Mitochondria: A Connecting Link in the Major Depressive Disorder Jigsaw

Shilpa       Sharma; Ravi    S.    Akundi
Abstract

Background: Depression is a widespread phenomenon with varying degrees of pathology in different patients. Various hypotheses have been proposed for the cause and continuance of depression. Some of these include, but not limited to, the monoamine hypothesis, the neuroendocrine hypothesis, and the more recent epigenetic and inflammatory hypotheses.
Objective: In this article, we review all the above hypotheses with a focus on the role of mitochondria as the connecting link. Oxidative stress, respiratory activity, mitochondrial dynamics and metabolism are some of the mitochondria-dependent factors which are affected during depression. We also propose exogenous ATP as a contributing factor to depression.
Result: Literature review shows that pro-inflammatory markers are elevated in depressive individuals. The cause for elevated levels of cytokines in depression is not completely understood. We propose exogenous ATP activates purinergic receptors which in turn increase the levels of various proinflammatory factors in the pathophysiology of depression.
Conclusion: Mitochondria are integral to the function of neurons and undergo dysfunction in major depressive disorder patients. This dysfunction is reflected in all the various hypotheses that have been proposed for depression. Among the newer targets identified, which also involve mitochondria, includes the role of exogenous ATP. The diversity of purinergic receptors, and their differential expression among various individuals in the population, due to genetic and environmental (prenatal) influences, may influence the susceptibility and severity of depression. Identifying specific receptors involved and using patient-specific purinergic receptor antagonist may be an appropriate therapeutic course in the future.
Keywords: Major depressive disorder, mitochondria, ATP, purinergic receptors, neuroinflammation, PBAIDs.
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Graphical Abstract

[1] 
Collins, P.Y.; Patel, V.; Joestl, S.S.; March, D.; Insel, T.R.; Daar, A.S. Scientific Advisory Board and the Executive Committee of
the Grand Challenges on Global Mental Health. Grand challenges
in global mental health Nature,,  2011, 475(7354), 27-30.
[http://dx.doi.org/10.1038/475027a]] [PMID:  21734685] 
[2] 
Gardner, A.; Boles, R. Beyond the serotonin hypothesis: mitochondria,
inflammation and neurodegeneration in major depression and
affective spectrum disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2011, 35(3), 730-743.
[http://dx.doi.org/10.1016/j.pnpbp.2010.07.030] [PMID:  20691744] 
[3] 
Tobe, E.H. Mitochondrial dysfunction.; oxidative stress.; and major
depressive disorder. Neuropsychiatr. Dis. Treat,  2013, 9, 567-73.
[http://dx.doi.org/10.2147/NDT.S44282] [PMID:  23650447] 
[4] 
Bansal, Y.; Kuhad, A. Mitochondrial dysfunction in depression Curr. Neuropharmacol.,  2016, 14(6), 610-8.
[http://dx.doi.org/10.2174/1570159X14666160229114755] [PMID: 26923778] 
[5] 
Mattson, M.P.; Gleichmann, M.; Cheng, A. Mitochondria in
neuroplasticity and neurological disorders. Neuron,  2008, 60(5), 748-66.
[http://dx.doi.org/10.1016/j.neuron.2008.10.010]] [PMID:  19081372] 
[6] 
Narendra, D.P.; Jin, S.M.; Tanaka, A.; Suen, D.F.; Gautier, C.A.; Shen, J.; Cookson, M.R.; Youle, R. J. Pink1 is selectively stabilized
on impaired mitochondria to activate Parkin. PLoS Biol,  2010, 8(1), e1000298.
[http://dx.doi.org/10.1371/journal.pbio.1000298] [PMID:  20126261] 
[7] 
Guedes-Dias, P.; Pinho, B.R.; Soares, T.R.; de Proenca, J.; Duchen, M.R.; Oliveira, J.M. Mitochondrial dynamics and quality control in
huntington’s disease. Neurobiol. Dis,  2016, 90, 51-7.
[http://dx.doi.org/10.1016/j.nbd.2015.09.008] [PMID:  26388396] 
[8] 
Klinedinst, N.J.; Regenold, W.T. A mitochondrial bioenergetics
basis of depression. J. Bioenergetics Biomembranes,  2014, 47(1-2), 155-71.
[http://dx.doi.org/10.1007/s10863-014-9584-6] [PMID:  25262287] 
[9] 
Gardner, A.; Johansson, A.; Wibom, R.; Nennesmo, I.; von Dobeln, U.; Hagenfeldt, L.; Hallstrom, T. Alterations of mitochondrial
function and correlations with personality traits in selected major
depressive disorder patients. J. Affect. Disord,  2003, 76, 55-68.
[http://dx.doi.org/10.1016/S0165-0327(02)00067-8] [PMID:  12943934] 
[10] 
Rezin, T.G.; Gonclaves, L.C.; Daufenbach, F.J.; Fraga, B.D.; Santos, M.P.; Ferreira, K.G.; Hermani, V.F.; Comim, M.C.; Quevedo, J.; Streck, L.E. Acute administration of ketamine reverses the inhibition
of mitochondrial respiratory chain induced by chronic mild
stress. Brain Res. Bull,  2009, 79, 418-21.
[http://dx.doi.org/10.1016/j.brainresbull.2009.03.010] [PMID:  19393724] 
[11] 
Chang, C.C.; Jou, S.H.; Lin, T.T.; Lai, T.J.; Liu, C.S. Mitochondria
DNA change and oxidative damage in clinically stable
patients with major depressive disorder. PLoS One,  2015, 10(5), e0125855.
[http://dx.doi.org/10.1371/journal.pone.0125855] [PMID: 25946463] 
[12] 
Czarny, P.; Wigner, P.; Galecki, P.; Sliwinski, T. The interplay
between inflammation, oxidative stress, DNA damage, DNA repair
and mitochondrial dysfunction in depression. Prog. Neuropsychopharmacol.
Biol. Psychiatry,  2017, Jun 29.
[http://dx.doi.org/10.1016/j.pnpbp.2017.06] [PMID:  28669580] 
[13] 
Forlenza, M.; Miller, G. Increased serum levels of 8-hydroxy-2’-
deoxyguanosine in clinical depression. Psychosom. Med,  2006, 68, 1-7.
