Journal of Critical Reviews

ISSN- 2394-5125 Vol 3, Issue 2, 2016

Review Article ROLE OF IN THE PATHOGENESIS OF DEPRESSION

VAIBHAV WALIA Division Pharmacology, Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India Email: [email protected] Received: 23 Dec 2015 Revised and Accepted: 01 Mar 2016 ABSTRACT Depression is one of the most prevalent neuropsychiatric disorders that occurs due to the alterations in the monoaminergic system of the body. Various factors may be responsible for the alterations in the monoaminergic system. MAO-A is an which metabolizes the monoamines and thus responsible for the reduction in the level of monoamines in the body. Stress induces the increase expression and levels of various proinflammatory cytokines such as IL-6, IL- - 2 involved in the pathogenesis of depression. proinflammatory cytokines increase or decrease the activity of various enzymes that further led to the reduction in the level of the . , it has been suggested that the depression which is considered as a1β, disorder TNF α thatand arisesPGE due to the imbalance in the neurotransmittersThese in the brain arises due to the alterations in the activities of the various enzymes. aim of present review is to demonstrate the role of theThus various enzymes in the pathogenesis of depression. Therefore the Keywords: Depression, , oxide, Stress.

Enzymes Nitric CC BY license (http://creativecommons.org/licenses/by/4.0/) © 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the INTRODUCTION Pathogenesis of depression Depression is a heterogeneous and one of the most prevalent Stress is a stimulus that disturbs the homeostasis of the body and neuropsychiatric disorders that affect 20% of the world’s induces depressive disorders through the activation of population. [1, 2] According to WHO, depression will result in more neuroendocrine system, neurotransmitter changes, and years of life lost to disability than any other illness by the year proinflammatory cytokines. [10] Stress increases the release of pro- 2030. disability- inflammatory cytokines, such as IL- -2, IL- - - . adjusted life years in the age category 15 to 44 y. [3] Depression is a [11] Also the - leadingToday, cause depression of morbidity is alreadyand mortality the second in youngster cause of s; the risk IL-6. [12] A - 1β, IL-1 6, IFN γ,produces and TNF theα begins in early teens and continues to rise in a linear fashion. [4] behavioral deficitspatients known with as depression “sickness havebehavior higher” including levels of diminished TNF α and feeding, motordministration activity, and of socialTNF α behavior and IL . β[13] in rodents IL-6 also contributes during their lifetime; up to 65% of individuals have recurrent the depression- . [13] Administration of - episodeNearly ones; many in four people women never and onereceive in six diagnosis men experience or treatment depression for significantly increases the plasma levels of IL-6, IL- - depression and therefore only about 30%-35% adults achieve corticosterone concentrationlike behavior, inand FST sickness behavior. IFN α remission using current pharmacotherapy. [5, 6] t -6 independently predict10, the TNF subsequentα, plasma mechanism that contributes to depression is not known but development of depression. [13] Elevated alterations in monoaminergic systems contributesThe to exacthe depressionlevels of CRPin inflammatory and IL medical illnesses also suggests a role of pathogenesis of depression and, therefore, the drugs that influence inflammation in the etiology and[14] pathogenesisThe high incidenceof depression of major. [15] the monoaminergic system influences depression-like behavioral the blockade of production of these pro-inflammatory alterations [7]. In spite of the introduction of tricyclic antidepressants cytokine results in the alleviation of depressive symptoms. Thus oxidase inhibitors (MAOIs) and specific serotonin-noradrenaline Indoleamine 2, 3-dioxygenase and depression (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine medical problem. Antidepressants generally have slow onset and Indoleamine 2, 3-dioxygenase (IDO) is an enzyme which metabolizes severereuptake side inhibitors effects that (SNRIs), is continued depression to be a continues problem for to the be patients a major. to yield and, therefore, decreases the [8] Antidepressants generally work by increasing the levels of . [16] IDO provides an alternative serotonin (5- pathway for tryptophankynurenine metabolism (KYN) and this pathway is ultimately and MAOIs have now limited application because they frequently responsibleavailability offor tryptophanthe decrease in in CNSthe levels of serotonin in the brain. [17] possess undesirableHT), norepinephrine side- (NE) and/or dopamine -(DA).generation TCAs - antidepressants, including offered more selectivity, improved tryptophan availability, leading to a reduction in serotonin synthesis in