Evaluation of Potentiation Effect of Omega-3 Fatty Acid on the Antidepressant Efficacy of Escitalopram in Albino Rats.
It has high impact on social and economic aspect, due to massive decrease in work productivity and increased usage of health care . Enhancement of monoaminergic neurotransmisssion is the current pharmacological treatment of depression. However, despite its widespread use in clinical practice, it has challenges like onset of action, poor efficacy and presence of side effects [4,5]. Contrary to expectations, existing therapeutic options are effective in only one-third of depressed patients. Moreover, the time required for its maximal antidepressant activity is approximately 3-4 weeks . Furthermore, single agent does not have more than 30% of remission rates [7,8].
Majority of patients have low compliance due to side effects and refuse to take antidepressants in appropriate doses. Therefore, the identification of novel drug or novel treatment combination with drugs that augment the efficacy of antidepressant is still needed. Role of nutrition has found greater role in depressive disorder as good amount of nutrients are essential for healthy mood [9-13]. Nutrients are essential for optimal production of neurotransmitters influencing mood . There are reports mentioning lower concentration of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) in depressed individuals as compared to non-depressed individuals [15,16].
Meta-analytic reviews [17-19] and several clinical trials [20-24] have reported an antidepressant effect of Polyunsaturated fatty acids (PUFAs). There is increased evidence from animal as well as human studies showing omega-3 fatty acids may play an etiological role in several inflammatory, autoimmune and neuropsychiatric disorders [25,26].
Hence this study was conducted with an aim to explore the possible effect of omega-3 fatty acids in depression models. It was compared aith a standard antidepressant escitalopram, a selective serotonin reuptake inhibitor used in India . Also their combination is used to study the role of omega-3 fatty acids inpotentiating efficacy of escitalopram.
MATERIALS AND METHOD
Sixty Albino Wistar rats of either sex (from Central animal house, KMC, Manipal) were used in the study. The rats used age 3-4 months and weight 150-250 gm at the beginning of the experimental procedure. Animals were housed three-four per cage in polycarbonate cages (28 x 17 x 12 cm). Except during testing, the animals were provided with pellet diet and water ad libitum throughout the study. Rats were maintained on a 12 h light (0700-1900 h)-12 h dark cycle at the ambient temperature of 25 [+ or -] 2ae%C and relative controlled humidity. They were allowed to acclimatize for a week before the onset of the experiment. Experiment was conducted in accordance with the Good laboratory practice (GLP) guidelines and CPCSEA guidelines after obtaining approval from Institutional Animal Ethics Committee IAEC/KMC/79/2015 dated 25-09-2015.
Escitalopram and omega-3 fatty acids were obtained from local pharmacy.
1) Escitalopram: 10 mg per kg and 5 mg per kg.
2) Omega-3 Fatty Acid: 500 mg per kg.
In both acute and chronic studies, the role of omega-3 fatty acids was evaluated alone and in combination with escitalopram.
There were total five groups, in each group 6 rats. Drugs were administered for 7 days as follows:
Group 1 (Control)-2% Gum Acacia orally 23.5 and 1 h before the test.
Group 2 (Escitalopram)-Escitalopram dissolved in 2% Gum acacia in a dose of 10 mg/kg orally 23.5 and 1 h before the test.
Group 3 (Omega-3 FA)-omega-3 fatty acids 500 mg/kg in 2% Gum acacia orally 2 h before the test.
Group 4 (Escitalopram plus omega-3 FA)-Rats were given omega-3 fatty acids in a dose of 500 mg/kg orally 2 h before the test and escitalopram dissolved in 2% Gum acacia in a dose of 10 mg/ kg orally 23.5 and 1 h before the test.
Group 5 (Escitalopram plus omega-3 FA)-This group test the efficacy and augmentation effect of omega-3 FA with sub therapeutic level of escitalopram. Rats were administered with omega-3 fatty acids in a dose of 500 mg/kg orally 2 h before the test and escitalopram dissolved in 2% Gum acacia in a dose of 5 mg/kg orally 23.5 and 1 h before the test.