[http://dx.doi.org/10.1097/01.psy.0000195780.37277.2a] [PMID:  16449405] 
[14] 
Maes, M.; De Vos, N.; Pioli, R.; Demedts, P.; Wauters, A.; Neels, H.; Christophe, A. Lower serum vitamin E concentrations in major
depression. Another marker of lowered antioxidant defenses in that
illness. J. Affect. Disord,  2000, 58(3), 241-246.
[http://dx.doi.org/10.1016/S0165-0327(99)00121-4] [PMID:  10802134] 
[15] 
Gałecki, P.; Szemraj, J.; Bienkiewicz, M.; Florkowski, A.; Galecka, E. Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol. Rep.,  2009, 61(3), 436-447. PMID: [19605942].
[16] 
Du, J.; Zhu, M.; Bao, H.; Li, B.; Dong, Y.; Xiao, C.; Zhang, G.Y.; Henter, I.; Rudorfer, M.; Vitiello, B. The role of nutrients in
protecting mitochondrial function and neurotransmitter signaling:
Implications for the treatment of depression, PTSD, and suicidal
behaviors. Crit. Rev. Food Sci. Nutr,  2016, 56(15), 2560-2578.
[http://dx.doi.org/10.1080/10408398.2013.876960] [PMID:  25365455] 
[17] 
Wang, Q.; Dwivedi, Y. Transcriptional profiling of mitochondria
associated genes in prefrontal cortex of subjects with major depressive
disorder. World J. Biol. Psychiatry,  2016, 11, 1-12.
[http://dx.doi.org/10.1080/15622975.2016.1197423] [PMID:  27269743] 
[18] 
Delgado, P.L. Depression: the case for a monoamien deficiency. J. Clin. Psychiatry,  2000, 61(6), 7-11. PMID: [10775018]
[19] 
Berton, O.; Nestler, E.J. New approaches to antidepressant drug
discovery: Beyond monoamines. Nat. Rev. Neurosci,  2006, 7(2), 137-151.
[http://dx.doi.org/10.1038/nrn1846] [PMID:  16429123] 
[20] 
Ruhe, H.G.; Mason, N.S.; Schene, A.H. Mood is indirectly related
to serotonin, norepinephrine and dopamine levels in humans: a
meta-analysis of monoamine depletion studies. Mol. Psychiatry,  2007, 12(4), 331-359.
[http://dx.doi.org/10.1038/sj.mp.4001949] [PMID:  17389902] 
[21] 
Meyer, J.H.; Ginovart, N.; Boovariwala, A.; Sagrati, S.; Hussey, D.; Garcia, A.; Young, T.; Praschak-Rieder, N.; Wilson, A.A.; Houle, S. Elevated monoamine oxidase a levels in the brain: An
explanation for the monoamine imbalance of major depression. Arch. Gen. Psychiatry,  2006, 63(11), 1209-1216.
[http://dx.doi.org/10.1001/archpsyc.63.11.1209] [PMID:  17088501] 
[22] 
Nautiyal, KM.; Hen, R. Serotonin receptors in depression: from A
to B F1000Res.,,  2017, 6, 123.
[http://dx.doi.org/10.12688/f1000research.9736.1] [PMID:  28232871] 
[23] 
Sowa-Kucma, M.; Panczyszyn-Trzewik, P.; Misztak, P.; Jaeschke, RR.; Sendek, K.; Styczen, K.; Datka, W.; Koperny, M. Vortioxetine:
a review of the pharmacology and clinical profile of the novel antidepressant Pharmacol Rep,  2017, 69(4), 595-601.
[http://dx.doi.org/10.1016/j.pharep.2017.01.030]] [PMID:  28499187] 
[24] 
Rosenblat, J.D.; Kakar, R.; McIntyre, R.S. The cognitive effects of
antidepressants in major depressive disorder: A systematic review
and meta-analysis of randomized clinical trials. Int. J. Neuropsychopharmacol.,,  2015, 19(2)
[http://dx.doi.org/10.1093/ijnp/pyv082] [PMID:  26209859] 
[25] 
Edmondson, D.E. Hydrogen peroxide produced by mitochondrial
monoamine oxidase catalysis: biological implications Curr.
Pharm. Des,  2014, 20(2), 155-60.
[http://dx.doi.org/10.2174/13816128113190990406] [PMID:  [23701542] 
[26] 
Thiffault, C.; Quirion, R.; Poirier, J. The effect of L-deprenyl.; D-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism leading to an adaptive increase in superoxide dismutase activity. Brain Res. Mol. Brain Res.,  1997, 49(1-2), 127-136. PMID:
[9387872]
[27] 
Wills, L.P.; Trager, R.E.; Beeson, G.C.; Lindsey, C.C.; Peterson, Y.K.; Beeson, C.C.; Schnellmann, R.G. The b2-adrenoceptor agonist
formoterol stimulates mitochondrial biogenesis. J. Pharmacol.
Exp. Ther,  2012, 342, 106-18.
[http://dx.doi.org/10.1124/jpet.
112.191528] [PMID: 22490378] 
[28] 
Garrett, M.S.; Whitaker, M.R.; Beeson, C.C.; Schnell, G.R. Agonism
of the 5-hydroxytryptamine 1F receptor promotes mitochondrial
biogenesis and recovery from acute kidney injury J. Pharmacol.
Exp. Ther.,  2014, 350, 257-64.
[http://dx.doi.org/10.1124/jpet.114.214700] [PMID: 24849926] 
[29] 
Rasbach, K.A.; Funk, J.A.; Jayavelu, T.; Green, P.T.; Schnellmann, R.G. 5-Hydroxytryptamine receptor stimulation of mitochondrial
biogenesis. J. Pharmacol. Exp. Ther,  2010, 332, 632-39.
[http://dx.doi.org/10.1124/jpet.109.159947] [PMID: 19875674] 
[30] 
Scaini, G.; Maggi, D.; De-Nes, B.T.; Goncalves, C.; Ferreira, K.G.; Teodorak, B.; Bez, G.; Ferreira, C.G.; Schuck, P.; Quevedo, J.; Emilo, S. Activity of mitochondrial respiratory chain is increased
by chronic administration of antidepressants. Acta. Neuropsychiatrica,  2011, 23(3), 112-18.
