Effects of Insulin and St. John's Wort Treatments on Anxiety, Locomotory Activity, Depression, and Active Learning Parameters of Streptozotocin-Diabetic Rats

• Abstract
• Abbreviations
• Introduction
• Materials and Methods
• Animals
• Chemicals
• Preparation of extracts and phytochemical analysis
• Pharmacological experiments
• Induction of DM
• Insulin treatment
• SJW extract treatment
• Behavioral tests
• Anxiety tests
• Activity cage tests
• Modified forced swimming test (MFST)
• Active avoidance tests
• Statistical analysis of data
• Results and Discussion
• Acknowledgements
• References

Abstract

The aim of this work was to investigate the effects of St. John's Wort (SJW) extract treatment on behavioral changes arising in streptozotocin (STZ)-diabetic rats. Plus-maze, activity cage, modified forced swimming, and active avoidance tests were performed for evaluating exploratory behaviors, spontaneous locomotor activities, depression levels, and learning parameters of animals, respectively. Obtained data exhibited a diabetes mellitus (DM)-induced increase in anxiety and depression levels, decrease in spontaneous locomotor activities, and impairment of learning parameters in rats even in the early stages of the disease. Daily insulin replacement (2 IU/kg/day) could not restore these impaired parameters completely, indicating the need of novel therapeutic approaches. SJW extract (125 and 250 mg/kg) treatments for seven days provided significant improvement in all of the impaired parameters observed in this study, probably due to its antidiabetic and central nervous system (CNS)-related effects.

Based on the findings of the present study, it may be suggested that SJW extracts may be of help to diabetic patients suffering from depressive moods, sleeping disturbances, and cognitive deficits and may provide a new potential alternative for the treatment of psychiatric complications of diabetes.

Abbreviations

GABA: γ-aminobutyric acid

HPLC: high-performance liquid chromatography

Introduction

Diabetes mellitus (DM) is defined as a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, protein, and fat metabolism resulting from defects in insulin secretion, insulin action, or both [1]. Diabetes can result in numerous acute complications including hypoglycemia, hyperglycemia, ketoacidosis, and hyperosmolar syndrome. In addition to acute complications, chronic conditions may lead to long-term metabolic disorders related to various organ dysfunctions [1]. The central nervous system (CNS) complications of this disease have come into prominence in recent years [2].

Type I diabetic patients have been reported to suffer from somatic symptoms, sleeping disturbances, compulsions, and depressive moods as well as impairments in cognitive functions and motor speed. In addition, a higher incidence of cognitive deficits and poorer performance in abstract reasoning and complex psychomotor functioning have been reported for type II diabetic patients when compared to the general population. Insulin deficiency-induced hyperglycemia or impairment of insulin action have been suggested as main reasons for CNS complications observed in both type I and type II diabetic patients [2].

Hypericum perforatum Linn. (Clusiaceae), also known as St. John's wort (SJW), is a quite popular plant in biomedical sciences due to its wide spectrum of pharmacological effects. Clinical investigations have exhibited the therapeutic effect of standardized extracts prepared from the plant against some CNS ailments such as depressive diseases, anxiety disorders, and insomnia [3], [4]. Commercial preparations of SJW such as Hyperiforce®, Jarsin® 300, Kira®, LI 160®, and Remotiv® have been used currently for the treatment of mild to moderate depression in several European countries and the USA [5].

Investigations are in progress to examine the effects of SJW extracts on various CNS-related disorders [6], [7]. Our research group has reported recently the therapeutic effect of the SJW extract on diabetic neuropatic pain in rats due to its antidiabetic and analgesic activities [8].

Based on the CNS-related pharmacological effects and the antidiabetic activity [8], we planned to investigate potential therapeutic effects of the SJW extract on behavioral changes arising in streptozotocin (STZ)-diabetic rats. Effects of daily insulin treatments on these alterations were also examined in the present study.