To test Omega-3 Fatty Acids Potentiation of the Antidepressant Efficacy of Escitalopram Groups Drugs Route: oral route Dose Group 1 Control group 2% Gum acacia Group 2 Escitalopram group 10mg/kg Group 3 Omega-3 FA group 500mg/kg Group 4 Omega-3 FA + Escitalopram group 500mg/kg + 10 mg/kg Group 5 Omega-3 FA + Escitalopram group 500mg/kg + 5mg/kg Groups Number of Rats Group 1 6 Group 2 6 Group 3 6 Group 4 6 Group 5 6
The schedule of drug administration was similar to acute study except that in chronic study omega-3 fatty acids was given 500 mg/kg orally for 28 days prior to the test both alone, as well as in combination with escitalopram. Two hours before the test, the last dose of omega-3 fatty acids was given.
To test Omega-3 Fatty Acids Potentiation of the Antidepressant Efficacy of Escitalopram Groups DrugsRoute: oral route Dose Group 1 Control group 2% Gum acacia Group 2 Escitalopram group 10mg/kg Group 3 Omega-3 FA group 500mg/kg Group 4 Omega-3 FA + Escitalopram group 500mg/kg + 10 mg/kg Group 5 Omega-3 FA + Escitalopram group 500mg/kg + 5mg/kg Groups Number of Rats Group 1 6 Group 2 6 Group 3 6 Group 4 6 Group 5 6
Forced swimming test (FST)
Porsolt et al. developed this model for antidepressant activity . Rats had to swim in a glass cylinder filled with water up to 30 cm at 25C. They were trained for a 15-min pretest swim followed by a 5-min test swim session next day. After the swim session, rats were removed from water, and after 20 min were returned to their cages. After each test, the cylinders were washed completely. In pretest session, rats are active. After 2-3 min activity decreases to produce immobility, it keeps its head above water. This immobility is attenuated by antidepressants. In the test session, the behavior of rats were judged in blocks of 5 s for: immobility, swimming & climbing. The experiment was video recorded and the behavioral scoring was done.
This test was used to assess the ambulatory behavior . The instrument consist of a wooden box (40cm x 60cm x 50cm), its floor was divided into 12 equal rectangles. At the initiation of each trial, a rat was placed in the left corner and was allowed to freely explore. In a 6 min session, the number of rectangles crossed with all paws were counted. The room was dimly lit to prevent anxiety behavior. In between the tests, the instrument was cleaned with 10% ethanol to avoid bias.
This test was performed ten minutes after the open-field test,  with minor modifications. Ten percent sucrose solution was squirted on the dorsum of a rat placed individually in clear plexiglass boxes (9 x 7 x 11 cm). The sucrose solution dirties the rat fur, due to its viscosity and initiates grooming behavior in animals which was recorded for 5 min as an index of self-care and motivational behavior. To hide animal clues, the apparatus was cleaned with a 10% ethanol.
After conducting the experiment, rats were sacrified and blood was used for testing--
1. Reduced glutathione (GSH)
2. Malondialdehyde (MDA)
P value <0.05 was taken as significant value was calculated by One-way ANOVA followed by Tukey's post-hoc test.
Forced swimming test
Effect of escitalopram and omega-3 fatty acid on forced swimming test
Table 1 shows the results of forced swimming test done at 1 week. One count is duration of 5 sec. The standard group (escitalopram) showed a significant reduction in the counts of immobility (23.00 [+ or -] 1.06, p<0.05) along with a significant increase in the counts of swimming (25.00 [+ or -] 1.26, p<0.05) compared to the control group. However, the Omega 3 FA group did not show any significant difference in the counts of immobility, counts of swimming and counts of climbing. The escitalopram 10mg + omega 3 FA group as well as the escitalopram 5mg + omega 3 FA group showed a significant reduction in the counts of immobility (21.00 [+ or -] 0.86, p<0.001; 24.00 [+ or -] 0.73, p<0.05 respectively) with a significant increase swimming counts in both the groups (24.00 [+ or -] 1.06, p<0.05; 24.00 [+ or -] 0.73, p<0.05) when compared to the control and escitalopram group. There were no significant increase in climbing counts in any of the groups when compared to control.
Open field test
Effect of escitalopram and omega-3 fatty acid on open field test
Table 2 shows the results of the open field test done at 1 week. The above results does not show any significant difference in the number of entries in any of the groups when compared with control and the standard treatment group (escitalopram) (p>0.05).