[http://dx.doi.org/10.1111/j.1601-
5215.2011.00548.x] [PMID: 26952897] 
[31] 
Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology,  2000, 23(5), 477-501.
[http://dx.doi.org/10.1016/S0893-133X(00)00159-7] [PMID: 11027914] 
[32] 
Van Bodegom, M.; Homberg, J.R.; Henckens, M.J.A.G. Modulation
of the hypothalamic-pituitary-adrenal axis by early life stress
exposure. Front. Cell Neurosci,  2017, 11, 87.
[http://dx.doi.org/10.3389/fncel.2017.00087] [PMID: 28469557] 
[33] 
Rieder, R.; Wisniewski, P.J.; Alderman, BL.; Campbell, S.C. Microbes and mental health: a review. Brain Behav. Immun.,  2017, Jan 25.
[http://dx.doi.org/10.1016/j.bbi.2017.01.016] [PMID: 28131791] 
[34] 
Fox, J.H.; Lowry, C.A. Corticotropin-releasing factor-related peptides,
serotonergic systems, and emotional behaviour. Front. Neurosci,  2013, 7, 169.
[http://dx.doi.org/10.3389/fnins.2013.00169] [PMID: 24065880] 
[35] 
Binneman, B.; Feltner, D.; Kolluri, S.; Shi, Y.; Qiu, R.; Stiger, T. A
6-week randomized, placebo-controlled trial of CP-316,311 (a selective
CRH1 antagonist) in the treatment of major depression. Am.
J. Psychiary,  2008, 165(5), 617-20.
[http://dx.doi.org/10.1176/
appi.ajp.2008.07071199]] [PMID: 18413705] 
[36] 
Van den Eede, F.; van Broeckhoven, C.; Claes, S.J. Corticotropinreleasing
factor-binding protein, stress and major depression. Ageing
Res. Rev,  2005, 4(2), 213-39.
[http://dx.doi.org/10.1016/j.arr.2005.02.002] [PMID: 15996902] 
[37] 
Lazaridis, I.; Charalampopoulos, I.; Alexaki, V-I.; Avlonitis, N.; Pediaditakis, I.; Efstathopoulos, P.; Calogeropoulou, T.; Castanas, E.; Gravanis, A. Neurosteroid dehydroepiandrosterone interacts
with nerve growth factor (NGF) receptors, preventing neuronal
apoptosis. PLoS Biol,  2011, 9(4), e1001051.
[http://dx.doi.org/10.1371/journal.pbio.1001051] [PMID: 21541365] 
[38] 
McIntosh, L.J.; Sapolsky, R.M. Glucocorticoids may enhance oxygen radicalmediated neurotoxicity. Neurotoxicology,  1996, 17, 873-882. PMID: [9086511].
[39] 
Epel, E.S.; Lin, J.; Dhabhar, F.S.; Wolkowitz, O.M.; Puterman, E.; Karan, L.; Blackburn, E.H. Dynamics of telomerase activity in response
to acute psychological stress. Brain Behav. Immun,  2010, 24(4), 531-9.
[http://dx.doi.org/10.1016/j.bbi.2009.11.018] [PMID: 20018236] 
[40] 
Filipovic, D.; Zlatkovic, J.; Inta, D.; Bjelobaba, I.; Stojiljkovic, M.; Gass, P. Chronic isolation stress predisposes the frontal cortex but
not the hippocampus to the potentially detrimental release of cytochrome
c from mitochondria and the activation of caspase 3. J.
Neurosci. Res,  2011, 89(9), 1461-70.
[http://dx.doi.org/10.1002/
jnr.22687]] [PMID: 21656845] 
[41] 
Lucca, G.; Comim, C.M.; Valvassori, S.S.; Reus, G.Z.; Vuolo, F.; Petronilho, F.; Dal-Pizzol, F.; Gavioli, EC.; Quevedo, J. Effects of
chronic mild stress on the oxidative parameters in rat brain mitochondria. Neurochem. Int.,  2009, 54, 358-62.
[http://dx.doi.org/10.1016/j.neuint.2009.01.001] [PMID: 19171172] 
[42] 
Du, J.; Wang, Y.; Hunter, R.; Wei, Y.; Blumenthal, R.; Falke, C.; Khairova, R.; Zhou, R.; Yuan, P.; Machado-Vieira, R.; McEwen, B.S.; Manji, H.K. Dynamic regulation of mitochondrial function by
glucocorticoids. Proc. Natl. Acad. Sci. U.S.A,  2009, 106(9), 3543-8.
[http://dx.doi.org/10.1073/pnas.0812671106] [PMID: 19202080] 
[43] 
Pittenger, C.; Duman, R. Stress, depression, and neuroplasticity: a
convergence of mechanisms. Neuropsychopharmacology,,  2008, 33(1), 88-109.
[http://dx.doi.org/10.1038/sj.npp.1301574] [PMID: 17851537] 
[44] 
Kempermann, G.; Kronenberg, G. Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol. Psychiatry,  2003, 54(5), 499-503.
[http://dx.doi.org/10.1016/S0006-3223(03)00319-6]] [PMID: 12946878] 
[45] 
Castren, E.; Voikar, V.; Rantamaki, T. Role of neurotrophic factors
in depression. Curr. Opin. Pharmacol,  2007, 7(1), 18-21.
[http://dx.doi.org/10.1016/j.coph.2006.08.009] [PMID: 17049922] 
[46] 
Yu, L.Y.; Saarma, M.; Arumae, U. Death receptors and caspases
but not mitochondria are activated in the GDNF- or BDNFdeprived
dopaminergic neurons. J. Neurosci,  2008, 28(30), 7467-
75.
[http://dx.doi.org/10.1523/JNEUROSCI.1877-08.2008] [PMID: 18650325] 
[47] 
Cattaneo, A.; Gennarelli, M.; Uher, R.; Breen, G.; Farmer, A.; Aitchison, K.J.; Craig, I.W.; Anacker, C.; Zunsztain, P.A.; McGuffin, P.; Pariante, C.M. Candidate genes expression profile associated
with antidepressants response in the GENDEP study: differentiating
between baseline 'predictors' and longitudinal 'targets'. Neuropsychopharmacology,  2013, 38(3), 377-85.