Materials and Methods

Animals

Wistar rats of local strain with body weight ranging from 200–250 g were maintained in an air-conditioned room (24 ± 1 °C) with a 12-h light/dark cycle. Food and water were provided ad libitum. The experimental protocols have been approved by the Local Ethical Committee on Animal Experimentation of the Eskişehir Osmangazi University, Turkey (01/2007).

Chemicals

Insulin (> 98 %, HPLC) and STZ (≥ 98 %, HPLC) were purchased from Sigma.

Preparation of extracts and phytochemical analysis

Preparation of the extracts and phytochemical analyses were performed as described in our previous study [8].

Aerial parts of Hypericum perforatum L. were collected in Tahtakuşlar village, Balıkesir, Turkey in June 2005. After collection, the plant material was dried at room temperature, and its voucher specimen was kept at the Herbarium of the Faculty of Science (OUFE 10337) Osmangazi University, Eskişehir, Turkey. Botanical identification of the collected material was made by Dr. Onur Koyuncu from Osmangazi University, Faculty of Science.

Fresh aerial parts of the plant were air-dried at room temperature and powdered. The crude powder was macerated in 50 % ethanol (1 : 10) for one night and extracted for 8 hours at 40 °C in a water bath, then filtered. This process was repeated three times; filtrates were collected and concentrated under reduced pressure in a rotary evaporator at 40 °C to remove ethanol. The remaining aqueous part was freeze-dried at −80 °C and lyophilized. The extract obtained was weighed to determine the yields of the soluble constituents. The yield of the extract was calculated as percentage (6.12 %).

The chromatographic analyses of the extract were performed using high-performance liquid chromatography (HPLC) coupled to diode array detection for phenolic compounds, hyperforin, and hypericin. The method used for identification of the components was the comparison of their retention times and UV spectra with respect to those of standards, chromatographed under the same conditions. In addition, the confirmation of the identified compounds was realized analyzing standard and sample solutions using an HPLC-MS equipped with an ESI interface in negative ionization mode using the same chromatographic conditions (formic acid was used instead of phosphoric acid at the same pH) [8].

Pharmacological experiments

Animals were divided into classes as control (normoglycemic), SJW extract-treated normoglycemic, STZ-diabetic, insulin-treated diabetic, and SJW extract-treated diabetic animals. Seven rats were placed in each of the groups. Administration of the testing substance into the animals was carried out in a conscious state.

Induction of DM

Diabetes was induced in animals fasted for 24 h by a single intravenous injection of STZ. STZ was dissolved in the citrate buffer (pH = 4.5, 0.1 M) and immediately injected at the dose of 60 mg/kg. 72 hours after the STZ injection, glucose was determined in blood samples obtained by pricking the tail using Glukotrend®. Animals with blood glucose levels higher than 300 mg/dL were accepted as diabetic [8].

Insulin treatment

Insulin treatment was initiated 72 hours after the STZ injection, when occurrence of diabetes was observed, and continued daily for 6 weeks. Insulin was administered via intraperitoneal (i. p.) route at a dose of 2 IU/kg per day [9]. STZ-diabetic animals that were used as the control groups of insulin-treated diabetic groups were treated with citrate buffer alone since insulin was prepared in citrate buffer (10 mM, pH = 6) [9].

SJW extract treatment

SJW extract was administered (i. p.) to animals in SJW extract-treated normoglycemic groups at 125 and 250 mg/kg per day during one week. The control-normoglycemic group was treated only with physiological saline since SJW extract was dissolved in it.

SJW extract was also administered to animals in the SJW extract-treated diabetic group in the same way as to SJW extract-treated normoglycemic animals. SJW extract treatment was initiated three weeks after the induction of diabetes when all depression, anxiety, locomotor activity, and learning parameters were observed to be impaired in our experiments. STZ-diabetic animals that were used as the control groups of the SJW extract-treated STZ-diabetic group were treated with physiological saline only.

Behavioral tests

On the same day of every week, behavioral measurements of each group of rats were taken. Anxiety, locomotor activity, depression, and learning parameters of the animals were assessed definitely at the same hours of the day.

