|Year : 2011 | Volume
| Issue : 3 | Page : 324-329
Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice
Anil Kumar, Ruchika Garg, Vaibhav Gaur, Puneet Kumar
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India
|Date of Submission||29-Jan-2010|
|Date of Decision||25-Nov-2010|
|Date of Acceptance||23-Feb-2011|
|Date of Web Publication||24-May-2011|
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014
Source of Support: None, Conflict of Interest: None
Background and Objective: The present study was designed to elucidate the possible nitric oxide (NO) mechanism in the protective effect of antidepressants using mice model of chronic fatigue syndrome (CFS).
Materials and Methods: Male albino laca mice were forced to swim for each 6 min session for 7 days and immobility period was measured on every alternate day (1 st , 3 rd , 5 th , 7 th ). After 7 days various behavioral tests (locomotor, mirror chamber, and plus maze tests for anxiety) were performed and biochemical estimations (lipid peroxidation, nitrite levels, GSH (reduced glutathione), and catalase activity) in mice brain were performed. Animals were pretreated with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) daily for 7 days.
Results: The present study showed that continued forced swimming for 7 days caused chronic fatigue-induced anxiety-like behavior as assessed in mirror chamber, plus maze tests, and impairment in locomotor activity followed by oxidative damage (as evidenced by increased lipid peroxidation, nitrite levels, depleted reduced glutathione, and catalase activity) in animals. Seven days pretreatment with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) significantly improved behavioral and biochemical alterations. Further, L-nitro-arginine methyl ester (L-NAME,5 mg/kg) and methylene blue (MB, 10 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) potentiated their protective effect. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) reversed their protective effect as compared with their effect per se (P < 0.05).
Conclusion: The present study suggests that protective effect of citalopram and imipramine might be due to its NO modulation against chronic fatigue induced behavioral and biochemical alterations.
Keywords: Anxiety, chronic fatigue syndrome, citalopram, imipramine, nitric oxide, oxidative stress
|How to cite this article:|
Kumar A, Garg R, Gaur V, Kumar P. Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice. Indian J Pharmacol 2011;43:324-9
|How to cite this URL:|
Kumar A, Garg R, Gaur V, Kumar P. Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice. Indian J Pharmacol [serial online] 2011 [cited 2020 Apr 4];43:324-9. Available from: http://www.ijp-online.com/text.asp?2011/43/3/324/81506
| » Introduction|| |
Chronic fatigue syndrome (CFS) is a heterogeneous disorder of unknown etiology, characterized by persistent and relapsing fatigue, neuropsychiatric symptoms, and various other somatic complaints.  CFS patients often complain of headache, joint pain, gastrointestinal disturbance, cognitive dysfunction, visual disturbance, paresthesia, and neuropsychiatric problems, including anxiety-like behavior.  Chronic fatigue is a complex disorder with unknown pathophysiology and therefore no adequate treatment available for this complex problem. Clinically, various pharmacological and supportive, nutritional, and exercise therapies are used with limited success.  However, exact mechanism or scientific explanation to reduce fatigue and other related problems in patients are needed to be understood.
Recent studies have demonstrated that elevated peroxinitrite levels leads to mitochondrial dysfunction and hypothalamus pituitary adrenal (HPA) dysfunction, which further leads to CFS.  It is hypothesized that a nitric oxide (NO)-dependent reduction in inhibitory activity of central nervous system (CNS) and consequent central sensitization accounts for manifestations in CFS patients.  Oxidative stress and NO have been proposed to interplay in CFS pathophysiology, however, exact cellular cascade are not fully understood so far.  This encourages researcher to further evaluate new treatment strategy against this disorder.