[http://dx.doi.org/10.1038/npp.2012.191] [PMID: 22990943] 
[48] 
Lee, H.Y.; Kim, Y.K. Plasma brain-derived neurotrophic factor as
a peripheral marker for the action mechanism of antidepressants. Neuropsychobiology,  2008, 57(4), 194-199.
[http://dx.doi.org/10.1159/000149817] [PMID: 18679038]] 
[49] 
Cheng, A.; Hou, Y.; Mattson, M.P. Mitochondria and neuroplasticity. ASN. Neuro,  2010, 2(5), e00045.
[http://dx.doi.org/10.1042/
AN20100019] [PMID: 20957078] 
[50] 
Markham, A.; Cameron, I.; Bains, R.; Franklin, P.; Kiss, J.P.; Schwendimann, L.; Gressens, P.; Spedding, M. Brain-derived neurotrophic
factor-mediated effects on mitochondrial respiratory coupling
and neuroprotection share the same molecular signalling
pathways. Eur. J. Neurosci,  2012, 35(3), 366–374.
[http://dx.doi.org/10.1111/j.1460-9568.2011.07965.x] [PMID: 22288477] 
[51] 
Blendy, J.A. The role of CREB in depression and antidepressant
treatment. Biol. Psychiatr,  2006, 59(12), 1144-1150.
[http://dx.doi.org/10.1016/j.biopsych.2005.11.003] [PMID: 16457782] 
[52] 
Aguiar, A.S., Jr; Stragier, E.; da Luz Scheffer, D.; Remor, A.P.; Oliveira, P.A.; Prediger, R.D.; Latini, A.; Raisman-Vozari, R.; Mongeau, R.; Lanfumey, L. Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behavior of mice. Neuroscience,  2014, 271, 56-63.
[http://dx.doi.org/10.1016/j.neuroscience.2014.04.027]] [PMID: 24780767] 
[53] 
Ripke, S. Major Depressive Disorder Working Group of the Psychiatric
GWAS Consortium. A mega-analysis of genome-wide association
studies for major depressive disorder. Mol. Psychiatry,  2013, 18(4), 497-511.
[http://dx.doi.org/10.1038/mp.2012.21] [PMID: 22472876] 
[54] 
Mullins, N.; Lewis, C.M. Genetics of depression: Progress at last. Curr. Psychiatry, Rep,  2017, 19(8), 43.
[http://dx.doi.org/10.
1007/s11920-017-0803-9] [PMID: 28608123] 
[55] 
Flint, J.; Kendler, K.S. The genetics of major depression. Neuron,  2014, 81(3), 484-503.
[http://dx.doi.org/10.1016/j.neuron.2014.
01.027] [PMID: 24507187] 
[56] 
Ignacio, Z.M.; Reus, G.Z.; Abelaira, H.M.; Quevedo, J. Epigenetic
and epistatic interactions between serotonin transporter and brainderived
neurotrophic factor genetic polymorphism: insights in depression. Neuroscience,  2014, 275, 455-68.
[http://dx.doi.org/10.
1016/j.neuroscience.2014.06.036] [PMID: 24972302] 
[57] 
Bagot, R.C.; Labonte, B.; Pena, C.J.; Nestler, E.J. Epigenetic signaling
in psychiatric disorders: stress and depression. Dialogues Clin.
Neurosci,  2014, 16(3), 281–295.
[http://dx.doi.org/10.1016/j.jmb.
2014.03.016] [PMID: 24709417] 
[58] 
Booij, L.; Wang, D.; Levesque, M.L.; Tremblay, R.E.; Szyf, M. Looking beyond the DNA sequence: the relevance of DNA methylation
processes for the stress–diathesis model of depression. Phil.
Trans. R. Soc. Lond. B. Biol. Sci.,  2013, 368(1615), 2012-51.
[http://dx.doi.org/10.1098/rstb.2012.0251] [PMID: 23440465] 
[59] 
Covington, H.E., 3rd; Maze, I.; LaPlant, Q.C.; Vialou, V.F.; Ohnishi, Y.N.; Berton, O.; Fass, D.M.; Renthal, W.; Rush, A.J., 3rd; Wu, E.Y.; Ghose, S.; Krishnan, V.; Russo, S.J.; Tamminga, C.; Haggarty, S.J.; Nestler, E.J. Antidepressant actions of histone deacetylase
inhibitors. J. Neurosci,  2009, 29(37), 11451-60.
[http://dx.doi.org/10.1523/JNEUROSCI.1758-09.2009] [PMID: 19759294] 
[60] 
Klengel, T.; Binder, E.B. Epigenetics of stress-related psychiatric
disorders and gene x environment interactions. Neuron,  2015, 86(6), 1343-57.
[http://dx.doi.org/10.1016/j.neuron.2015.05.036] [PMID: 26087162] 
[61] 
Massart, R.; Mongeau, R.; Lanfumey, L. Beyond the monoaminergic
hypothesis: neuroplasticity and epigenetic changes in a transgenic
mouse model of depression. Phil. Trans. R. Soc. Lond. B.
Biol. Sci.,  2012, 367(1601), 2485-94.
[http://dx.doi.org/10.1098/
rstb.2012.0212] [PMID: 22826347] 
[62] 
Szyf, M.; Weaver, I.; Meaney, M. Maternal care, the epigenome
and phenotypic differences in behavior. Reprod. Toxicol,  2007, 24(1), 9-19.
[http://dx.doi.org/10.1016/j.reprotox.2007.05.001] [PMID: 17561370] 
[63] 
Loenen, W.A. S-adenosylmethionine: jack of all trades and master
of everything? Biochem. Soc. Trans,  2006, 34(Pt 2), 330-3.
[http://dx.doi.org/10.1042/BST20060330] [PMID: 16545107] 
[64] 
Stover, P.J. Polymorphisms in 1-carbon metabolism.; epigenetics
and folate-related pathologies. J. Nutrigenet. Nutrigenomics,  2011, 4(5), 293-305.