Effect of escitalopram and omega-3 fatty acid on splash test
Table 3 shows the splash test done at 1 week. It indicates that there is a significant difference in the time taken by the escitalopram 10mg+omega 3 FA group and escitalopram 5 mg+ omega 3 group when compared to control (163.00 [+ or -] 3.25, p<0.001 and 174.83 [+ or -] 3.27, p< 0.05 along with a significant reduction in time taken by the escitalopram 10mg + omega 3 group when compared with the standard treatment group (escitalopram) (163.00 [+ or -] 3.25, p<0.05).
Effect of escitalopram and omega-3 fatty acid on MDA
As shown in table 4 and figure 4 there was no significant difference among the control group and the test groups p<0.005.
Effect of escitalopram and omega-3 fatty acid on GSH
Table 5 shows the GSH levels at 1 week. Levels of glutathione reductase was significantly more in the escitalopram group (1.327 [+ or -] 0.015, p<0.05 and significantly increase in GSH in test groups, escitalopram 10mg+omega-3 (1.525 [+ or -] 0.017; p<0.05) and escitalopram 5 mg+omega-3 FA (1.345 [+ or -] 0.014; p<0.05) compared to control group
Forced swimming test
Effect of escitalopram and omega-3 fatty acid on forced swimming test
Table 6 shows the results of forced swimming test done at 4th week. The standard group (escitalopram) showed a significant reduction in the counts of immobility (21.00 [+ or -] 1.43, p<0.01) along with a significant increase in the counts of swimming (26.00 [+ or -] 1.06, p<0.01) compared to the control group. However, the omega 3 FA group did not show any significant difference in the counts of immobility, counts of swimming and counts of climbing. The escitalopram 10mg + omega 3 group as well as the escitalopram 5mg + omega 3 FA group showed a significant reduction in the counts of immobility (15.00 [+ or -] 0.73, p<0.001; 17.00 [+ or -] 0.58, p<0.01 respectively) with a significant increase swimming counts in both the groups (27.33 [+ or -] 1.30, p<0.05; 27.00 [+ or -] 1.24- p<0.01 respectively) when compared to the control and escitalopram group. There were no significant increase in climbing counts in any of the groups when compared to control.
Open field test
Effect of escitalopram and omega-3 fatty acid on open field test
Table 7. The number of entries increased significantly in the standard group escitalopram (44.00 [+ or -] 1.26; p<0.05) when compared with control along with significant increase in the number of entries in the escitalopram 10mg+omega-3 FA (47.00 [+ or -] 2.67; p<0.05) group when compared to control.
Effect of escitalopram and omega-3 fatty acid on splash test
As shown in table 8 there was a significant decrease in time in test groups escitalopram (182.00 [+ or -] 5.46; p<0.05), escitalopram 10mg+omega-3 (154.00 [+ or -] 2.12; p<0.001) and escitalopram 5mg+omega-3(168.00 [+ or -] 4.03; p<0.001) when compared to control.
Effect of escitalopram and omega-3 fatty acid on MDA
As shown in table 9 and figure 9 there was significant increase in MDA in the test group escitalopram 10mg+ omega-3 (0.100 [+ or -] 0.003; p<0.05) when compared with the control.
Effect of escitalopram and omega-3 fatty acid on GSH
groups escitalopram (1.410[+ or -]0.014; p<0.001). The test groups escitalopram 10mg+omega-3 (1.625 [+ or -] 0.017; p<0.001) and ecitalopram 5mg+omega-3(1.445 [+ or -] 0.014; p<0.001) also showed a significant increase in GSH when compared to the control group.
The present study shows that Omega-3 fatty acids have antidepressant activity and have shown significant antidepressant efficacy in their combination with escitalopram. The study was divided into 2 parts acute (1 week) and chronic study (4 weeks). The results showed that omega-3 has no effect in short term either alone or in potentiating the escitalopram but in chronic study done over 4 weeks it showed potentiation effect with escitalopram.
The results are consistent with that of previous studies which have reported good efficacy of omega-3 supplementation with antidepressants in uncomplicated MDD. [21,22,31,32] The present study shows the antidepressant effect of omega-3 fatty acids, and its combination with escitalopram will potentiate the antidepressant efficacy than the standard drug escitalopram alone.