Our previous studies have demonstrated that citalopram and imipramine can alleviate symptoms of depression and chronic fatigue in animal models.  However, exact mechanisms by which it alleviates depression-like symptoms in CFS patients are still unknown. It was previously found that the NMDA receptor/NO/cyclic GMP pathway can be inhibited by drugs acting through 5-HT receptors. Recent study has also shown that inhibition of nitric oxide synthase (NOS) could be used to enhance the clinical efficacy of serotonergic antidepressants. , The objective of the present study was to explore the protective effect of citalopram and imipramine in animal model of CFS.
| » Materials and Methods|| |
Male laca mice (20-25 g) bred in the central animal house of Panjab University were used in the present study. Animals were acclimatized to laboratory conditions prior to experimentation. The animals were kept under standard conditions of light and dark cycle with food and water ad libitum in groups of 2 in plastic cages with soft bedding. All the experiments were carried out between 09:00 and 15:00 h. The protocol was approved by the Institutional Animal Ethics Committee and carried out in accordance with the Indian National Science Academy Guidelines for the use and care of animals.
The animals were randomly divided into 15 groups of 10 each. Group 1: Naïve group (nonstressed animals), Group 2: CFS for 7 days, Group 3 and 4 received IMP (10 and 20 mg/kg) + CFS, groups 5 and 6 received CIT (5 and 10 mg/kg) + CFS, Group 7 received L-NAME (5) + CFS, Group 8 received MB (10) + CFS, Group 9 received l-ARG (100) + CFS, Group 10 received L-NAME (5) + IMI (10) + CFS, Group 11 received L-NAME (5) + CIT (5) + CFS, Group 12 received MB (10) + IMI (10) + CFS, Group 13 received MB (10) + CIT (5) + CFS, Group 14 received l-ARG (100) + IMI (10) + CFS, Group 15 received l-ARG (100) + CIT (5) + CFS. In the present study, L-NAME, MB and l-arginine were administered 1 h prior to imipramine or citalopram treatment. All the drugs were dissolved in saline.
Forced Swimming Test (Measurement of Period of Immobility)
The animals were forced to swim individually in a glass jar (25 × 12 × 25 cm) containing water at room temperature (22°C ± 3°C). The water depth was adjusted to 15 cm and was kept constant throughout the experiments. After an initial period of vigorous activity, each animal assumed a typical immobile posture. The duration of immobility was measured during a total period of 6 min. The mice were judged immobile when they ceased struggling movement of their limbs to keep the head above water. They were forced to swim, 6 min test session each for 7 days. The enhancement in immobility period induced by continued forced swimming was considered as a situation related to CFS. 
Elevated Plus Maze Test
Elevated plus maze developed as a novel test for testing selective anxiogenic and anxiolytic drug effect in rodents. The animals were placed individually at the center of the elevated plus maze with their heads facing toward an open arm. During the 5 min test, the average time spent per entry in open arm of the maze was recorded. 
Mirror Chamber Test
The mirror chamber consisted of a wooden chamber having a mirror chamber enclosed within it. During the 5 min test session, following parameters were noted: (a) latency to enter the mirror chamber, (b) average time spent in mirror chamber. Animal was placed individually at the outside of the distal corner of mirror chamber at the beginning of the test. An anxiogenic response was defined as decreased average time spent in the mirror chamber. 
Measurement of Ambulatory Activity
The ambulatory activity was recorded by using actophotometer (IMCORP, Ambala, India). Before the locomotor task, the animals were placed individually in the activity meter for 3 min as habituation. The locomotor activity was recorded using actophotometer for a period of 5 min. Ambulatory activity was recorded and expressed in terms of total photo beam counts for 5 min per animal. 
On day 7, after behavioral quantification, the animals were sacrificed by decapitation immediately. The whole brains were removed and 10% (w/v) tissue homogenate was prepared in 0.1 M phosphate buffer (pH 7.4). The homogenate was centrifuged at 10,000 × g for 15 min at 4°C. Aliquots of supernatant was separated and used for biochemical estimations.
