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Research report

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Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats

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Zahra Jabbarpour a , Siamak Shahidi a,∗ , Massoud Saidijam b , Abdolrahman Sarihi a , Taghi Hassanzadeh c , Rasoul Esmaeili d a

Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran c Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran d School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran b

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Article history: Received 26 August 2013 Received in revised form 10 December 2013 Accepted 30 December 2013 Available online xxx

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Keywords: Diabetes Tempol Memory Rat

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1. Introduction

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Diabetes mellitus (DM) has several effects, including cognitive impairment. Oxidative stress is associated with complications from diabetes. It seems that antioxidants can reduce some complications of the diabetes induced by oxidative stress. The objective of this study was to evaluate the effect of synthetic antioxidant, tempol on the passive avoidance (PA) memory and novel object recognition (NOR) tests in the diabetic rats. Forty male Wistar rats randomly divided into the control, diabetic, diabetic receiving tempol and healthy receiving tempol groups. Diabetes was induced by injection of streptozotocin (STZ) (60 mg/kg, i.p.). Then, the rats received saline or tempol (30 mg/kg) orally by gavages for 60 days. After that, they were assessed using the PA memory and NOR tests. The results of NOR test showed that the discrimination index (DI) in the healthy receiving tempol group and diabetic control group was significantly lower than control group. Also the amount of this index in diabetic receiving tempol group was significantly higher than diabetic group. The results of PA test indicated that the number of trials to acquisition in the diabetic rats is significantly more than control and diabetic tempol treated groups. Also, the time spent in the dark compartment (TDC) in the control and diabetic receiving tempol groups was less than diabetic group. TDC in the healthy receiving tempol group was more than control group. It can be concluded that although use of tempol is restricted as a cognitive enhancer in non-diabetic subjects but long-term administration of synthetic antioxidant, tempol, is able to dramatically improve diabetes-induced learning and memory deficit in both PA and NOR tests. © 2014 Published by Elsevier Inc.

Diabetes mellitus (DM) is an endocrine disorder of carbohydrate metabolism resulting from impaired insulin secretion [Type I insulin-dependent diabetes mellitus], resistance to insulin action, or both [Type II non-insulin-dependent diabetes mellitus] (Balakrishnan et al., 2009). Diabetes is associated neurological complications in both the peripheral and central nervous system (Baydas et al., 2003b; Di Luca et al., 1999). Passive avoidance learning (PAL) and memory impairment also occur in streptozotocin (STZ)-induced diabetic rats (Baydas et al., 2003a,b; Kucukatay et al., 2007; Lupien et al., 2003; Patil et al., 2006). Learning deficits in diabetic rats have been partly associated with the structural and

∗ Corresponding author at: Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Tel.: +98 811 8380462x337; fax: +98 811 8380208. E-mail address: [email protected] (S. Shahidi).

functional deficits in certain brain regions such as the hippocampus and cerebral cortex. For example, changes in hippocampal synaptic plasticity have been reported in diabetes (Baydas et al., 2003b; Biessels et al., 1994; Tuzcu and Baydas, 2006). DM has been reported to specifically impair the memory performance in experimental animals with powerful involvement of hippocampus and cerebral cortex. This finding may show impairment of acquisition and/or consolidation of memory (Flood et al., 1990). Hyperglycemia induced by diabetes is usually accompanied by increased production of free radicals and reactive oxygen species (ROS), (Baynes, 1991; Baynes and Thorpe, 1999) or impaired antioxidant defenses Q2 (Chang et al., 1993; Halliwell and Gutteridge, 1990; Young et al., 1995). Vitamin C and vitamin E were found to reduce oxidative stress; in addition vitamin C can enhance learning and memory and prevent memory deficits in various experimental conditions (Delwing et al., 2006; Hasanein and Shahidi, 2010; Landmark, 2006; Monteiro et al., 2005; Parle and Dhingra, 2003; Reis et al., 2002; Shahidi et al., 2008a). In addition, clinical studies suggest that vitamin E may be a supplemental intervention for patients with