[http://dx.doi.org/10.1159/000334586] [PMID: 22353665] 
[65] 
Papakostas, G.I.; Mischoulon, D.; Shyu, I.; Alpert, J.E. Fava. M S-adenosyl methionine (SAMe) augmentation of serotonin reuptake
inhibitors for antidepressant nonresponders with major depressive
disorder: a double-blind, randomized clinical trial. Am. J. Psychiatry,  2010, 167, (8), 942-8.
[http://dx.doi.org/10.1176/appi.ajp.
2009.09081198] [PMID: 20595412] 
[66] 
De Berardis, D.; Orsolini, L.; Serroni, N.; Girinelli, G.; Iasevoli, F.; Tomasetti, C.; de Bartolomeis, A.; Mazza, M.; Valchera, A.; Fornaro, M.; Perna, G.; Piersanti, M.; Di Nicola, M.; Cavuto, M.; Martinotti, G.; Di Giannantonio, M. A comprehensive review on the
efficacy of S-adenosyl-L-methionine in major depressive disorder. CNS Neurol. Disord. Drug Targets,  2016, 15(1), 35-44.
[http://dx.doi.org/10.2174/1871527314666150821103825] [PMID: 26295824] 
[67] 
Sharma, A.; Gerbarg, P.; Bottiglieri, T.; Massoumi, L.; Carpenter, L.L.; Lavretsky, H.; Muskin, P.R.; Brown, R.P.; Mischoulon, D. Work Group of the American Psychiatric Association Council on
Research. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders:
a clinician-oriented review of research. J. Clin. Psychiatry,  2017, 78(6), e656-67.
[http://dx.doi.org/10.4088/JCP.16r11113] [PMID: 28682528] 
[68] 
Lopez, J.P.; Fiori, L.M.; Cruceanu, C.; Lin, R.; Labonte, B.; Cates, H.M.; Heller, E.A.; Vialou, V.; Ku, S.M.; Gerald, C.; Han, M.H.; Foster, J.; Frey, B.N.; Soares, C.N.; Muller, D.J.; Farzan, F.; Leri, F.; MacQueen, G.M.; Feilotter, H.; Tyryshkin, K.; Evans, K.R.; Giacobbe, P.; Blier, P.; Lam, R.W.; Milev, R.; Parikh, S.V.; Rotzinger, S.; Strother, S.C.; Lewis, C.M.; Aitchison, K.J.; Wittenberg, G.M.; Mechawar, N.; Nestler, E.J.; Uher, R.; Kennedy, S.H.; Turecki, G. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers
of antidepressant response and regulate MAPK/Wnt-system
genes. Nat. Commun,  2017, 8, 15497.
[http://dx.doi.org/10.1038/
ncomms15497]] [PMID: 28530238] 
[69] 
Wei, Y.B.; Melas, P.A.; Villaescusa, J.C.; Liu, J.J.; Xu, N.; Christiansen, S.H.; Elbrond-Bek, H.; Woldbye, D.P.; Wegener, G.; Mathe, A.A.; Lavebratt, C. MicroRNA 101b is downregulated in
the prefrontal cortex of a genetic model of depression and targets
the glutamate transporter SLC1A1 (EAAT3) in vitro. Int. J. Neuropsychopharmacol,  2016, 19(12), yw069.
[http://dx.doi.org/10.1093/ijnp/pyw069] [PMID: 27507301] 
[70] 
Lei, Q.; Liu, X.; Fu, H.; Sun, Y.; Wang, L.; Xu, G.; Wang, W.; Yu, Z.; Liu, C.; Li, P.; Feng, J.; Li, G.; Wu, M. miR-101 reverses hypomethylation
of the PRDM16 promoter to disrupt mitochondrial
function in astrocytoma cells. Oncotarget,  2016, 7(4), 5007-22.
[http://dx.doi.org/10.18632/oncotarget.6652] [PMID: 26701852] 
[71] 
Roy, B.; Dunbar, M.; Shelton, R.C.; Dwivedi, Y. Identification of
microRNA-124-3p as a putative epigenetic signature of major depressive
disorder. Neuropsychopharmacology,  2017, 42(4), 864-75.
[http://dx.doi.org/10.1038/npp.2016.175] [PMID: 27577603] 
[72] 
Valentino, A.; Calarco, A.; Di Salle, A.; Finicelli, M.; Crispi, S.; Calogero, RA.; Riccardo, F.; Sciarra, A.; Gentilucci, A.; Galderisi, U.; Margarucci, S.; Peluso, G. Deregulation of MicroRNAs
mediated control of carnitine cycle in prostate cancer: molecular
basis and pathophysiological consequences. Oncogene, 2017.
[http://dx.doi.org/10.1038/onc.2017.216]] [PMID: 28671672] 
[73] 
Wang, H.; Ye, Y.; Zhu, Z.; Mo, L.; Lin, C.; Wang, Q.; Wang, H.; Gong, X.; He, X.; Lu, G.; Lu, F.; Zhang, S. mir-124 regulates apoptosis
and autophagy process in MPTP model of Parkinson’s disease
by targeting to Bim. Brain Pathol,  2016, 26(2), 167-76.
[http://dx.doi.org//10.1111/bpa.12267]] [PMID: 25976060] 
[74] 
Alural, B.; Genc, S.; Haggarty, S.J. Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: past, present and future. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2017, 73, 87-103.
[http://dx.doi.org/10.1016/j.pnpbp.2016.03.010] [PMID:  27072377] 
[75] 
Audet, M.C.; Anisman, H. Interplay between pro-inflammatory
cytokines and growth factors in depressive illnesses. Front. Cell
Neurosci.,  2013, 7, 68.
[http://dx.doi.org/10.3389/fncel.2013.
00068]] [PMID: 23675319] 
[76] 
Solomon, G.F.; Allansmith, M.; McCellan, B.; Amkraut, A. Immunoglobulins in psychiatric patients. Arch. Gen. Psychiatry,  1969, 20(3), 272–7. PMID: [4974471].
[77] 
Yolken, R.H.; Torrey, E.F. Are some cases of psychosis caused
by microbial agents? A review of the evidence. Mol. Psychiatry,  2008, 13(5), 470-9.