The quantitative measurement of lipid peroxidation in the whole brain was measured according to the method of Wills.  Reduced glutathione in the brain was estimated according to the method of Ellman.  Nitrite concentration was measured in cell free supernatants from brain homogenates by spectrophotometer assay based on Greiss reagent.  The protein content was measured by biuret method using bovine serum albumin as standard.  Catalase activity was assayed by the method of Luck. 
All the values are expressed as mean ± SEM. The data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's test. In all the test criterion for statistical significance was P < 0.05.
| » Results|| |
Effect of Citalopram or Imipramine and their Modulation by L-NAME or MB, and/or L-arginine on Mean Immobility Period
Immobility period was significantly increased on 3 rd , 5 th , and 7 th day after continued forced swimming daily (6-min session), as compared with naïve animal (P < 0.05). Pretreatment with citalopram (5 and 10 mg/kg), or imipramine (10 and 20 mg/kg) significantly (P < 0.05) and dose dependently reduced immobility period as compared with control (chronic fatigue) group [Table 1]. Furthermore, L-NAME (5 mg/kg) and MB (10 mg/kg) pretreatment with citalopram (5 mg/kg), or imipramine (10 mg/kg) caused further reduction in immobility period as compared with their effect per se (P < 0.05) [Table 1]. However, pretreatment of l-arginine (100 mg/kg) with citalopram (5 mg/kg), or imipramine (10 mg/kg) significantly (P < 0.05) reversed protective effect (increased immobility period) as compared with their effect per se (5 mg/kg). L-NAME (5 mg/kg), MB (10 mg/kg), and l-arginine (100 mg/kg), did not show any significant effect on the immobility period on each day as compared with the control [Table 1].
|Table 1: Effect of citalopram and imipramine and their modulation by L-NAME, methylene blue, and L-arginine on immobility period|
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Effect of Citalopram or Imipramine and their Modulation by L-NAME or MB, and/or L-arginine on Ambulatory Activity
Seven days of continued forced swimming for 7 days significantly (P < 0.05) impaired locomotor activity as compared with naïve group. Citalopram (5 and 10 mg/kg) or imipramine (10 and 20 mg/kg) pretreatment significantly (P < 0.05) attenuated the impaired locomotor activity as compared with control (chronic fatigue) [Table 2]. L-NAME (5 mg/kg) and MB (10 mg/kg) pretreatments with citalopram (5 mg/kg), or imipramine (10 mg/kg) significantly potentiated their protective effect on locomotor activity as compared with their effect per se (P < 0.05) [Table 2]. However, pretreatment of l-arginine (100 mg/kg) with citalopram (5 mg/kg), or imipramine (10 mg/kg) significantly (P < 0.05) reversed their protective effect and showed reduced locomotor activity as compared with their effect per se [Table 2]. L-NAME (5 mg/kg), MB (10 mg/kg), and l-arginine (100 mg/kg), treatment did not show any significant effect on locomotor activity as compared with control (P < 0.05).
|Table 2: Effect of citalopram and imipramine and their modulation by L-NAME, methylene blue, and L-arginine on locomotor activity, elevated plus maze and mirror chamber test|
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Effect of Citalopram or Imipramine and their Modulation by L-NAME or MB or L-arginine on Anxiety (Plus Maze and Mirror Chamber Test)
Seven days continued forced swimming caused anxiety-like behavior as assessed by elevated plus maze (decreased average time spent per entry in open arm) as well as mirror chamber test (decreased latency to enter and average time spent per entry in mirror chamber), which was significant (P < 0.05) as compared with naïve group [Table 2]. Citalopram (5 and 10 mg/kg) or imipramine (10 and 20 mg/kg) pretreatment once daily for 7 days, significantly caused anti-anxiety-like effect in both test models (ie, increased average time spent per entry in open arm in case of plus maze test, increased latency to enter and average time spent per entry in mirror chamber in case of mirror chamber test) that was significant (P < 0.05) as compared with the control [Table 2]. L-NAME (5 mg/kg), MB (10 mg/kg), and l-arginine (100 mg/kg), per se, did not show any significant effect in both test models as compared with the control (P < 0.05). Further, L-NAME (5 mg/kg) and MB (10 mg/kg) pretreatments with citalopram (5 mg/kg) or imipramine (10 mg/kg) caused potentiation in the protective effect of respective antidepressants, which was significant as compared with their effect per se. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) reversed the anxiolytic effect of citalopram (5 mg/kg) or imipramine (10 mg/kg) in both test models as compared with their effect per se [Table 2].