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Please cite this article in press as: Jabbarpour, Z., et al., Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2013.12.013

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cognitive dysfunction (Chan et al., 2004; Mecocci et al., 2004). Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a member of a family of nitroxide compounds that has been studied extensively in animal models of increased ROS. Tempol is a superoxide dismutase (SOD) mimetic. It is an efficient scavenger of free radicals and improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia (Wilcox, 2010). However, at present, no specific treatment options are available for the management of cognitive deficits induced by diabetes (Biessels et al., 2007). According to these reports so far it has not been investigated tempol effect on improves the neurological complications induced by diabetes, we examined whether treatment with tempol could protect against learning and memory deficits in diabetic rats with using PA and NOR? These tests are useful as a screen for testing new drugs and antioxidants which may alter memory processes such as diabetes (Hasanein and Shahidi, 2010; Jurdak and Kanarek, 2009; Raghavendra and Kulkarni, 2001).

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2. Materials and methods

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2.1. Animals

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In this study, forty adult male Wistar rats with the body weight of 200–250 g were used in which they purchased from the breeding colony of Iran Pasteur Institute, Tehran. The animals were put in separate cages under 12-h light:12-h darkness periods and were fed by some standard food pellets and water ad libitum. All procedures for the treatment of animals were approved by the research committee of the Hamadan University of Medical Sciences. 2.2. Induction of diabetes and treatment

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In this study, the animals were divided into the following groups as Control [C] (n = 10), Diabetic [D] (n = 10), Diabetic tempol recipients [D + T] (n = 10), and Control group receiving Tempol [C + T] (n = 10). This experimental model of rats made diabetic with streptozotocin (STZ) injection has been validated in previous studies (Arison et al., 1967; Haider et al., 2013; Hohenegger and Rudas, 1971; Tuzcu and Baydas, 2006). Diabetes disease was induced by only a single intra peritoneal (i.p.) injection of STZ (60 mg/kg body weight) which was prepared by citrate buffer, pH 4.5 (Arison et al., 1967; Hasanein and Shahidi, 2010; Hohenegger and Rudas, 1971). The control rats received i.p. injections of physiological saline. The fasting blood glucose levels were determined three days after STZ injection by using a strip-operated blood glucose sensor (Accuchek; Roche, Mannheim, Germany). Animals were considered diabetic if plasma glucose levels exceeded 250 mg/dl. Finally, tempol (Sigma) was fed to [D + T] and [C + T] groups by the gavage process at a dose of 30 mg/kg per day for 60 days. The control and non-treated diabetes groups received the physiological saline with the same volume during this time. Behavioral test (PAL and NOR tests) were conducted respectively on 2 and 3 consecutive days at the same time of the day between 12:00 and 3:00 PM.

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2.3. Behavioral tests

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2.3.1. Novel object recognition (NOR) test The object recognition task is a working memory task that primarily relies on cortical functioning and to a lesser extent, hippocampal functioning. The utilized set-up consists of a cubic open arena (50 cm × 45 cm × 35 cm) and a video recording system. During the first day, the rats were given one habituation session (5 min) in the arena without any object. On the second day, two identical

objects were placed close to (10 cm) two adjacent corners of arena. One rat was then placed in the middle of the box and allowed to explore the two objects for 5 min. Exploration process of an object was defined as smelling the object. During the third day, one of the objects was replaced with a novel object and the rat was put back into the open field for a 5-min test session. The rat response to the novel object was assessed by subtracting the mean exploration time of the familiar object from the mean exploration time of the novel object (Akirav and Maroun, 2006; Broadbent et al., 2004; Ennaceur et al., 1997).