safety, and tolerability. Buteffects the andproblems toxic effects. such Neweras intolerability, theCytokines brain. Activation such as IFNof IDOγ induces led to the IDO depletion and causes of tryptophan the reduction rapidly in delayed therapeutic onset, SSRIslimited efficacy and treatment-resistant and precipitates depressive symptoms. [17] so formed by the depression still persist [9]. there is a need of newer and safer enzymatic action of IDO, . antidepressants and to develop the newer drugs we have to select [17] -releaseKYN of glutamate in the some new targets. DepressionThus, is considered as an imbalance of striatum and cortex, [16]is then metabolized to quinolinic acid (QUIN) neurotransmitters, the production of these neurotransmitters is receptorsQUIN which was contributeshown to tocause neurotoxicity an over. [17] catalyzed by various enzymes. , it has been suggested that of the inflammatory resultcytokine in theled subsequent to the activationamelioration of NMDA of alterations in the levels of expression of the neurotransmitters may the depressive symptoms, [18] and it may be dueTherefore to the inhibition the blockade of the arise due to the alterations in Thusthe enzymes that catalyzed the IDO pathway. production and metabolism of these neurotransmitters. , these and depression enzymes may be good therapeutic targets for the pharmacotherapy of n the present manuscript authors Thusconsidered n that the depression occurred due to the imbalancein the expression of from l-arginine. exists in three different thedepression. various Therefore, enzymes i that directly or indirectly influences the isoformNitric oxides: synthase catalyzed the production of itric oxide (NO) neurotransmitters involved in the pathogenesis of depression Nitric oxide synthase (NOS). [22] NOS1 (nNOS or neuronal NOS), NOS2 (iNOS or inducible NOS) and NOS3 (eNOS or endothelial NOS) NO is synthesized

Walia et al. J Crit Rev, Vol 3, Issue 2, 11-16

of - such as acetylcholine, serotonin, and glutamate. [50] COX-2 plays an the cytokines such as IL- - , 21] Activation of - important role in the pathogenesis of the depressive disorder. [51] from iNOS upon the induction NF κB, which in turn is activated by Also the chronic celecoxib treatment reverse the effect of the chronic 1 and TNF α [19 . [20]NF κB unpredictable stress-induced depressive-like behavior therefore, the physiologicalpathway increased concentrations the expression acts as of a iNOS, neurotransmitter, which when expressedsignaling selective COX-2 inhibitors could be developed as potential remedies componentresults in the, [22]production and re ofgulates, the NO bloodin the largerflow, quantityneurotransmission,NO at for the treatment of depression. [52] Chronic treatment with celecoxib memory formation and prevents apoptosis in the neurons, [23] but reduced depressive-like behavior and caused a dose-dependent an uncontrolled manner decrease in the expression of COX-2 and concentration o contributes to the development of several neuropathological states. stressed rats. [53] Both -2 participate in the signaling of [24production] Stress- ofinduced NO in largerpro-inflammatory quantities and cytokines in are responsible for inflammatory processes, and they are likely implicated inf neuronal PGE2 in , death and inflammationPGE2-mediated and COX cytotoxicity. [54] IL-6 increase the activity of COX-2 and it, in turn, activates the release of IL- - responsiblethe induction for of theiNOS neurotoxic[27] and actionsthe expression, [22, 28, of 29 iNOS] is responsible by . [17] Besides inhibiting the enzyme COX-2, COX-2 for the usesexcessive the induction production of apoptosis.of NO for Inhibitiona longer periodof mitochondrial of time is inhibitors influence serotonergic system by inhibit the release1β and of TNF IL-1 respiration and regulation of oxidative phosphorylation,NO generated in addition andα as ILwell-6 andas PGE2 thus exerts the beneficial toiNOS its caexerts cytotoxic effects on target cells. [30] effect in the depression. [50]. tion of peroxynitrite, a the CNS from effects of QUIN, potent oxidant formed by the interaction of nitricThe oxide cytotoxic with and depression superoxideeffects of NO anion are tightly. [31] related to the producis also involved in the d emerging target A for the treatment and study of mood disorders. [55] Besides iNOS, nNOS . [25] Stress-mediated theTryptophan rate-limiting hydroxylase step in 5 (TPH)- synthesis is a very, andstrong thus an its alterations play releaseproduction of IL of- NO. ctivation of NMDA receptors led to the activation a major role in the pathogenesis of several psychiatricTPH disorders catalyzes. furtherof nNOS which when express produces NO . [26] [56, 57, 58] and HT are expressed in the human brain, and important role6 furtherin the pathogenesisactivates NMDA of moodreceptors disorders whose, [32,activation 33] and is genetic variation