Effect of Citalopram or Imipramine and their Modulation by L-NAME or MB or L-arginine on Lipid Peroxidation, Reduced Glutathione, Nitrite, and Catalase Activity
Seven days of forced swimming significantly raised lipid peroxidation, nitrite level, depleted reduced glutathione, and catalase enzyme activity as compared with naïve animals (P < 0.05). Citalopram (5 and 10 mg/kg) or imipramine (10 and 20 mg/kg) pretreatment significantly and dose dependently attenuated lipid peroxidation, nitrite levels, and restored reduced glutathione as well as catalase activity as compared with the control group (P < 0.05) [Table 3]. L-NAME (5 mg/kg), MB (10 mg/kg), and l-arginine (100 mg/kg) treatment did not show any significant effect on oxidative products and antioxidant defense enzymes as compared with the control (P < 0.05). Furthermore, L-NAME (5 mg/kg) and MB (10 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) caused further potentiation in the protective effects of respective antidepressants on oxidative products and antioxidants enzymes, which was significant as compared with their effect per se [Table 3]. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) significantly reversed the antioxidant activity of citalopram and imipramine [Table 3].
|Table 3: Effect of citalopram and imipramine and their modulation by L-NAME, methylene blue, and L-arginine on oxidative damage|
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| » Discussion|| |
CFS is an illness characterized by persistent and relapsing fatigue, often accompanied by several neuropsychiatric problems. It is well established that there is a high lifetime prevalence of affective symptoms, such as depression, dysthymia, and anxiety in the chronic fatigue population. There are many overlapping symptoms between chronic fatigue and major depression.  Therefore, various antidepressant drugs are being investigated and proved to have clinical utility in chronic fatigue condition. However, patients suffering from chronic fatigue demonstrated poor response to conventional antidepressant therapy.  Supporting the present study and previous studies conducted in our laboratory,  forced swimming for 6 min daily for 7 days, produced CFS-like symptoms. These behavioral changes might be due to chronic stress. Demitrack and co-workers  proposed that the biological as well as behavioral features of CFS may be linked to endocrine dysfunction of the HPA axis. Chronic stress has been well documented to cause anxiety-like behavior, reduced locomotor activity, and stress-induced depression.  However, mechanisms for these changes have not been well understood. Research studies examined and hypothesized oxidative stress, genetic predisposition, HPA axis abnormalities, immune dysfunction, as well as mental and psychosocial factors causing or contributing to the condition. 
The present study suggests citalopram and imipramine pretreatments attenuated the chronic fatigue-induced behavioral and biochemical alterations in the animals. These results are in accordance with the previous clinical findings, which showed that continued antidepressant treatment particularly SSRIs positively influence symptoms of the CFS patients at faster rate and reduce the associated neuropsychiatric problems.  Previous reports of our laboratory also suggested that citalopram and imipramine have neuroprotective effect against chronic fatigue-induced behavioral and biochemical alterations,  but the mechanism by which these drugs produce protective effect is yet to be understood. Therefore, an attempt has been made to elucidate the possible NO mechanism of antidepressants against chronic fatigue syndrome. Therefore, in the present study, different NO modulators (positive and negative) with subeffective dose of citalopram and imipramine have been tried.