[http://dx.doi.org/10.1038/mp.2008.5] [PMID: 18268502] 
[78] 
Claypoole, L.D.; Zimmerberg, B.; Williamson, L.L. Neonatal
lipopolysaccharide treatment alters hippocampal neuroinflammation,
microglia morphology and anxiety-like behavior in rats selectively
bred for an infantile trait. Brain Behav. Immunity,  2017, 59, 135-46.
[http://dx.doi.org/10.1016/j.bbi.2016.08.017] [PMID: 27591170] 
[79] 
Liu, Y.; Ho, RC.; Mak, A. Interleukin (IL)-6, tumour necrosis
factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R)
are elevated in patients with major depressive disorder: a metaanalysis
and meta-regression. J. Affect. Disord,  2012, 139(3), 230-9.
[http://dx.doi.org/10.1016/j.jad.2011.08.003] [PMID: 21872339] 
[80] 
Dhabhar, F.S.; Burke, H.M.; Epel, E.S.; Mellon, S.H.; Rosser, R.; Reus, V.I.; Wolkowitz, O.M. Low serum IL-10 concentrations
and loss of regulatory association between IL-6 and IL-10 in
adults with major depression. J. Psychiatr. Res,  2009, 43(11), 962-9.
[http://dx.doi.org/10.1016/j.jpsychires.2009.05.010] [PMID: 19552919] 
[81] 
Raison, C.L.; Capuron, L.; Miller, A.H. Cytokines sing the blues:
inflammation and the pathogenesis of depression. Trends Immunol,  2006, 27(1), 24–31.
[http://dx.doi.org/10.1016/j.it.2005.11.006] [PMID: 16316783] 
[82] 
Hestad, K.A.; Tonseth, S.; Stoen, C.D.; Ueland, T.; Aukrust, P. Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J. ECT,  2003, 19(4), 183-8. PMID: [14657769].
[83] 
Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents:
the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry,  2009, 65(9), 732-41.
[http://dx.doi.org/10.1016/j.biopsych.2008.11.029]] [PMID: 19150053] 
[84] 
Müller, N.; Schwarz, MJ.; Dehning, S.; Douhe, A.; Cerovecki, A.; Goldstein-Muller, B.; Spellmann, I.; Hetzel, G.; Maino, K.; Kleindienst, N.; Moller, H.J.; Arolt, V.; Riedel, M. The cyclooxygenase-
2 inhibitor celecoxib has therapeutic effects in major depression:
results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry,  2006, 11(7), 680-4.
[http://dx.doi.org/10.1038/sj.mp.4001805] [PMID: 16491133] 
[85] 
Alcocer-Gómez, E.; de Miguel, M.; Casas-Barguero, N.; Nunez-Vasco, J.; Sanchez-Alcazar, J.A.; Fernandez-Rodriguez, A.; Cordero, M.D. NLRP3 inflammasome is activated in mononuclear
blood cells from patients with major depressive disorder. Brain Behav.
Immun.,  2014, 36, 111-7.
[http://dx.doi.org/10.1016/j.bbi.
2013.10.017] [PMID: 24513871] 
[86] 
Hunter, R.L.; Dragicevic, N.; Seifert, K.; Choi, D.Y.; Liu, M.; Kim, H.C.; Cass, W.A.; Sullivan, P.G.; Bing, G. Inflammation induces
mitochondrial dysfunction and dopaminergic neurodegeneration
in the nigrostriatal system. J. Neurochem,  2007, 100(5), 1375-
86.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04327.x] [PMID: 17254027] 
[87] 
Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C.J. Circulating mitochondrial
DAMPs cause inflammatory responses to injury. Nature,  2010, 464(7285), 104-7.
[http://dx.doi.org/10.1038/nature08780] [PMID: 20203610] 
[88] 
Liu, C.S.; Adibfar, A.; Herrmann, N.; Gallagher, D.; Lanctot, K.L. Evidence for inflammation-associated depression. Curr. Top. Behav.
Neurosci,  2017, 31, 3-30.
[http://dx.doi.org/10.1007/7854_
2016_2] [PMID: 12604600] 
[89] 
Anderson, G.; Maes, M. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression: treatment implications. Curr. Pharm. Des.,  2014, 20(23), 3812-47.
[http://dx.doi.org/10.2174/13816128113196660738]] [PMID: 24180395] 
[90] 
Zarate, C.A., Jr; Singh, J.B.; Carlson, P.J.; Brutsche, N.E.; Ameli, R.; Luckenbaugh, D.A.; Charney, D.S.; Manji, H.K. A randomized
trial of an N-methyl-D-aspartate antagonist in treatment-resistant
major depression. Arch. Gen. Psychiatry,  2006, 63(8), 856-64.
[http://dx.doi.org/10.1001/archpsyc.63.8.856] [PMID: 16894061] 
[91] 
Hare, B.D.; Ghosal, S.; Duman, R.S. Rapid acting antidepressants
in chronic stress models: molecular and cellular mechanisms. Chronic Stress (Thousand Oaks),  2017, Feb 1.
[http://dx.doi.org/10.1177/2470547017697317] [PMID: 28649673] 
[92] 
Pehrson, AL.; Sanchez, C. Serotonergic modulation of glutamate
neurotransmission as a strategy for treating depression and cognitive
dysfunction. CNS spectr,  2014, 19(2), 121–33.
[http://dx.doi.org/10.1017/S1092852913000540] [PMID: 23903233] 
[93] 
Ghasemi, M.; Phillips, C.; Fahimi, A.; McNerney, M.W.; Salehi, A. Mechanisms of action and clinical efficacy of NMDA receptor
modulators in mood disorders. Neurosci. Biobehav Rev,  2017, 80, 555-72.
[http://dx.doi.org/10.1016/j.neubiorev.2017.07.002] [PMID: 28711661] 
[94] 
Yuksel, C.; Ongur, D. Magnetic resonance spectroscopy studies of
glutamate-related abnormalities in mood disorders. Biol. Psychiatry,  2010, 68(9), 785-94.
[http://dx.doi.org/10.1016/j.biopsych.
2010.06.016] [PMID: 20728076] 
[95] 
Hasler, G.; van der Veen, J.W.; Tumonis, T.; Meyers, N.; Shen, J.; Drevets, W.C. Reduced prefrontal glutamate/glutamine and
gamma-aminobutyric acid levels in major depression determined
using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry,  2007, 64, 193–200.