Anxiety tests

Elevated plus-maze test was used to examine the exploratory behavior of rats as described earlier by Zanoli and coworkers in 2005 [10]. The number of entries and the time spent in the open and closed arms for 10 min were recorded. Percentage of the time spent in the open arms relative to the total time spent in both arms (PTOA) and percentage of number of entries into open arms relative to the total number of entries into any arm (PEOA) were calculated as a parameter of anxiety level [10].

Activity cage tests

The spontaneous locomotor activities of rats were registered by the locomotor activity apparatus Ugo Basile No. 7420. Horizontal and vertical locomotor activities were recorded for a period of 10 min [11].

Modified forced swimming test (MFST)

Depression levels of rats were measured by MFST as described earlier by Cryan and coworkers in 2002 [12]. Swimming, climbing, and immobility times over a 5-sec interval during 5 min were recorded by a stopwatch [12].

Active avoidance tests

Learning parameters were tested through a two-way active avoidance procedure taking place in an Ugo-Basile (model 7530) automated shuttle box device as described earlier by Sanchez and coworkers in 1998 [13]. Number of avoidances (number of crossings during unconditioned stimulus) and latency periods (time before crossing) were recorded. The first session was preceded by 10 min of accommodation to the box [13].

Statistical analysis of data

The data used in statistical analysis was acquired from seven animals for each group. Statistical evaluation of the data was performed using GraphPad Prism 4.03 (GraphPad Software). Experimental data obtained from the same group of animals during 6 weeks were analyzed by repeated measures ANOVA followed by Tukey HSD test. Data coming from different groups of animals were analyzed by one-way ANOVA followed by Tukey's HSD test for multiple comparisons. Experimental results were expressed as mean ± standard error of mean (SEM). Differences between given sets of data were considered as significant when the p value was less than 0.05.

Results and Discussion

The aim of this work was to investigate the effects of one-week SJW extract treatment on behavioral changes arising in STZ-diabetic rats.

The first part of this study consisted in the examination of the behavioral effects of SJW extract in nondiabetic animals. In this normoglycemic group, extract administration did not change the blood glucose levels of rats ([Table 1]). One-week treatment with SJW extract caused a significant and dose-dependent decrease in both exploratory behavior parameters (PEOA and PTOA) in plus-maze tests ([Table 2]). Horizontal and vertical spontaneous locomotor activities were also decreased dose-dependently in activity cage measurements ([Table 3]). It is generally believed that locomotor activity results from brain activation, which is manifested as an excitation of central neurons involved in different neurochemical mechanisms, and an increase in cerebral metabolism [14]. Therefore, reduction in the spontaneous locomotory activities of animals as well as inhibition of exploratory behaviors indicate a general inhibition of neuronal activity in the CNS [15]. A CNS depressant effect has already been reported for SJW extracts previously [16].

In MFST, immobility times of rats significantly and dose-dependently decreased whereas swimming times increased in a dose-dependent manner ([Table 4]). Reduction in immobility durations and prolongation of swimming times of rats pointed out the antidepressant effect of the extract [12], as expected from the results of previous studies [17].

In normoglycemic animals, 250 mg/kg dose of the extract caused a significant decrease in the latency periods and increase in the number of avoidances in shuttle-box tests ([Table 5]) indicating the enhancement of cognitive behaviors in normoglycemic animals by administration of the extract. These results are in general agreement with the findings of previous reports indicating attention, learning, and memory enhancing effects of SJW extracts in rodents [18].

The second part of this study consisted in examining the progressive behavioral changes of STZ-diabetic animals and observing the effect of daily insulin treatment on these alterations.

Induction of diabetes caused statistically significant decreases in the PEOA and PTOA values of animals until the third week, and these parameters did not change any more in the following weeks ([Fig. 1]). Decrease in the PEOA and PTOA values indicates a suppression of exploratory behavior and a high anxiety level of diabetic animals ([Fig. 1]). The values for horizontal and vertical locomotor activity of diabetic animals were also decreased until the second week and did not change any more in the following weeks ([Fig. 2]). In MFST, immobility times of diabetic animals were increased until the third week, and this enhancement was slightly decreased at the fifth and sixth weeks. Conversely, climbing and swimming times were decreased by the occurrence of diabetes until the third and second weeks, respectively. This reduction then gave way to a slight increase in the last weeks ([Fig. 3]). Increase in immobility and decrease in active behaviors of the animals indicated the augmented depression levels in diabetic animals.