L-NAME, MB, and NOS inhibitors were combined with citalopram and imipramine, which potentiated the protective effect of these drugs on locomotor activity and anxiety-like behavior. Furthermore, pretreatment of l-arginine, (NO precursor) with citalopram or imipramine caused reversal of their protective effect, confirms involvement of NO pathway in the pathogenesis of CFS. This study further indicates that citalopram and imipramine might produce its neuroprotective action by involving NO pathway. , Several in vivo studies have shown a modulatory role of NO in the extracellular levels of serotonin re-uptake mechanism in the CNS.  Similarly, the antidepressant effects of imipramine were also blocked by pretreatment with l-arginine and contrary to this, NOS inhibitor; NG-nitro-l-arginine augmented the behavioral effect of imipramine or fluoxetine in the forced swim test. 
There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and involvement of NO pathways in its pathogenesis.  Stress exerts detrimental effects on several cell functions, through impairment of antioxidant defenses, leading to oxidative damage, which is central to many diseases.  It has been suggested that chronic fatigue illness can stimulate numerous pathways leading to increased production of free radicals. Various studies have indicated the upregulation of inducible nitric oxide synthase (iNOS) enzyme in patients suffering from stress and related disorders.  Increased iNOS expression can lead to increased production of NO, which can initiate inflammatory process in the body. Moreover, NO together with increased expression of cyclooxygenase-2 (COX-2) can further deteriorate the illness.
Similarly with above reports, in the present study, continued forced swimming for 7 days significantly increased lipid peroxidation and nitrite activity, depleted reduced glutathione and catalase enzymes activity suggesting the involvement of oxidative damage in fatigue-like conditions. Elevated levels of peroxynitrite and its precursor NO and oxidative stress and related free radical generation have been well documented in the pathogenesis of CFS.  Reactive oxygen species generated by a severe stressor significantly compromises the in vivo antioxidant defenses of animal submitted to chronic fatigue stress.  Citalopram or imipramine pretreatment for 7 days restored lipid peroxidation and nitrite activity as well as reduced glutathione and catalase enzymes activity, suggesting its direct ability to protect against highly damaging hydroxyl radicals that damage most cellular targets, including lipids, proteins, and DNA.  Elevated peroxynitrite levels cause lipid peroxidation, mitochondrial dysfunction, and Ca 2+ elevation.  Our study showed that treatment with citalopram and imipramine effectively prevented membrane lipid peroxidation. Antidepressants act on many different neurotransmitter systems and receptors; it is proposed that one of the shared mechanisms of action of antidepressants is the upregulation of antioxidant enzymes. Our study provides evidence that citalopram- and imipramine-enhanced antioxidant enzyme activity following continued forced swimming exposure. Chronic antidepressant treatment has been demonstrated to upregulate cAMP-response element-mediated gene expression in rat cortex and hippocampus.  To further confirm the specific mechanism of antidepressants on these biochemical changes we combine the l-arginine, NO precursor with subeffective dose of impiramine and citalopram, it further enhances the oxidative damage as indicated by raised lipid peroxidation, nitrite activity, and decreased in endogenous antioxidant defense enzymes in the brain. l-arginine produces NO acting on NOS, which combines with superoxide to form the potent oxidative peroxinitrite, thus continuing the cycle peroxinitrite targets the mitochondria and this may be related to observed mitochondrial dysfunction in CFS patients. When L-NAME and MB, NOS inhibitors combine with antidepressants it further potentiated their effect against oxidative damage in the brain. It seems that NO pathways are involved in explaining oxidative stress theory of chronic fatigue syndrome.
In conclusion, treatment with citalopram and or imipramine ameliorates chronic fatigue-induced behavioral as well as oxidative alterations and shows its neuroprotective effect with possible involvement of NO pathway. Therefore, our study suggests that enhancement of in vivo antioxidant defenses and improvements in the cellular antioxidant status might be an important mechanism underlying the neuroprotective action of citalopram and imipramine.
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[Table 1], [Table 2], [Table 3]
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