[http://dx.doi.org/10.1001/archpsyc.
64.2.193]] [PMID: 17283286] 
[96] 
Mirza, Y.; Tang, J.; Russell, A.; Banerjee, S.P.; Bhandari, R.; Ivey, J.; Boyd, C.; Moore, G.J. Reduced anterior cingulate cortex glutamatergic
concentrations in childhood major depression. J. Am.
Acad. Child Adolesc. Psychiatry,  2004, 43, 341–48.
[http://dx.doi.org/10.1097/00004583-200403000-00017] [PMID: 15076268] 
[97] 
Wang, X.; Li, Y.H.; Li, M.H.; Lu, J.; Zhao, J.G.; Sun, X.J.; Zhang, B.; Ye, J.L. Glutamate level detection by magnetic resonance spectroscopy
in patients with post-stroke depression. Eur. Arch. Psychiatry
Clin. Neurosci,  2012, 262, 33-8.
[http://dx.doi.org/10.1007/s00406-011-0209-3] [PMID: 21424280] 
[98] 
Binesh, N.; Kumar, A.; Hwang, S.; Mintz, J.; Thomas, M.A. Neurochemistry
of late-life major depression: a pilot two-dimensional
MR spectroscopic study. J. Magn. Reson. Imaging,  2004, 20, 1039-
45.
[http://dx.doi.org/10.1002/jmri.20214] [PMID: 15558563] 
[99] 
Sanacora, G.; Gueorguieva, R.; Epperson, C.N.; Wu, Y-T.; Appel, M.; Rothman, D.L.; Krystal, J.H.; Mason, G.F. Subtype-specific alterations
of GABA and glutamate in major depression. Arch.
Gen. Psychiatry,  2004, 61, 705-713.
[http://dx.doi.org/10.1001/
archpsyc.61.7.705] [PMID: 15237082] 
[100] 
Rajkowska, G.; Stockmeier, C. Astrocyte pathology in major depressive
disorder: insights from human postmortem brain tissue. Curr. Drug Targets,  2013, 14(11), 1225-36.
[http://dx.doi.org/10.1074/jbc.M212878200] [PMID: 23469922] 
[101] 
Kalra, J.; Brosnan, J.T. The subcellular localization of glutaminase isoenzymes in rat kidney cortex. J. Biol. Chem.,  1974, 249(10), 3255-60. PMID: [4364419].
[102] 
Hyder, F.; Rothman, D.L.; Bennett, M.R. Cortical energy demands
of signaling and nonsignaling components in brain are conserved
across mammalian species and activity levels. Proc. Natl. Acad.
Sci. U.S.A,  2013, 110(9), 3549-54.
[http://dx.doi.org/10.1073/
pnas.1214912110] [PMID: 23319606] 
[103] 
Abdallah, C.G.; Jiang, L.; De Feyter, H.M.; Fasula, M.; Krystal, J.H.; Rothman, D.L.; Mason, G.F.; Sanacora, G. Glutamate
metabolism in major depressive disorder. Am. J. Psychiatry,  2014, 171(12), 1320-7.
[http://dx.doi.org/10.1176/appi.ajp.2014.
14010067] [PMID: 25073688] 
[104] 
Velletri, T.; Romeo, F.; Tucci, P.; Peschiaroli, A.; Annicchiarico-Petruzzelli, M.; Niklison-Chirou, M.V.; Amelio, I.; Knight, R.A.; Mak, T.W.; Melino, G.; Agostini, M. GLS2 is transcriptionally
regulated by p73 and contributes to neuronal differentiation. Cell
Cycle,  2013, 12(22), 3564-73.
[http://dx.doi.org/10.4161/cc.
26771] [PMID: 24121633] 
[105] 
Hu, W.; Zhang, C.; Wu, R.; Sun, Y.; Levine, A.; Feng, Z. Glutaminase
2, a novel p53 target gene regulating energy metabolism
and antioxidant function. Proc. Natl. Acad. Sci. USA,  2010, 107(16), 7455-60.
[http://dx.doi.org/10.1073/pnas.1001006107] [PMID: 20378837] 
[106] 
Burnstock, G.; Krugel, U.; Abbracchio, M.P.; Illes, P. Purinergic signalling: from normal behaviour to pathological brain function. Prog. Neurobiol,  2011, 95(2), 229-74.
[http://dx.doi.org/10.
1016/j.pneurobio.2011.08.006] [PMID: 21907261] 
[107] 
Schaefer, L. Complexity of danger: the diverse nature of damageassociated
molecular patterns. J. Biol. Chem.,  2014, 289(51), 35237-45.
[http://dx.doi.org/10.1074/jbc.R114.619304] [PMID: 25391648] 
[108] 
Ferrari, D.; Chiozzi, P.; Falzoni, S.; Dal Susino, M.; Melchiorri, L.; Baricordi, O.R.; di Virgilio, F. Extracellular ATP triggers IL-1beta release by activating the purinergic P2Z receptor of human macrophages. J. Immunol.,  1997, 159(3), 1451-8. PMID: [9233643].
[109] 
Fiebich, B.L.; Akter, S.; Akundi, R.S. The two-hit hypothesis for
neuroinflammation: role of exogenous ATP in modulating inflammation
in the brain. Front. Cell Neurosci.,  2014, 8, 260.
[http://dx.doi.org/10.3389/fncel.2014.00260] [PMID: 25225473] 
[110] 
Lindberg, D.; Shan, D.; Ayers-Ringler, J.; Oliveros, A.; Benitez, J.; Prieto, M.; McCullumsmith, R.; Choi, D.S. Purinergic
signaling and energy homeostasis in psychiatric disorders. Curr.
Mol. Med.,  2015, 15(3), 275-95.
[http://dx.doi.org/10.2174/
1566524015666150330163724] [PMID: 25950756] 
[111] 
Rial, D.; Lemos, C.; Pinheiro, H.; Duarte, J.M.; Goncalves, F.Q.; Real, J.I.; Prediger, R.D.; Goncalves, N.; Gomes, C.A.; Canas, P.M.; Agostinho, P.; Cunha, R.A. Depression as a glial-based synaptic
dysfunction. Front. Cell Neurosci,  2016, 9, 521.