2.3.2. Passive avoidance learning (PAL) test In this study, a passive avoidance apparatus and a procedure similar to our previous studies were used (Hasanein and Shahidi, 2010; Lashgari et al., 2006; Shahidi et al., 2008a,b; Shahidi et al., 2004). This step-through apparatus had a bright chamber (20 cm × 20 cm × 30 cm) made of transparent plastic and a dark chamber with walls made of dark opaque plastic (20 cm × 20 cm × 30 cm). It was also used stainless steel rods (3 mm diameter) with the distance of 1 cm from each other for the floor of the chambers. A shock generator was used for electrifying the floor of the dark chamber and a rectangular opening (6 cm × 8 cm) was located between the two chambers and could be closed by an opaque guillotine door.

2.3.2.1. Training. In order to habituate the groups to the apparatus, they were given two habituation trials. At first, the rats were entered into a lighted section of the apparatus and 5 s later the guillotine door was opened. Because of the natural tendency of the rats to the dark environment, they were trying to enter the dark compartment. The door was closed upon the rats entering the dark compartment and after 30 s they were taken from the dark compartment and placed in their cage. After 30 min this trial was repeated and then the acquisition trial was carried out after the same interval. The measurement of the entrance latency to the dark compartment (step-through latency, STLa) was carried out after the rats had completely entered the dark compartment. Then, the door was closed and an electrical shock was used (0.9 mA) for 2.5 s and the experimental rat was returned to its cage after 30 s. This procedure was repeated again after 2 min. For the next stages, the foot-shock process was applied for the rat after it reentered the dark and had placed all four paws in the dark compartment. Finally, the training method of the experimental rats was terminated when they remained continuously in the bright compartment for 120 s and the number of entries into the dark chamber to acquisition was recorded.

2.3.2.2. Retention test. Exactly 24 h after performing the PAL acquisition trial, the retention test was performed. In this step, like the PAL training trial, the rat was placed in the light chamber and after 5 s, the guillotine door was opened in order to start the recording process of the step-through latency (STLr) and the spending time in the dark compartment (TDC) for up to 300 s. If the rat does not enter the dark chamber within 300 s, the retention test is terminated and a ceiling score of 300 s was recorded.

2.4. Statistical analysis One-way ANOVA was used to determine the statistical significance of differences between experimental groups which were followed by Tukey as post hoc test. The obtained probability values less than 0.05 were considered significant and the data were expressed as the mean ± SEM.

Please cite this article in press as: Jabbarpour, Z., et al., Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2013.12.013

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Groups Fig. 2. Effect of long term oral administration of tempol on the discrimination index in object recognition task between experimental groups. C, control group; C + T, a control group receiving tempol; D, diabetic group; D + T, diabetic group received tempol. *, (p < 0.05); ***, (p < 0.001) as compared with control group. #, (p < 0.05); ###, (p < 0.001) compared with diabetic control group.

of plasma between experimental groups 60 days after treatment (F(3,36) = 40.18, p < 0.0001). Tukey post hoc test showed that treatment of the diabetic rats by tempol caused a significant decrease in plasma glucose compared to untreated diabetic rats at the end of experiment (p < 0.01). 3.2. Behavioral test 3.2.1. Effects of treatment on novel object-recognition test As clarified by one-way ANOVA, there is a significant difference between the discrimination indexes of objects between groups (F(3,36) = 13.42, p < 0.0001) (Fig. 2). Furthermore, as shown by Turkey test, this index for the control group of rats receiving tempol is significantly lower than that of the control group (p < 0.05) and greater than that of the diabetic group (p < 0.001). It was also observed that there is no significant difference in this parameter between the control group and the diabetic group treated by tempol (p > 0.05). One of the other results indicated by the Tukey test showed that the index for the diabetic control group was significantly lower than that of the control group receiving tempol (p < 0.05) and the diabetic group receiving tempol (p < 0.001). These results indicate that administration of tempol improves cognitive dysfunction in diabetic rats but deficits cognition in healthy subject.