The suggestive possible mechanisms are as follows. Inflammatory processes are linked with depression. Omega-3 fatty acids reduce the inflammatory mediators, also hasan effect on brain-derived neurotrophic factor, which gives neuroprotection, and enhances neurotransmission.  A third possible mechanism is omega-3 fatty acids maintain membrane integrity and fluidity . Animal studies have shown involvement of omega-3 fatty acids in receptor functioning, neurotransmitter levels, and monoamine metabolism in depression. [35,36]
Proinflammatory cytokines such as interleukin-1 beta, interleukin-2, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha lower precursor neurotransmitter levels, activate hypothalamic-pituitary axis, and alter neurotransmitter metabolism in the central nervous system. Increase in these cytokines are associated with severity of depression . Different factors such as psychological stress, infection, trauma, allergies, and toxins increase the cytokines. Omega-3 fatty acids are inhibitors of these proinflammatory cytokines, although the precise mechanism is unclear . Reports on (in vitro) experiments with mouse mast cells suggest that omega-3 fatty acids suppress prostaglandin E2, thromboxane A2 and histamine and improve depressive symptoms. (Kaneniwa and co-workers) .
There are literature evidences suggesting antidepressants can promote neurogenesis. [40,41]. Chronic treatment with omega-3 fatty acids increases brain-derived neurotrophic factor (BDNF), which play a role in the plasticity of adult nervous system [42,43]. This is brought about by increase in the cyclic AMP (cAMP) signal-transduction which increases of cAMP response element-binding protein (CREB) leading to increase in BDNF. Serum BDNF was found to correlate negatively with the severity of depressive symptoms [44-48]. Bourre  et al. mentioned that omega-3 fatty acids are essential central nervous system membrane components . Any alterations in membrane lipids can alter function due to change in fluidity. Proteins are incorporated into the lipid bilayer and are sensitive to the lipid microenvironment. They act as receptors, enzymes, and transporters [51-53] For binding of neurotransmitter and for signalling within the cell an optimal fluidity is required .
Haag  suggested that there are straight carbon chains in saturated fatty acids. Cis-desaturation of a fatty acid results in more curved carbon chain due to insertion of cis-double bonds in the cell membrane there is curling of the hydrophobic ends of the kinked chains which results in incorporation of more space when it is built into cell membrane phospholipids, thereby increasing the fluidity and functionality of the cell membrane .
Omega fatty acids in neuronal membranes can modulate many of the signal transduction mechanisms Different neurotransmitters such as serotonin, catecholamines and acetylcholine interact with members of a heptahelical transmembrane receptor family (55, 57-58). Murphy et al. and Nicholas et al [59,60] have confirmed that omega-3 fatty acids can increase adenylyl cyclase activity, which drives the cAMP messenger system. This pathway is used by 5-HT1 (serotonin) receptors, alpha-2 adrenergic and beta-adrenergic receptors, and both D1 and D2 (dopamine) receptors. It is well known in depression there is decreased serotonergic neurotransmission, Omega-3 fatty acids increase the activity of adenyl cyclase and thus facilitate serotonergic transmission. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and increases 5-HT synaptic concentration, 5-HT signal transduction is operational via cAMP pathway, fluoxetine in combination with omega-3 fatty acids exerts augmented effect by utilizing this facilitated 5-HT pathway. SSRIs are associated with various serotonergic side effects such as anxiety, insomnia, sexual dysfunction, serotonin syndrome etc., while omega-3 fatty acids are free from any significant adverse effects. As a long-term nutritional supplement, the combination of escitalopram and omega-3 fatty acids can decrease the dose and duration of SSRI administered, it may prove beneficial for prevention of depression in susceptible population.
Omega-3 Fatty acid and escitalopram were used to demonstrate the effect of antidepressant action and potentiation effect of omega-3 fatty acid on escitalopram.
The study was divided in 2 parts acute and chronic. In acute study was significant potentiation effect seen in forced swimming test, splash test and GSH test. So, omega-3 fatty acid does not have antidepressant effect in short duration of activity. In chronic study all the test showed significant difference indicating omega-3 FA has potentiation effect in chronic use (28 days).
