Diclofenac Sodium Inhibits Hepatic Tryptophan 2,3-Dioxygenase but Augments Brain Indoleamine 2,3-Dioxygenase Activities in Rats


 Dicolfenac sodium, tryptophan, kynurenine, indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase.

How to Cite

Shazia Dawood, Elvis O. Wambiya, & Samina Bano. (2016). Diclofenac Sodium Inhibits Hepatic Tryptophan 2,3-Dioxygenase but Augments Brain Indoleamine 2,3-Dioxygenase Activities in Rats. Journal of Basic & Applied Sciences, 12, 140–145. https://doi.org/10.6000/1927-5129.2016.12.21


Tryptophan 2,3-dioxygenase (TDO) exist only in liver while indoleamine 2, 3-dioxygenase (IDO) exists ubiquitously in the body, these are the most rate-limiting enzymes of kynurenine pathway (KP). In response to elevated levels of cortisol and pro-inflammatory cytokines, both enzymes show increase activity in patients with depression or Alzheimer disease (AD). Non-steroidal anti-inflammatory drugs may protect against both depression and AD, but observational studies have offered contradictory results. Present study evaluates the effects of anti-inflammatory diclofenac sodium (DS) on rat hepatic TDO and brain IDO activities. Adult Albino Wistar rats were divided into control and test groups, each test group received DS (2mg/kg) i.p. injection daily and were killed either after 3.5 hours (acute treatment) or after 3, 5 and 7 days (chronic treatment) while control groups received an equal volume of vehicle. Results show that TDO enzyme activity was inhibited and liver tryptophan concentrations were increased after 3 to 7 days treatment of DS; however no effect was seen on these parameters after 3.5hrs. Brain IDO activity was increased after both acute and chronic DS treatment. It is concluded that DS inhibits hepatic TDO enzyme activity following chronic treatment, while augments brain IDO activity following both acute and chronic DS treatment, this may result in rise in cerebral kynurenic acid and/or quinolinic acid concentrations. Therefore there is a need that effects of DS on kynurenine pathway should be further investigated to rule out the protective effect of DS in inflammation-induced depression and Alzheimer disease.



Leonard BE, Myint A. Inflammation and depression? Is there a causal connection with dementia. J Neurotoxicity Research 2006; 10(2): 149-160. http://dx.doi.org/10.1007/BF03033243

Sublette ME, Postolache TT. Neuroinflammation and depression. The role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. Psychosomatic Medicine 2012; 74(7): 668-672. http://dx.doi.org/10.1097/PSY.0b013e318268de9f

Duleu S, Mangas A, Sevin F, Veyret B, Bessede A, Geffard M. Circulating antibodies to IDO/THO pathway metabolites in Alzheimer's disease. International Journal of Alzheimer's Disease 2010; Article ID 501541 6 pages. doi:10.4061/2010/501541

Bonda DJ, Mailankot M, Stone JG, Garrett MR, Staniszewska M, Castellani RJ, et al. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease. Redox Report: Communications in Free Radical Research 2010; 15(4): 161-168. http://dx.doi.org/10.1179/174329210X12650506623645

Leonard BE, Myint A. Changes in the immune system in depression and dementia: Causal or coincidental effects? Dialogues in Clinical Neuroscience 2006; 8(2): 163-174.

Corona AW, Norden DM, Skendelas JP, Huang Y, O'Connor JC, Lawson M, et al. Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice. Brain Behav Immun 2013; 31: 134-42. http://dx.doi.org/10.1016/j.bbi.2012.08.008

Oxenkrug GF. Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: The serotonin hypothesis revisited 40 years later. The Israel Journal of Psychiatry and Related Sciences 2010; 47(1): 56-63.

Christmas DM, Potokar JP, Davies JC. A biological pathway linking inflammation and depression. Activation of indoleamine 2,3-dioxygenase. J Neuropsychiatric Dis Treat 2011; 7: 431-439.

Jacobson CM, Rosenfeld B, Pessin H, Breitbart W. Depression and IL-6 blood plasma concentrations in advanced cancer patients. Psychosomatics 2008; 49: 64-6. http://dx.doi.org/10.1176/appi.psy.49.1.64

Dantzer R, O’Connor JC, Lawson MA. Inflammation-associated depression: From serotonin tokynurenine. J Psychoneroendocrinology 2011; 36: 426-436. http://dx.doi.org/10.1016/j.psyneuen.2010.09.012

Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3-dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathology and Applied Neurobiology 2005; 31(4): 395-404. http://dx.doi.org/10.1111/j.1365-2990.2005.00655.x

De La Garza R 2nd, Asnis GM. The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus. Brain Res 2003; 977(1): 70-9. http://dx.doi.org/10.1016/S0006-8993(03)02757-4

Hirohata M, Ono K, Naiki H, Yamada M. Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. Neuropharmacology 2005; 49(7): 1088-99. http://dx.doi.org/10.1016/j.neuropharm.2005.07.004

Bano S, Sherkheli MA. Inhibition of tryptophan pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats. JCPSP 2003; 13: 5-10.