Induction of diabetes caused statistically significant increase in the latency periods and a decrease in the number of avoidances of animals until the second week. Both parameters did not change any more in the following weeks ([Fig. 4]). These data clearly exhibited the impairment of learning behavior in this diabetic group.

Data obtained from the STZ-diabetic animals in this study are supported by the previous papers suggesting high anxiety levels [19], depressive behaviors [20], and cognitive deficits [2] observed in diabetic animals even in early stages of diabetes.

Since STZ causes type I-like DM syndrome in animals as a result of the destruction of β-cells in their pancreatic Langerhans islets, which is believed to be initiated by an autoimmune reaction [21], daily insulin treatment was applied to diabetic animals in the present study. Change of blood glucose levels with insulin treatments are shown in [Table 1]. Insulin treatments improved the hyperglycemia in diabetic animals, as expected.

Daily treatment with insulin was not able to restore the high anxiety levels ([Fig. 1]) or reduced locomotor activity parameters ([Fig. 2]) in diabetic animals. In accordance with these findings, previous studies by Merali et al. [22] and by Howarth et al. [23] have also demonstrated the ineffectiveness of insulin treatment on decreased locomotor activity in diabetic animals. On the other hand, insulin treatment significantly but partially restored the high depression levels ([Fig. 3]) and impaired learning parameters ([Fig. 4]) of STZ-diabetic rats. These findings confirmed the previous reports suggesting partial restoration of depression parameters [20] and cognitive deficits [24] in insulin-treated STZ-diabetic animals.

The obtained findings indicated clearly that insulin treatment at a 2 IU/kg/day dose could not restore the impaired behavioral parameters of STZ-diabetic animals to the values of normoglycemic rats. A reason for this data was probably the applied dose of insulin (2 IU/kg/day), which is the lowest dose required to improve hyperglycemia in diabetic animals [9]. Higher doses were not preferred in order to avoid insulin administration-induced hypoglycemic periods which are known to affect the measured behavioral parameters [20], [25]. Hypoglycemic episodes are accepted as major factors for the development of DM-induced CNS complications in diabetic patients [25]. C-peptide deficiency, which cannot be replaced by exogenous insulin treatment, might be another reason for the effectiveness of insulin administration to provide a total restoration on the impaired behavioral parameters of STZ-diabetic rats [25]. As a matter of fact, occurrence of CNS complications in type I diabetic patients in spite of chronic insulin treatment [2], [25] has already pointed out the incapability of insulin treatment alone in preventing CNS complications of DM.

In this context, discovery and development of novel therapeutic modalities for the management of DM-induced psychiatric disorders gain importance. From this point of view, we here hypothesized that SJW extract may have therapeutic potential for the treatment of behavioral deficits observed in diabetic rats, based on its antidiabetic effects [8] and CNS related activities. For investigating a probable therapeutic effect, SJW extract treatment (125 and 250 mg/kg) was initiated three weeks after the induction of diabetes, when obvious impairments in depression, anxiety, locomotor activity, and cognitive parameters were observed in diabetic animals ([Fig. 1]–[4]). SJW treatments did not change the blood glucose levels of normoglycemic rats but induced a significant and dose-dependent decrease in the high blood glucose levels of STZ-diabetic animals ([Table 1]). Besides, administrations of SJW extract during the fourth week improved the impaired anxiety ([Table 2]), locomotor activity ([Table 3]), and depression ([Table 4]) parameters of diabetic rats in a dose-dependent manner. 250 mg/kg dose of the extract achieved restoration of the high depression levels of diabetic animals completely. Additionally, in shuttle-box experiments, 250 mg/kg SJW extract treatment during the fourth week caused an improvement of the diabetes-induced alterations in learning parameters ([Table 5]).