in both isoforms has been associated with has beenresponsible implicated for in thethe productionpathophysiology of NO of depressionNO plays. [34, an alterations inTPH1 mood andTPH2 5- 35] the recurrent depressive disorder was associated with the severity of HT function. Classical TPH , called depressiveHigher concentrationsymptom suggesting of plasma that NOxan overproductionin patients with of brainTPH1, stemis expressed. [57, 59 in] the gut, pineal gland, spleen, and thymus whileer of results in oxidative stress and cell damage. Increased production of polymorphismsthe second TPH genethat calledmight TPH2serve is as predominantly useful markers expressed for complex in the nitrosylation NOof behavioral phenotypesThe. [62 gene] for TPH2 contains gene a numbspans 97 proteins that appears related to the pathogenesis of depression. [36, kilobases (kb), consists of 11 exons, and is located on 37NO] and peroxynitrite- may cause nitration and arm 12q15. [61] A single Thenucleotide human TPH2 polymorphism in 5- -uptake and appears to interact with selective 5- - human alters, uptakeNO modulateinhibitors 5usedHT release in the from treatment specific ofbrain depression. structures, Several affect associated with the depression. [60] HT re HT re TPH2 TPH enzymatic efficiency and is found to be antidepressant-like actions in a variety of animal paradigms [34]. mood disorders. [63] Genetic variation that studies have demonstrated that NOS inhibitors produce influences TPH enzymatic activity results in the development of the Monoamine oxidase and depression the amount of 5- -HIAA in the brain, but does not reduce their levels in the peripherThe geneticy; however deletion the of TPH2combined strongly deletion reduces of Monoamine oxidase (MAO) is an enzyme responsible for the HT and 5 - breakdown of monoamines. [38] MAO-A metabolite, in both brain and periphery. [64] It has also been and B, are synthesized by two distinct . [38] MAO-A is found TPH1 and TPH2 resulted in ashow near no total loss of loss serotonergic of 5 HT andcells itsin primarily in the intestinal tract, Twoliver, forms and ofperipheral the enzyme, adrenergic the raphe nucleus of the brain in spite of total loss of 5- neurons whereas MAO-B is found mostly in the brain and liver. [39] micereported did thatnot differTPH2 significantlyKO animals in peripheral 5- levels. However Both MAO-A and MAO- levels of 5- -HIAA, were stronglyHT. reducedTPH2KO in and astroglia. [40] MAO-A and MAO- -dependent enzymes all brain regions examined. [65] HT responsible for the metabolismB are found inof CNS,neurotransmitters in particular in suchneurons as HT and its metabolite, 5 dopamine, serotonin, adrenaline, andB arenoradrenaline FAD and for the brain 5- In a recent report, a TPH2 knockin inactivation of exogenous aryl alkyl amines. Both enzymes are mouse line with reduced TPH2 activity and an 80%. [65reduction] in bound to the mitochondrial outer membrane and catalyze the HT, due to a rare human SNP (R441H), was reported to have oxidative deamination of their substrates. [41] MAO-A mainly fearsignificantly response, increased increased immobility times and depression in the TST-like behavior.Genetic metabolizes 5- thus [66inactivation] of TPH2 function in mice led to enhanced conditioned the drug which inhibits the action of MAO-A acts as antidepressant. markedly reduced 5- [42] MAO inhibitorsHT, dopamine emerged (DA) in anda consistent norepinephrine way (NE),as being increasedTPH2 depressionR439H mice-like (Tph2behaviors knockin. [67 ]mice Detection henceforth) of linkage have substantially more effective than conventional reuptake-blocking of haplotypes toHT major synthesis depression and tissue provided levels evidence and exhibit of a antidepressants in bipolar depression. [43] Currently, MAO functional locus somewhere within ]. It has been found that inhibitors are typically reserved for third-or-fourth-line treatment. t TPH2 Drug interactions, side effects, preference for other treatments, and TPH2 [68 dietary restrictions were the reasons most, often cited for not he human TPH2 gene coding region contains a functional prescribing these drugs. [39] Selegiline is an irreversible MAO-B reducepolymorphism, 5- G1463A, .leading [69, 70 to] the replacement of the 441 arginine inhibitor; the transdermal formulation of it conveys safety. [43] mediatedposition with reduction histidine of 5 (R441H).