Badawy AAB, Christopher J Morgan. Rapid isocratic liquid chromatographic separation and quantification of tryptophan and six kynurenine metabolites in biological sample with ultraviolet and fluorimetricdetection. J Int Tryptophan Research 2010; 3: 175-186. http://dx.doi.org/10.4137/IJTR.S6225

Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence of plasma tryptophan levels. J Sci 1971; 173: 149-152. http://dx.doi.org/10.1126/science.173.3992.149

Badawy AAB. Mini review: Function and regulation of TDO. J Life Sci1977; 21: 755. http://dx.doi.org/10.1016/0024-3205(77)90402-7

Badawy AAB, Evans M. Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by acute administration of small doses of antidepressants. Br J Pharmacol 1982; 77(1): 59-67. http://dx.doi.org/10.1111/j.1476-5381.1982.tb09269.x

Bano S, Gitay M, Ara I, Badawy AA. Acute effects of serotonergic antidepressant on TRP metabolism &corticosterone levels in rats. Pak J Pharm Sci 2010; (23): 266-272.

Ara I, Bano S. St. John’s Wort modulate brain regional serotonin metabolism in stressed rats. Pak J Pharm Sci 2009; 22(1): 94-101.

Litman DA, Correia MA. Elevated brain TRP and enhanced 5-HT turnover in acute hepatic haem deficiency: clinical implications. J Pharmacology and Experimental Therapeutics 1985; 232(2): 337-345. doi:10.1124/jpet.107.124602.

Badawy AAB, Morgan CJ. Effect of acute paroxetine administration on tryptophan metabolism and disposition in rat. Br J Pharmacol 1991; 102: 429-433. http://dx.doi.org/10.1111/j.1476-5381.1991.tb12190.x

Oretti R, Bano S, Morgan CJ, Badawy AA, Bonner A, Buckland P, et al. Prevention by cycloeximide of the audiogenic seizures and TRP metabolic disturbances of ethanol withdrawal in rats. Alcohol and Alcoholism 1996; 31(3): 243-247. http://dx.doi.org/10.1093/oxfordjournals.alcalc.a008143

Curzon G. Tryptophan pyrrolase. A biochemical factor in depressive illness. Br J Psychiat 1969; 115: 1367-1374. http://dx.doi.org/10.1192/bjp.115.529.1367

Rose DP, Braidman IP. Oral contraceptives depression and amino acid metabolism. Lancet 1970; 1(656): 1117-1118. http://dx.doi.org/10.1016/S0140-6736(70)92789-3

Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G et al. The inflammatory and neurodegenerative hypothesis of depression. Leads for future research and new drug developments in depression. J Metab Brain Dis 2009; 24(1): 27-53. http://dx.doi.org/10.1007/s11011-008-9118-1

Werner ER, Fuchs D, Hausen A, Jaeger H, Reibnegger G, Werner-Felmayer G, et al. Tryptophan degradation in patients infected by human immunodeficiency virus. J Biol Chem Hopper-Seyler 1988; 369: 337-340. http://dx.doi.org/10.1515/bchm3.1988.369.1.337

Barua CC, Roy JD, Buragohain B, Barua AG, Borah P,Lahkar M, Anxiolytic effect of hydroethanolic extract of Drymariacordata L Willd, Indian Journal of Experimental Biology 2009; 47(12): 969-973.

Choi JK, Jenkins BG, Carreras I, Kaymakcalan S, Cormier K, Kowall NW, et al. Anti-inflammatory treatment in AD mice protects against neuronal pathology. Exp Neurol 2010; 223: 377-384. http://dx.doi.org/10.1016/j.expneurol.2009.07.032

Schwieler L, Erhardt S, Erhardt C, Engberg G. Prostaglandin-mediated control of rat brain kynurenic acid synthesis--opposite actions by COX-1 and COX-2 isoforms. J Neural Transm 2005; 112(7): 863-72. http://dx.doi.org/10.1007/s00702-004-0231-y

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright (c) 2016 Shazia Dawood, Elvis O. Wambiya , Samina Bano