Fig. 1. Blood glucose levels at the beginning (A), after induction of diabetes (B) and at the end of the study (C). C, control group; C + T, a control group receiving tempol; D, diabetic group; D + T, diabetic group received tempol. **, (p < 0.01) as compared with control. ##, (p < 0.01) as compared with control group receiving tempol. $$, (p < 0.01) as compared with diabetic group.

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Fig. 1 shows the glucose levels of rat groups at the beginning, after diabetes induction and the end of experiment. A statistical analysis by one-way ANOVA confirms that there is no significant difference between the groups at beginning (F(3,36) = 0.3, p = 0.82). A significant difference among the experimental groups of rats (F(3,36) = 52.96, p < 0.0001) was observed by the same analysis after the induction of diabetes. Tukey post test revealed that plasma glucose levels of diabetic induction groups were significantly higher than non-diabetic groups (p < 0.01). Furthermore, one-way ANOVA showed that there was significant difference in the glucose level

3.2.2. Effects of treatments on the PAL test It was found that no significant difference in the STLa among the experimental and control groups of rats was observed in the first acquisition trial (before the electrical shock) indicating that there is no difference in the exploratory behavior of the groups in the dark compartment. However, as shown in Fig. 3, significant differences were found among the experimental groups with respect to the number of trials to acquisition (F(3,36) = 24.1, p < 0.0001). Tukey showed that this number for the diabetic receiving tempol group was significantly less than that of the diabetic group (p < 0.001) and the latter one was prominently greater than that of the control group (p < 0.001) due to the presence of a cognitive deficit. On the other hand, significant differences were not observed between the control and control tempol recipient groups (p > 0.05). It can be found from these results that use of tempol improves the impairment of learning caused by induction of diabetes. 3.2.3. Effects of treatments on the PAL retention The PAL retention test performed 24 h after the training process showed a significant difference in the STLr among the groups (F(3,36) = 41.96, p < 0.0001) (Fig. 4A). Tukey test showed that the control group had the STLr values greater than those of the control group receiving tempol and diabetic groups (p < 0.01). In addition, a prominent difference in STLr was observed between the control group and the tempol treated diabetic group (p < 0.01). It was also

Please cite this article in press as: Jabbarpour, Z., et al., Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2013.12.013

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Fig. 3. Effect of long term oral administration of tempol on the number of trials to acquisition in the passive avoidance learning (PAL) task. C, control group; C + T, a control group receiving tempol; D, diabetic group; D + T, diabetic group received tempol. **, (p < 0.01); ***, (p < 0.001) as compared with healthy control group. ###, (p < 0.001) compared with diabetic group.

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found that application of tempol to diabetic animals caused a longer STLr compared to diabetic animals (p < 0.05). Also, one-way ANOVA indicated a significant difference in TDC was observed among the experimental groups (F(3,36) = 25.24, p < 0.0001) (Fig. 4B). It is also worth of mentioning by Tukey that the tempol treated diabetic group spent less time in the dark chamber than the diabetic group (p < 0.01). Furthermore, the diabetic group had a greater TDC value than the other groups (p < 0.01) which is consistent with a cognitive impairment. Based on the obtained results, it can be concluded that administration of tempol to diabetic rats improves memory disorders caused by diabetes but not in healthy subject.

Q6 Fig. 4. Effect of long term oral administration of tempol on the step-through latency (STLr) (A) and time spent in the dark compartment (TDC) (B) in the retention trial of passive avoidance task which was carried out 24 h after acquisition trial. C, control group; C + T, a control group receiving tempol; D, diabetic group; D + T, diabetic group received tempol. **, (p < 0.01); ***, (p < 0.001) as compared with control group. #, (p < 0.05); ###, (p < 0.001) compared with diabetic group.