- levels TPH2 provides function direct loss evidence and significantly that Selegiline enhances dopaminergic neural transmission and thus controls HTbrain generation serotonin synthesisThe functional, [71] and SNP, intherefore, mouse TPH2the exerts overall antidepressant effect [44]. decreased activity reducesHT the 5- in the brain. [72]. TPH2 served as a new target for the treatment of COX and depression depression.TPH2 HT Therefore, the enzyme TPH can be (COX) catalyzed the production of prostaglandins by AKT/GSK3 and depression metabolizing arachidonic acid (AA). [45] COX exists in two isoforms, COX-1 and COX-2. [46] COX-1 is constitutively expressed in the gastrointestinal tract whereas the COX-2 predominates at sites of plays an important role in many cellular processes such as inflammation. [47] COX-1 is a constitutive enzyme, whereas COX-2 is proliferationThe serine/threonine and survival kinase. [73 (Akt)] Akt alsois most known widely as proteinassociated kinase with B inducible and short-lived. [48] COX-1 is responsible for the the phosphatidylinositol 3- pathway, and it is in gastric mucosa and kidney, whereas COX-2 is responsible for the biosynthesis in inflammatory cells and phosphatidylinositol 3,4-bisphosphatekinase (PI3K) signalingand phosphatidylinositol biosynthesis. [49] COX of-2 PGs has been shown to interact with neurotransmitters 3,4,5activated- by the enzyme PI3K that catalyzes- the production- of of PGs CNS trisphosphate. Glycogen synthase kinase 3β (GSK 3β) is the

12 Walia et al. J Crit Rev, Vol 3, Issue 2, 11-16 substrate of Akt, [74] and affects many cellular functions such as cell glutamate into glutamine in cortical astrocytes. erefore, a decline cycle, gene , and cytoskeletal integrity. [75] Activity of in the expression of glutamine synthetase at the site of injury may - - significantly reduce the ability of glial cells to removeTh extracellular is inhibited by the phosphorylation of Ser9. glutamate, thereby exacerbating the process of neuronal responsibleGSK 3β is increased for the by phosphorylation the phosphorylation of Ser9 of Tyr216 and, whiletherefore, GSK 3βis degeneration. [92] Higher level of extracellular glutamate could be a - . [75PI3K/Akt] Several signaling different is cause of depressive behaviors and it may be due to the lower levels kinases including Akt (protein kinase B), protein kinase C, and and/or lower activity of glutamine synthetase. , the enzyme proteinresponsible kinase for A theare ca inhibition of GSK 3β - . glutamine synthetase plays an important role in mood regulation [76] 5- and 5- and should be further investigated for the preventionThus and treatment - . [77]pable Activation of phosphorylating of 5- serines on GSK 3β- of depressive disorders [91]. HT1 HT2 receptors are- involved in regulating the- activity. [73] ofStimulation GSK 3β of 5- receptors enhancesHT1 receptors phosphorylation inhibits GSK of Histone acetyltransferases and histone deacetylases and Ser3β -activity9 residue whereas the activation of 5 HT2 receptors the activates stimulation GSK depression of3β 5- receptor reducesHT1 phosphorylation of Ser-9 residue, results in the inactivationand causes the inhibition, theof GSK3βdeficiency and of 5- exerts chromatin. [93] Chromatin modifications are important for elevating HT2 - . [78] moodDNA isin clinical tightly depression associated . with[94] Alterations histones embedded in the level deep and activity within been found to beof GSK3β.altered Thereforein the patients of psychiatricHT illnesses. of histone deacetylase affect depression-related behaviors. [95] differential effects on GSK 3β activity Akt/GSK3β pathway has Antidepressants generally upregulate the expression of phospho- Histone acetylation is a dynamic process, controlled by specific rylated Akt protein. [79] element binding protein (HDACs) which either add or remove the acetyl group. [93] Acute Cyclic AMP response psychologicalenzymes histone stressors acetyltransferases cause the acetylation (HATs) and of histone lysine 14 deacetylases of histone signaling(CREB) is pathway a key . transcription[80] Antidepressants factor involved inhibit s in the several criticaland H3 (H3K14) and an overall increase in acetylation in nucleus contributefunctions of to the brain and it is known to be activated by PI3K/Akt accumbens has been associated with depressive-like symptoms in GSK3β]. mice. [96] the increases in CREB. Thus, in mood- disorders impaired inhibitory control of GSK3β may reduce CREB activity [77 Therefore for the novel treatments of psychiatric disorders. [97] effects in depression. Thus histone acetylation has become a promising target the drugs that inhibits the expression of GSK 3β exerts beneficial mice to chronic social defeat stress alters acetylation of histones in MMPs and depression nucleus accumbens, [98] and show reduced mobility Exposurein a forced of swim test; this may be due to chromatin modification. [99] neutral proteases that contributes to c social stress produces a transient reduction in interactions between cells and their matrix, allowing movement and H3 acetylation after social defeat stress may MMPs are a family of shape changes in processes such as development and neuronal contributeTherefore chronito depressive symptoms. [97] Administration of HDAC inhibitorsNAc that (HDACi) into thus exerts an antidepressantin NAc that effect, . [81] -9 serum levels