Based on the findings of the current study, we conclude that omega-3 has antidepressant activity in chronic use but not in acute duration. Omega-3 fatty acid can be considered as a part of therapeutic use along with escitalopram. Further preclinical and clinical studies may be required to assess the similar properties of omega-3 fatty acid.
We acknowledge Manipal Academy of Higher Education for their support in conduct of this study.
[1.] Depression Fact Sheet No. 369. World Health Organisation (WHO) 2012. Accesed on September 18th 2017. Available from: http:// www.who.int/mediacentre/factsheets/fs369/en/
[2.] Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global burden of disease study. Lancet 1997; 349:1498-1504.
[3.] Nemeroff CB. The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res 2007;41:189-206.
[4.] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13-25.
[5.] Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci 2001;2:343-51.
[6.] Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx 2005;2:590-611.
[7.] Kennedy SH, Eisfeld BS, Meyer JH, Bagby RM. Antidepressants in clinical practice:limitations of assessment methods and drug response. Hum Psychopharmacol 2001; 16:105-114.
[8.] Nemeroff CB, Entsuah R, Benattia I, et al. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry 2008; 63:424-434.
[9.] Leung BM, and Kaplan BJ. Perinatal depression: prevalence, risks, and the nutrition link--a review of the literature. J Am Diet Assoc 2009;109:1556.
[10.] Ruusunen, A., Lehto, S. M., Tolmunen, T., Mursu, J., Kaplan, G. A., and Voutilainen, S. Coffee, tea and caffeine intake and the risk of severe depression in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Public Health Nutr 2010; 13:1215-1220.
[11.] Shim RS, Baltrus P, Ye J, and Rust G. Prevalence, treatment, and control of depressive symptoms in the United States: results from the National Health and Nutrition Examination Survey (NHANES), 2005-2008. J Am Board Fam Med 2011;24: 33-38.
[12.] Jacka FN, Mykletun A, Berk M, Bjelland I, Tell GS. The association between habitual diet quality and the common mental disorders in community dwelling adults: the Hordaland Health study. Psychosom Med 2011;73: 483-490
[13.] Le Port A, Gueguen A, Kesse-Guyot E, Melchior M, Lemogne C, et al. Association between Dietary Patterns and Depressive Symptoms Over Time: A 10-Year Follow-Up Study of the GAZEL Cohort. PLoS ONE 2012;7: e51593.
[14.] Kemper KJ and Shannon S. CAM Therapies to Promote Healthy Moods. Pediat Clin North Am 2007;54: 901-926.
[15.] Ellis FR, Sanders TA. Long chain polyunsaturated fatty acids in endogenous depression. J Neurol Neurosurg Psychiatry 1977; 40:168-169.
[16.] Fehily AM, Bowey O, Ellis FR, Meade BW. Plasma and erythrocyte membrane long chain polyunsaturated fatty acids in endogenous depression. Neurochem Int 1981; 5: 37-42.
[17.] Appleton KM, Rogers PJ and Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010;91: 757-70.
[18.] Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006;67:1954-1967.
[19.] Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 2007; 68:1056-1061.
[20.] Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267-271.
[21.] Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002; 159:477-479.
[22.] Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002; 59: 913-919.
[23.] Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression:randomised double-blind placebo controlled study. Br J Psychiatry 2006; 188: 46-50.
[24.] Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH: Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 2006; 163:1098-1100.
[25.] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. JAm Coll Nutr 2002; 21:495-505.
[26.] Young G, Conquer J. Omega-3 fatty acids and Neuropsychiatric disorders. Reprod Nutr Dev 2005; 45:1-28.
[27.] Grover S, Avasthi A, Sinha V, et al. Indian Psychiatric Society multicentric study:Prescription patterns of psychotropics in India. Indian J Psychiatry 2014;56:253-26.
[28.] Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977;229:327-36.
[29.] Hall C, Ballachey EL. A study of the rat's behavior in a field: A contribution to method incomparative psychology. University of California Publications in Psychology 1932;6:112.
[30.] Isingrini E, Camus V, Le Guisquet AM, Pingaud M, Devers S, Belzung C. Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS ONE 2010;5:e10404.