Results of this present study are in agreement with a recent study of Hasanein and Shahidi, who have reported that SJW treatment improved learning and memory parameters in normoglycemic rats and reversed the diabetes-induced learning and memory impairment in STZ-diabetics [26]. In the study of Hasanein and Shahidi, SJW extracts were applied at low doses (6, 12, and 25 mg/kg) for 30 days, whereas 125 and 250 mg/kg doses of SJW were used for one week in the present study. Both long-term administration with low doses and short-term administration with high doses improved learning and memory parameters of diabetic animals.

As indicated in our recent report, phenolic compounds detected in our tested SJW extract were rutin (2225.45 ppm), quercetin (741.82 ppm), quercitrin (556.36 ppm), isoquercitrin (556.36 ppm), hyperosid (370.91 ppm), chlorogenic acid (137.05 ppm), hyperforine (42.65 ppm), and hypericin (40.71 ppm) [8]. Rutin was the major phenolic compound in the extract according to these results. This flavonoid is known for its activating effect on GABA(A)/benzodiazepine receptor sites [27], as well as its antidiabetic activity [28]. Increase in GABAergic activity by SJW extract administration may be speculated as a factor restoring DM-induced GABAergic dysfunction in CNS and may at least partially explain the treatment of high anxiety and depression levels of diabetic animals observed in the present study. On the other hand, quercetin, another high concentrated compound detected in the tested extract, has been reported previously for its insulin secreting activities [29] as well as diabetes-associated depression [30] and memory dysfunction improving effects [31]. Since the extract used in the present study has high flavonoid content [8], it may be suggested that the effects of SJW both on diabetes and depression, at least partly, seem to be related to flavonoids.

In summary, the present study displayed the therapeutic potential of SJW on psychiatric and cognitive disorders. Since depression, anxiety, and sleep disorders generally occur together in psychiatric patients, and learning disorders accompany all of these diseases [32], treatment with SJW extract may offer a monotherapy chance alone and provide prevention from polypharmacy.

Another result of this study was the DM-induced increase in anxiety and depression levels, decrease in spontaneous locomotor activities, and learning deficits in rats even in the early stages of the disease. Insulin treatment could not restore these impaired parameters totally, signifying the needs of discovery and development of new drugs.

SJW extract, due to its both antidiabetic [8] and CNS-related effects, may help diabetic patients to control their blood glucose levels as well as to improve their psychiatric disorders. As conventional antidepressant drugs, such as nortriptyline, clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline may have deleterious side effects on glycemic controls [33], [34], the use of SJW in the therapeutic management of affective disorders may provide an additional advantage in patients with DM. However, the clinical efficacies of SJW extracts wait for further investigations.

In conclusion, this study may serve to establish a preclinical base for the management of depressive moods, sleeping disturbances, and cognitive deficits in diabetic patients [2] as a novel therapeutic approach.

Acknowledgements

This work was financially supported by the Anadolu University Research Foundation (Eskisehir, Turkey), Project No. 040345.

Conflict of Interest

There is no conflict of interest. The authors alone are responsible for the content and writing of the paper.

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Özgür Devrim Can

Department of Pharmacology
Anadolu University, Faculty of Pharmacy

Tepebaşı

26470 Eskisehir

Turkey

Phone: +90 222 3 35 05 80 ext. 37 49

Fax: +90 222 3 35 07 50

Email: ozgurdt@anadolu.edu.tr

References

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  Search in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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  Search in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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• 9 Romanovsky D, Cruz N F, Dienel G A, Dobretsov M. Mechanical hyperalgesia correlates with insulin deficiency in normoglycemic streptozotocin-treated rats.  Neurobiol Dis. 2006;  24 384-394
  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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Özgür Devrim Can

Department of Pharmacology
Anadolu University, Faculty of Pharmacy

Tepebaşı

26470 Eskisehir

Turkey

Phone: +90 222 3 35 05 80 ext. 37 49

Fax: +90 222 3 35 07 50

Email: ozgurdt@anadolu.edu.tr