significantly correlated also the systemic or intracerebral administration of various HDACi, plasticity. Oxygen radicals, NO and proteases have been implicated with the depressive phases in younger subjects (<45 y), [82] either alone or in combinationNAc with antidepressants, improved in MMP activation MMP Specifically, depressed patients reporting higher levels of chronic antidepressant responses in a variety of animal models. [100] -9 Chronic social defeat stress led to a transient increase in the level of , - - histone acetylation followed by a persistent decrease the histone stress, current stress, and negative affect showed higher MMP adrenergic receptors on human monocytes and, therefore, activates acetylation in the hippocampus. expression.- Stress induces NE release which-9 as acts well on as α1 IL-and6. [87 β] - -9 subsets expressionNF κB, which. [83mediates] Depressed the expression patients of MMPare unable to express of genes in different brain regions mediate opposite effects on appropriatelyNF κB, is itself the- primary transcriptional may regulators, in turn, of lead MMP to depressionThese changes-related were behavior reversed. [100by imipramine.] HDAC5 expression Thus the sameis decreased defective molecular expression. [84] - in the hippocampus of chronically defeated mice that receive chronic the induction NFof manyκB at mRNAinflammatory levels whichcytokines which activate a imipramine treatment, and HDAC5 over central inflammatory response associatedActivation with altered of NF κB metabolism results in blocked the behavioral efficacy of imipramine treatment. [101] of serotonin involved in depression. Stress- - activation ith HDAC inhibitors is associatedexpression with neuroprotective in the DG leads to depressive-like behavior in rodents and inhibits effects and may be beneficial in the treatment of various psychiatric neurogenesis in brain regions involved in induceddepression NF .κB [85 ] Stress- disorders.Treatment w , it has been suggested that the HDAC5 is likely induced anhedonia, a core symptom of depression, is also dependent to be involved in a behavioral pathway common to multiple - ]. - psychiatricTherefore disorders [102]. Antidepressants increase H3 acetylation depression.on NF κB [86 Therefore, the selective inhibition of NF κB and expression o MMPs may exert beneficial effects in the pharmacotherapy of beat BDNFnecessary promoters, for the and behavioral this effect effects was associated of chronic with antidepressant a decrease in Glutamine synthetase and depression treatment [103f HDAC5.]. This downregulation in HDAC5 was shown to the brain and plays an important CONCLUSION Glutamateprocesses linkedis the majorto the excitatorypathogenesis neurotransmitters and pathophysiology in of several Depression occurs due to alterations in monoaminergic systems. disorders. [88] role in the regulation of several-mortem important studies CNS of monoamines is catalyzed by various enzymes depressed patients have found that the depressed patients have and therefore, increase or decrease in activity of these enzymes is increased serum aRecentnd plasma clinical levels and of glutamate post compared with responsibleThe production for alterations of in the levels of monoamines. Stress is controls. [89] an important factor that disturbs the homeostasis of the body. glucose through the process of transamination and by the Stress has been shown to increase the production of pro- conversion of glutamineGlutamate to is glutamate formed inside by the the enzyme neurons, glutaminase. from the inflammatory cytokines, which are responsible for the activations [90] is released from the neurons upon depolarization in of enzymes responsible for the degradation, inactivation, a calcium-dependent manner into the synapse and removed from inhibition of action or release of monoamines in body, or these the extracellularGlutamate space by highly efficient excitatory amino acid pro-inflammatory cytokines inhibit the enzymes responsible for – glutamate is the production or synthesis of monoamines in body rapidly converted into the ‘inert’ intermediate glutamine by enzyme manuscript explains how different enzymes influence the glutaminetransporters synthetase (EAAT1 in2). the After glial cells uptake. by EAATs,is converted back depression-related behaviors. , this manuscript. The supports present into glutamate and the glutamate so formed is transferred into the that the increase or decrease in the activities of certain enzymes synaptic vesicles through vesicularGlutamine glutamate transporters results in the depressive behaviors.Therefore and these enzymes can be –3). [90] mine synthetase thus provides served as a good target for the drug development for the neuroprotection by influencing the clearance of extracellular pharmacotherapy of the patients of depression. (VGLUT1 Gluta

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