[31.] Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients with Major Depressive Disorder. Journal of Clinical Psychopharmacology 2012;32:61-64.
[32.] Lesperance F, Frasure SN, Andre E, Turecki G, Lesperance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry 2011; 72:1054-62.
[33.] Ikemoto A, Nitta A, Furukawa S, et al. Dietary n-3 fatty acid deficiency decreases nerve growth factor content in rat hippocampus. Neurosci Lett 2000; 285:99-102
[34.] Yehuda S, Rabinovitz S, Carasso RL, et al. Fatty acids and brain peptides. Peptides 1998;19:407-419
[35.] Logan AC. Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression. Altern Med Rev 2003; 8:410-425.
[36.] Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995; 62:1-9.
[37.] Suarez EC. C-reactive protein is associated with psychological risk factors of cardiovascular disease in apparently healthy adults. Psychosom Med 2004;66:684-91.
[38.] James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71:343-348.
[39.] Ishihara K, Murata M, Kaneniwa M, Saito H, Shinohara K, Maeda-Y M et al. Effect of tetracosahexaenoic acid on the content and release of histamine, and eicosanoid production in MC/9 mouse mast cell. Lipids 19981;33:1107-1114.
[40.] Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol. Psychiatry 2000;48:755-65.
[41.] Rajkowska G, Miguel-HJJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry 1999;45:1085-1098.
[42.] Ikemoto A, Nitta A, Furukawa S, Ohishi M, Nakamura A, Fujii Y et al. Dietaryn-3 fatty acid deficiency decreases nerve growth factor content in rat hippocampus. Neurosci. Lett 2000;285:99-102.
[43.] Ikemoto A, Kobayashi T, Watanabe S, Okuyama H. Membrane fatty acid modifications of PC12 cells by arachidonate or docosahexaenoate affect neurite outgrowth but not norepinephrine release. Neurochem Res. 1997;22:671-688.
[44.] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13-25.
[45.] Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C et al.. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressant. Biol. Psychiatry 2003;54:70-75.
[46.] Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 2002;112:803-814.
[47.] Contreras MA, Rapoport SI. Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues. Curr Opin Lipidol 2002;6:267-272.
[48.] Tore F, Tonchev AB, Fiore M, Tuncel N, Atanassova P, Aloe L, Chaldakov GN. From adipose tissue protein secretion to adipopharmacology of disease. Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Immunology, Endocrine and Metabolic Agents) 2007;7:149-155.
[49.] Bourre JM, Dumont O, Piciotti M, Clement M, Chaudiere J, Bonneil M, Nalbone G, Lafont H, Pascal G, Durand G. Essentiality of U3 fatty acids for brain structure and function 1. Health Effects of Omega 3 Polyunsaturated Fatty Acids in Seafoods. World Rev Nutr Diet 1991;66:103-117.
[50.] Russo-Neustadt A. Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry 2003;8:109-118.
[51.] Brenner RR. Effect of unsaturated acids on membrane structure and enzyme kinetics. Prog Lipid Res 1984;23:69-96.
[52.] Spector AA, Yorek MA. Membrane lipid composition and cellular function. J Lipid Res 1985;26:1015-35.
[53.] Bourre JM, Bonneil M, Clement M, Dumont O, Durand G, Lafont H et al. Function of dietary polyunsaturated fatty acids in the nervous system. Prostaglandins Leukot Essent Fatty Acids 1993;48:5-15.
[54.] Fernstrom JD. Effects of dietary polyunsaturated fatty acids on neuronal function. Lipids 1999;34:161-169.
[55.] Haag M. Essential fatty acids and the brain. Can J Psychiatry. 2003;3:195-203.
[56.] Heron DS, Shinitzky M, Hershkowitz M, Samuel D. Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes. Proc. Natl. Acad.Sci.USA 1980;77:7463-7467.
[57.] Van Rooyen JM, Offermeier J, Stahmer SD. Serotonin receptors. The Medicine Journal (SA) 1991;33:3-19.
[58.] Lakhwani LA, Tongia SK, Pal VS, Agrawal RP, Nyati PR, Phadnis PR. Omega-3 fatty acids have antidepressant activity in forced swimming test in Wistar rats. Acta Pol Pharm 2007;64:271-6.