Three main findings were obtained in this study. The first result was that the long-term diabetes resulted in some disturbances in animal performance in PA and NOR. The other finding is that administration of tempol for 60 days improved learning disorders and cognitive dysfunction occurred in diabetic rats as evaluated by PA and NOR. Third finding is that tempol caused cognitive impairments in all learning tests in the healthy control group. As mentioned before, on the basis of previous studies, PAL and NOR tests are useful as a screen for testing new drugs and antioxidant agents which may alter memory processes such as STZ which induces diabetes condition (Hasanein and Shahidi, 2010; Jurdak and Kanarek, 2009; Raghavendra and Kulkarni, 2001). Memory enhancing agents increase novel object exploration time in the NOR test; decrease the number of trials to acquisition, TDC and increase STL in the PAL test. In the present study it was specified that the diabetic rats exhibited the anticipated cognitive function deficits in NOR and less time was spent by them exploring the novel object and more time exploring the familiar object than the control rats. Furthermore, increasing the number of trials to acquisition in diabetic rats during the PA task is an indicator of learning impairment. STLr was decreased and TDC was increased in the retention test representing memory retention deficits induced by diabetes. This result is similar to the previous studies. Learning and memory deficits induced by diabetes mellitus have been previously reported in animals and humans (Baydas et al., 2003b; Kucukatay et al., 2007; Patil et al., 2006; Reaven et al., 1990; Tun et al., 1990; Tuzcu and Baydas, 2006). Previous studies indicated that streptozotocin-induced diabetes is a well-documented model of experimental diabetes (Low et al., 1997). Impaired cognitive function and neurochemical and brain structural abnormalities are reported to occur both in diabetic patients and streptozotocin (STZ)-induced diabetic rodents (Allen et al., 2004; Biessels et al., 2007; Sima, 2004). The pathogenesis of the CNS changes associated with diabetes is multifactorial and may involve inflammation, microvascular dysfunction, and oxidative stress (Patil et al., 2006). Inflammation plays a central role in diabetic tissue damage (Somfai et al., 2006). Also, brain vascular abnormality is one of the other reasons of the cognitive impairments in diabetes (Biessels et al., 2007; Stewart and Liolitsa, 1999; Süleyman et al., 1999; Tuma, 2007; van Deutekom et al., 2008). The roles of oxidative stress in nerve damage were studied in experimental diabetes and diabetic patients (Baynes, 1991). It is also worth mentioning that some consequences of oxidative stress are neuronal damage and death through protein oxidation, peroxidation of membrane lipids, and DNA damage (Hawkins and Davies, 2001; Süleyman et al., 1999). One of the initial causes of most complications of diabetes disease is chronic hyperglycemia which can lead to cognitive impairments in diabetes (Biessels et al., 2007; Suji and Sivakami, 2003; Tuzcu and Baydas, 2006). Streptozotocin-diabetes provides a relevant example of endogenous chronic oxidative stress due to the resulting hyperglycemia (Low et al., 1997). Hyperglycemia reduces the levels of protective antioxidants, including reduced glutathione (GSH) and glutathione peroxidase (GSH-Px), a key antioxidative enzyme (Baydas et al., 2003a,b). Q3 Oxidative damage to rat synapse in the cerebral cortex and hippocampus has been previously reported to contribute to the deficit of cognitive functions (Fukui et al., 2001, 2002). Deficits in learning in the diabetic rats were associated with the changes in hippocampal synaptic plasticity (Baydas et al., 2003a,b; Q4 Biessels et al., 1998). The increased oxidative stress in diabetes produces oxidative damage in many regions of rat brain including the hippocampus (Baydas et al., 2002). These oxidant radicals

Please cite this article in press as: Jabbarpour, Z., et al., Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2013.12.013

