction of plasma corticosterone levels. Also, Cheng et al. [7] observed that neurotrophic factorα1 may be involved in the mechanisms of rosiglitazone exerting antidepressant action. Similarly, Budni et al. [5]have demonstrated that rosiglitazone (1 μg/site, i.c.v.) in combination with a dose of folic acid (10 mg/kg, p.o.) significantly decreased the immobility time in the FST, suggesting PPARγ activation is of great importance for the onset of antidepressant action of folic acid. Furthermore, a pilot clinical study using the Hamilton Depression Rating Scale and the Clinical Global Impression Scale demonstrated eight patients after rosiglitazone treatment exhibited a significant decline in depression evaluation scores [38]. It has been reported that 5-Aminoimidazole-4-carboxamide-1-β-dribofuranoside (AICAR), a pharmacological activator of AMPK originally used to improve insulin resistance (IR). A previous study found that

decreased in the L5SNT rats, and the immobility time of FST and TST significantly increased in the L5SNT rats when compared with sham group. These data suggested that L5SNT -induced depression has been successfully constructed. In the present study, our results showed that rosiglitazone orally treated at a dose of 20 mg/kg/d for consecutive 7 d could exert antidepressant effects in L5SNT rat model. More importantly, we found that AMPK antagonist Compound C and autophagic inhibitor 3-MA both could counteract the beneficial effects of rosiglitazone for depressive symptoms in L5SNT model. These results suggested that AMPK-dependent autophagic pathway may be involved in the analgesic and antidepressant effect of rosiglitazone in the L5SNT rats. Through the behavioral tests we also found that the analgesic effects of morphine in neuropathic pain rats was similar to rosiglitazone. But morphine has no beneficial effects in the depression-like behavior test. This result suggested that the antidepressant effect of rosiglitazone was not due to its anti-nociceptive effects, at least not completely. In the present study, rosiglitazone orally administered at a dose of 20 mg/kg/d for consecutive 7 d exerted a significant antidepressant effect in the L5SNTrats model. This dose for the onset of antidepressant 319

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Fig. 4. The levels of inflammatory and oxidative cytokines in rat hippocampus. (A) TNF-α levels in rat hippocampus; (B) IL-1β expression; (C) SOD and (D) MDA levels in rat hippocampus. ***P < 0.001. n = 12.

of depression. Yu Wang's investigation found that the serum BDNF levels were significantly decreased in Parkinson disease (PD) patients with than without depression, and suggested that decreased serum BDNF play acritical role in the pathophysiology of depression in PD patients [44]. Serra, MP's study found that a reduced BDNF/trkB signaling in the hippocampus of RLA versus RHA rats may contribute to their more pronounced vulnerability to stress-induced depression [39]. These studies all indicated that BDNF signaling pathway was a critical potential target for antidepressant therapy. In the present study, western blot showed a significant down-regulation of BDNF in the hippocampus of L5SNT rats, and rosiglitazone could counteract this downregulation induced by L5SNT, which also indirectly supported the evidence that BDNF was involved in the therapeutic effect of rosiglitazone. Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the actions oflysosomes [50]. Autophagy participated in neuronal cell death and functional loss induced following stress. Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via AMPK modulation [46].Another study demonstrated that rosiglitazone treatment suppressed neuro inflammation and neuronal autophagic death in a rat model of global cerebral ischemia [40]. In the present study, 3-MA, a specific inhibitor for autophagic activation, caused attenuation of antidepressant action induced by rosiglitazone, indicating that autophagic activation is likely to be involved in the rosiglitazone antidepressant effects in the L5 SNT model.

the activation of AMPK in rat hippocampus contributed to the antidepressant effect of ketamine [48]. Zhu et al. [52] reported that Phosphorylation of AMPK was decreased in UCMS mice. These findings showed that AMPK agonist probably could be applied as a potential antidepressant agent. A previous study performed by Fryer et al. [14] using incubation of muscle cells with rosiglitazone leaded to a dramatic increase in AMP/ATP ratio with the concomitant activation of AMPK, which raised a possibility that a number of the beneficial effects of the rosiglitazone may be mediated, at least partially, via the activation of AMPK. Furthermore Liu et al. found rosiglitazone leaded to antidepressant effect by strengthening insulin actions of skeletal muscle in the context of long-term high fat diet [28]. Here our results showed that AMPK inhibitor blocked the antidepressant effects of rosiglitazone, validating the hypothesis that AMPK probably mediates the beneficial effects of rosiglitazone for depression. Furthermore, we also found that rosiglitazone counteracted down-regulation of AMPK induced by L5 SNT in hippocampus, which also indirectly supported the evidence that the therapeutic effect of rosiglitazone requires the activation of AMPK. A previous study showed that rosiglitazone increased the levels of BDNF and, as a result, activated cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus [25]. Xu's study showed [47] that hippocampal BDNF signaling pathway played an important role in the antidepressant effects of Rg5,and this beneficial effects could be counteracted by the K252a (the potent inhibitor of BDNF receptor TrkB). Qiao et al. [37]have showed that the unbalance of BDNF and pro-BDNF may be one of the potential mechanisms of the development 320

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Intriguingly, in the present study, western blot showed a dramatic upregulation of the two representative markers of autophagy including Bcline-1 and LC3B after treatment of rosiglitazone. Collectively, autophagic activation was probably implicated in the therapeutic mechanisms of rosiglitazone for depression. It has been reported that inflammatory cytokines and oxidative cytokines were potentially involved in the mechanisms underlying the incidence of depression ([3,24,31]. Several lines of evidence suggest that IL-1β and IL-6 may be involved in the pathogenesis of major depression as well as in therapeutic mechanisms of antidepressant treatment ([16,27,29]. Dellarole's stdy in rats with chronic constriction injury of the sciatic nerve found that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1[11]. A previous study showed that rosiglitazone administered at a dose of 10 mg/kg significantly decreased carrageenan-induced over expression of IL-1β, TNF-α, suggested rosiglitazone displayed an anti-inflammatory action [9]. Moreover, Morais et al.[10]have demonstrated that increased oxidative stress in prefrontal cortex and hippocampus was likely related to depressive symptoms in STZ diabetic rats. In the present study, our results showed that rosiglitazone robustly restored L5 SNT-induced excessive expression of inflammatory and oxidative cytokines including IL-1β, TNF-α, SOD and MDA. These findings were consistent with previous results. Interestingly, we also found that only 3-MA, but not Compound C, blocked the expression of L-1β, TNF-α, SOD and MDA, indicating autophagic pathway, but not AMPK, played a critical role in the rosiglitazone eliciting anti-inflammatory and antioxidative effects.

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