[59.] Murphy MG. Membrane fatty acids, lipid peroxidation and adenylate cyclase activity in cultured neural cells. Biochem. Biophys.Res. Commun 1985;132:757-63.
[60.] Nicolas C, Lacasa D, Giudicelli Y, Demarne Y, Agli B, Lecourtier MJ, Lhuillery C. Dietary (n-6) polyunsaturated fatty acids affect beta-adrenergic receptor binding and adenylate cyclase activity in pig adipocyte plasma membrane. J Nutr 1991;121:1179-1186.
Amberkar Mohanbabu Vittalrao (1), Saurabh Agarwal (2), Meena Kumari Kamalkishore (1) * and Basavaraj Poojar (3)
(1) Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India-576104.
(2) Medical Science Liaison, Sanofi Pasteur India Pvt. Ltd, Dalibagh, Lucknow-226001, India.
(3) Basavaraj Poojar-Department of Pharmacology, Kasturba Medical College, Mangaluru, Manipal Academy of Higher Education, Manipal, Karnataka, India.
* Corresponding author Efirstname.lastname@example.org
(Received: 20 June 2019; accepted: 16 September 2019)
Table 1. Forced swimming test done at 1 week, a-P<0.05 versus control group, b-P<0.001 versus control group Sl. No. Group(n=6) Counts of immobility (Mean [+ or -] S.E.M) 1. Control 30.00 [+ or -] 1.71 2. Standard(escitalopram) 23.00 [+ or -] 1.06 (a) 3. Omega-3 FA 27.00 [+ or -] 1.29 4. Escitalopram10mg+Omega-3 FA 21.00 [+ or -] 0.86 (b) 5. Escitalopram 5mg+Omega-3 FA 24.00 [+ or -] 0.73 (a) Sl. No. Counts of swimming Counts of climbing (Mean [+ or -] S.E.M) (Mean [+ or -] S.E.M) 1. 19.00 [+ or -] 0.73 12.00 [+ or -] 0.58 2. 25.00 [+ or -] 1.26 (a) 14.00 [+ or -] 0.58 3. 20.00 [+ or -] 1.06 12.00 [+ or -] 0.58 4. 24.00 [+ or -] 1.06 (a) 13.00 [+ or -] 0.58 5. 24.00 [+ or -] 0.73 (a) 13.00 [+ or -] 0.58 Table 2. Open field test done at 1 week S. Group(n=6) Number of entries No (Mean [+ or -] S.E.M) 1. Control 33.50 [+ or -] 1.31 2. Escitalopram 39.50 [+ or -] 3.10 3. Omega-3 29.17 [+ or -] 2.73 4. Escitalopram10mg+omega-3 FA 40.33 [+ or -] 2.59 5. Escitalopram 5mg+omega-3 FA 37.33 [+ or -] 1.76 Table 3. Splash test done at 1 week, a-P<0.05 versus group control, b-denotes P<0.001 versus control, c-denotes the time in seconds of escitalopram 10mg+ omega 3 group compared to escitalopram group; S. Group(n=6) Time in sec. No. (Mean [+ or -] S.E.M) 1. Control 201.00 [+ or -] 5.67 2. Escitalopram 187.00 [+ or -] 4.47 3. Omega-3 FA 201.33 [+ or -] 5.50 4. Escitalaopram.10mg+ omega-3 FA 163.00 [+ or -] 3.25 (b,c) 5. Escitalopram 5mg+ omega-3 FA 174.83 [+ or -] 3.27 (a) Table 4. MDA test done at 1 week S. Group(n=6) MDA No. (Mean [+ or -] S.E.M) 1. Control 0.047 [+ or -] 0.003 2. Escitalopram 0.041 [+ or -] 0.001 3. Omega-3 0.045 [+ or -] 0.003 4. Escitalopram.10mg+omega-3 FA 0.051 [+ or -] 0.002 5. Escitalopram 5mg+omega-3 FA 0.041 [+ or -] 0.002 Table 5. GSH test done at 1 week, [(a)- p <0.001 versus control group] S. Group(n=6) GSH