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contribute to increased neuronal death through protein oxidation, DNA damage, and peroxidation of membrane lipids (Hawkins and Davies, 2001). Increases in oxidative stress observed in the hippocampus following hyperglycemia or stress may result from modulation of anti-oxidant pathways, such as the isoforms of the anti-oxidant enzyme superoxide dismutase (SOD). For example, manganese-SOD (Mn-SOD) and copper/zinc-SOD (Cu/Zn-SOD) inactivate superoxide anions, which are the first compounds in the chain reaction that leads to lipid peroxidation (Mattson, 1998). MnSOD and Cu/Zn-SOD expression and activities are increased in the hippocampus of STZ-treated rats (Huang et al., 1999), supporting the view that SOD isoforms are activated to compensate for hyperglycemia mediated increases in oxidative stress. Briefly, diabetes induces learning and memory deficit due to the hyperglycemia, oxidative stress, microvascular dysfunction, inflammation and apoptosis in the central nervous system structure such as hippocampus. In the present study, it was indicated that administration of tempol decreased the number of trials to acquisition in the PA task which is an evidence of improvement in acquisition. Also, results showed that increasing STLr and decreasing TDC during the retention test had positive effects of tempol on memory retention (Baydas et al., 2003a; Kucukatay et al., 2007; Shahidi et al., 2008a). Furthermore, it was found that increase in time of exploring the novel object in NOR test was a reason for improvement of cognitive function. In this study, tempol receiving diabetic rats had lower glucose levels than the diabetic rats. This result indicates that tempol may have a significant role in preventing hyperglycemia. These results are in agreement with the previous reports indicating that tempol reduces the elevated plasma glucose levels and insulin action in diabetes (Wilcox, 2010). Previous studies have indicated the tempol hypoglycemic action. For example, tempol has several mechanisms of action that mitigate the effects of reduced insulin release or insulin resistance in animal models of these conditions (Banday et al., 2005). Tempol enhanced insulin secretion from rat cultured pancreatic islet cells subjected to oxidative stress by high ambient glucose concentrations. Tempol also enhanced insulin releases in vivo in glucose-infused rats (Tang et al., 2007). Thus tempol promoted insulin release from the pancreas. Tempol can enhance insulin-stimulated glucose uptake. Thus tempol increased the membrane abundance of the glucose transporter- 1 and enhanced glucose uptake (Alpert et al., 2004). Thus tempol can both enhance the expression of the glucose transporter and enhance the cellular actions of insulin. Tempol corrected insulin resistance. Thus, these results along with the findings of present study indicate that tempol may modulate glucose metabolism and confirm its hypoglycemic effects in diabetes. Therefore, in this work, tempol was used in order to partly restore some cognitive functions in diabetic animals and treat hyperglycemia. However, oxidative stress may also contribute to learning and memory deficits during hyperglycemia. Thus, the effects of tempol in the present study may due to its antioxidant and hypoglycemic effect. Also, several studies have shown antiinflammatory and neuroprotective effects of tempol (Cuzzocrea et al., 2000; Di Paola et al., 2005; Kurihara et al., 2002; Wilcox, 2010; Volk et al., 2000). It can be concluded that tempol reduce hyperglycemia, oxidative stress, lipid peroxidation, inflammation and neural damage. These protective effects decrease the diabetes induce memory impairment. This is in agreement with previous report that, oxidative damage causes cognitive impairments and therefore a therapeutic approach like treatment with antioxidants is effective in various types of neurodegenerative diseases (Fukui et al., 2001, 2002; Kucukatay et al., 2007; Süleyman et al., 1999; Tuzcu and Baydas, 2006). It has been found by some works that the

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memory deficits are treated by using antioxidants and neuroprotective agents (Tuzcu and Baydas, 2006). One of the interesting result of the present study was that, tempol decreased impaired learning and memory in NOR and PAL in the healthy group. This interesting result may be explained by the fact that ROS are useful as signaling molecules (Hancock et al., 2001). On the other hands, tempol is a superoxide dismutase SOD mimetic and significantly more effective than other frequently used antioxidants and it is far more effective than vitamins (Wilcox, 2010). Thus removal of excess ROS by tempol may impair normal cell signaling pathways of memory processing in the healthy subject. In conclusion, we believe although tempol caused cognitive impairments in all learning tests in the healthy control group; it might be used at proper doses to prevent development of diabetic complications.