No. (Mean [+ or -] S.E.M) 1. Control 1.141 [+ or -] 0.013 2. Escitalopram 1.327 [+ or -] 0.015 (a) 3. Omega-3 FA 1.180 [+ or -] 0.007 4. Escitalopram10mg+omega-3 FA 1.525 [+ or -] 0.017 (a) 5. Escitalopram 5mg+omega-3 FA 1.345 [+ or -] 0.014 (a) Table 7. Open field test done at 4 weeks [(a)- P<0.05 versus control group] S. Group(n=6) Number of entries No (Mean [+ or -] S.E.M) 1. Control 34.67 [+ or -] 1.70 2. Escitalopram 44.00 [+ or -] 1.26 (a) 3. Omega-3 FA 41.16 [+ or -] 1.90 4. Escitalopram 10mg+omega-3 FA 47.00 [+ or -] 2.67 (a) 5. Escitalopram 5mg+omega-3 FA 39.00 [+ or -] 2.62 Table 6. Forced swimming test done at 4 weeks [(a)- P<0.001 versus control group] S. Group(n=6) Count of immobility No. (Mean [+ or -] S.E.M) 1. Control 29.00 [+ or -] 0.96 2. Escitalopram 21.00 [+ or -] 1.43 (a) 3. Omega-3 FA 25.00 [+ or -] 0.89 4. Escitalopram 10mg+omega-3 FA 15.00 [+ or -] 0.73 (a) 5. Escitalopram 5mg+omega-3 FA 17.00 [+ or -] 0.58 (a) S. Group(n=6) Count of swimming No. (Mean [+ or -] S.E.M) 1. Control 17.00 [+ or -] 0.73 2. Escitalopram 26.00 [+ or -] 1.06 (a) 3. Omega-3 FA 23.00 [+ or -] 0.86 4. Escitalopram 10mg+omega-3 FA 27.33 [+ or -] 1.30 (a) 5. Escitalopram 5mg+omega-3 FA 27.00 [+ or -] 1.24 (a) S. Group(n=6) Counts of climbing No. (Mean [+ or -] S.E.M) 1. Control 12.00 [+ or -] 1.06 2. Escitalopram 13.50 [+ or -] 0.89 3. Omega-3 FA 13.00 [+ or -] 1.13 4. Escitalopram 10mg+omega-3 FA 14.33 [+ or -] 1.20 5. Escitalopram 5mg+omega-3 FA 13.50 [+ or -] 0.96 Table 8. Splash test done at 4 weeks [(a)-p<0.05 versus control group; (b)-p<0.001 versus control group] S. Group (n=6) Time in secs. No. (Mean [+ or -] S.E.M) 1. Control 210.00 [+ or -] 11.94 2. Escitalopram 182.00 [+ or -] 5.46 (a) 3. Omega-3FA 196.00 [+ or -] 4.70 4. Escitalopram 10mg+omega-3 FA 154.00 [+ or -] 2.12 (b) 5. Escitalopram 5mg+omega-3 FA 168.00 [+ or -] 4.03 (b) Table 9. MDA test done at 4 weeks [(a)- P<0.05 versus control group] S. Group(n=6) MDA No. (Mean [+ or -] S.E.M) 1. Control 0.055 [+ or -] 0.005 2. Escitalopram 0.048 [+ or -] 0.004 3. Omega-3 FA 0.068 [+ or -] 0.008 4. Escitalopram 10mg+omega-3 FA 0.100 [+ or -] 0.003 (a) 5. Escitalopram 5mg+omega-3 FA 0.058 [+ or -] 0.012 Table 10. GSH test done at 1week [(a)- P<0.001 versus control group] S. No. Group(n=6) GSH (Mean [+ or -] S.E.M) 1. Control 1.242 [+ or -] 0.013 2. Escitalopram 1.410 [+ or -] 0.014 (a) 3. Omega-3 FA 1.280 [+ or -] 0.007 4. Escitalopram 10mg+omega-3 FA 1.625 [+ or -] 0.017 (a) 5. Escitalopram 5mg+omega-3 FA 1.445 [+ or -] 0.014 (a)
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|Author:||Vittalrao, Amberkar Mohanbabu; Agarwal, Saurabh; Kamalkishore, Meena Kumari; Poojar, Basavaraj|
|Publication:||Biomedical and Pharmacology Journal|
|Date:||Sep 1, 2019|
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