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The authors declare that there is no conflict of interest. Uncited references Biessels and Gispen (2005) and Stranahan et al. (2008). Acknowledgments This work was a part of a MSc thesis and it was supported by a grant from Hamadan University of Medical Sciences. References Akirav, I., Maroun, M., 2006. Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cerebral Cortex 16, 1759–1760. Allen, K.V., Frier, B.M., Strachan, M.W., 2004. The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. European Journal of Pharmacology 490, 169–175. Alpert, E., Altman, H., Totary, H., Gruzman, A., Barnea, D., Barash, V., Sasson, S., 2004. 4-Hydroxy tempol-induced impairment of mitochondrial function and augmentation of glucose transport in vascular endothelial and smooth muscle cells. Biochemical Pharmacology 67, 1985–1990. Arison, R.N., Ciaccio, E.I., Glitzer, M.S., Cassaro, A.V., Pruss, M., 1967. Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin. Diabetes 16, 51–56. Balakrishnan, S., Kumar, P., Paulose, C.S., 2009. Glutamate (mGluR-5) gene expression in brain regions of streptozotocin induced diabetic rats as a function of age: role in regulation of calcium release from the pancreatic islets in vitro. Journal of Biomedical Science 16, 1–11. Banday, A.A., Marwaha, A., Tallam, L.S., Lokhandwala, M.F., 2005. Tempol reduces oxidative stress, improves insulin sensitivity, decreases renal dopamine D1 receptor hyperphosphorylation, and restores D1 receptor-G-protein coupling and function in obese Zucker rats. Diabetes 54, 2219–2220. Baydas, G., Reiter, R.J., Yasar, A., Tuzcu, M., Akdemir, I., Nedzvetskii, V.S., 2003a. Melatonin reduces glial reactivity in the hippocampus, cortex, and cerebellum of streptozotocin-induced diabetic rats. Free Radical Biology and Medicine 35, 797–804. Baydas, G., Nedzvetskii, S., Nerush, P.A., Kirichenko, S.V., Yoldas, T., 2003b. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sciences 73, 1907–1910. Baydas, G., Canatan, H., Turkoglu, A., 2002. Comparative analyses of the protective effects of melatonin and vitamin E on streptozotocin-induced diabetes mellitus. Journal of Pineal Research 32, 225–230. Baynes, J.W., 1991. Role of oxidative stress in development of complications in diabetes. Diabetes 40, 405–412. Biessels, G.J., Kerssen, A., de Haan, E.H., Kappelle, L.J., 2007. Cognitive dysfunction and diabetes: implications for primary care. Primary Care Diabetes 1, 187–193. Biessels, G.J., Gispen, W.H., 2005. The impact of diabetes on cognition: what can be learned from rodent models? Neurobiology of Aging 26, 36–41. Biessels, G.J., Kamal, A., Urban, I.J., Spruijt, B.M., Erkelens, D.W., Gispen, W.H., 1998. Water maze learning and hippocampal synaptic plasticity in streptozotocindiabetic rats: effects of insulin treatment. Brain Research 800, 125–135. Biessels, G.J., Kappelle, A.C., Bravenboer, B., Erkelens, D.W., Gispen, W.H., 1994. Cerebral function in diabetes mellitus. Diabetologia 37, 643–650. Broadbent, N.J., Squire, L.R., Clark, R.E., 2004. Spatial memory, recognition memory, and the hippocampus. Neuroscience 101, 14515–14520.

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Please cite this article in press as: Jabbarpour, Z., et al., Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2013.12.013

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Effect of tempol on the passive avoidance and novel object recognition task in diabetic rats.

Diabetes mellitus (DM) has several effects, including cognitive impairment. Oxidative stress is associated with complications from diabetes. It seems ...
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