[http://dx.doi.org/10.3389/fncel.2015.00521] [PMID: 26834566] 
[112] 
Cao, X.; Li, L.P.; Wang, Q.; Wu, Q.; Hu, H.H.; Zhang, M.; Fang, Y.Y.; Zhang, J.; Li, S.J.; Xiong, W.C.; Yan, H.C.; Gao, Y.B.; Liu, J.H.; Li, X.W.; Sun, L.R.; Zeng, Y.N.; Zhu, X.H.; Gao, T.M. Astrocyte-
derived ATP modulates depressive-like behaviors. Nat.
Med,  2013, 19(6), 773-7.
[http://dx.doi.org/10.1038/nm.3162]] [PMID: 23644515] 
[113] 
Krügel, U. Purinergic receptors in psychiatric disorders. Neuropharmacology,  2016, 104, 212-25.
[http://dx.doi.org/10.1016/
j.neuropharm.2015.10.032]] [PMID: 26518371] 
[114] 
Dziubina, A.; Szmyd, K.; Zygmunt, M.; Sapa, J.; Dudek, M.; Filipek, B.; Drabczynska, A.; Zaluski, M.; Pytka, K.; Kiec-Kononowicz, K. Evaluation of antidepressant-like and anxiolyticlike
activity of purinedione-derivatives with affinity for adenosine
A2A receptors in mice. Pharmacol. Rep,  2016, 68(6), 1285-92.
[http://dx.doi.org/10.1016/j.pharep.2016.07.008]] [PMID: 27689756] 
[115] 
López-Cruz, L.; Carbó-Gas, M.; Pardo, M.; Bayarri, P.; Valverde, O.; Ledent, C.; Salamone, J.D.; Correa, M. Adenosine A2A receptor
deletion affects social behaviors and anxiety in mice: Involvement
of anterior cingulate cortex and amygdala. Behav. Brain Res.,  2017, 321, 8-17.
[http://dx.doi.org/10.1016/j.neuropharm.2011.
12.033] [PMID: 22261384] 
[116] 
Halmai, Z.; Dome, P.; Vereczkei, A.; Abdul-Rahman, O.; Szekely, A.; Gonda, X.; Faludi, G.; Sasvari-Szekely, M.; Nemoda, Z. Associations
between depression severity and purinergic receptor
P2RX7 gene polymorphisms. J. Affect. Disord.,  2013, 150(1), 104-9.
[http://dx.doi.org/10.1016/j.jad.2013.02.033] [PMID: 23602648] 
[117] 
Lucae, S.; Salyakina, D.; Barden, N.; Harvey, M.; Gagné, B.; Labbé, M.; Binder, E.B.; Uhr, M.; Paez-Pereda, M.; Sillaber, I.; Ising, M.; Brückl, T.; Lieb, R.; Holsboer, F.; Müller-Myhsok, B. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is
associated with major depressive disorder. Hum. Mol. Genet,  2006, 15(16), 2438-45.
[http://dx.doi.org/10.1093/hmg/ddl166] [PMID: 16822851] 
[118] 
Basso, A.M.; Bratcher, N.A.; Harris, R.R.; Jarvis, M.F.; Decker, M.W.; Rueter, L.E. Behavioral profile of P2X7 receptor knockout
mice in animal models of depression and anxiety: relevance for
neuropsychiatric disorders. Behav. Brain Res,  2009, 198(1), 83-90.
[http://dx.doi.org/10.1016/j.bbr.2008.10.018] [PMID: 18996151] 
[119] 
Otrokocsi, L.; Kittel, A.; Sperlágh, B. P2X7 receptors drive spine
synapse plasticity in the learned helplessness model of depression
research. Int. J. Europsychopharmacol.,  2017, Jun 13.
[http://dx.doi.org/10.1093/ijnp/pyx046] [PMID: 28633291] 
[120] 
Zhang, K.; Liu, J.; You, X.; Kong, P.; Song, Y.; Cao, L.; Yang, S.; Wang, W.; Fu, Q.; Ma, Z. P2X7 as a new target for chrysophanol
to treat lipopolysaccharide-induced depression in mice. Neurosci.
Lett,  2016, 613, 60-5.
[http://dx.doi.org/10.1016/j.neulet.2015.
12.043] [PMID: 26724370] 
[121] 
Yue, N.; Huang, H.; Zhu, X.; Han, Q.; Wang, Y.; Li, B.; Liu, Q.; Wu, G.; Zhang, Y.; Yu, J. Activation of P2X7 receptor and NLRP3
inflammasome assembly in hippocampal glial cells mediates
chronic stress-induced depressive-like behaviors. J. Neuroinflammation,  2017, 14(1), 102.
[http://dx.doi.org/10.1186/s12974-017-
0865-y] [PMID: 28486969] 
[122] 
Csolle, C.; Baranyi, M.; Zsilla, G.; Kittel, A.; Goloncser, F.; Illes, P.; Papp, E.; Vizi, E.S.; Sperlagh, B. Neurochemical changes in the
mouse hippocampus underlying the antidepressant effect of genetic
deletion of P2X7 receptors PLoS One,  2013, 8(6), e66547.
[http://dx.doi.org/10.1371/journal.pone.0066547] [PMID: 23805233] 
[123] 
Ali-Sisto, T.; Tolmunen, T.; Toffol, E.; Viinamaki, H.; Mantyselka, P.; Valkonen-Korhonen, M.; Honkalampi, K.; Ruusunen, A.; Velagapudi, V.; Lehto, S.M. Purine metabolism is dysregulated in patients
with major depressive disorder. Psychoneuroendocrinology,  2016, 70, 25-32.
[http://dx.doi.org/10.1016/j.psyneuen.2016.04.
017] [PMID: 27153521] 
[124] 
Moore, C.M.; Christensen, J.D.; Lafer, B.; Fava, M.; Renshaw, P.F. Lower levels of nucleoside triphosphate in the basal ganglia of depressed
subjects: a phosphorus-31 magnetic resonance spectroscopy
study. Am. J. Psychiatry,  1997, 154(1), 116-18.
[http://dx.doi.org/10.1176/ajp.154.1.116] [PMID: 8988971] 
[125] 
Manji, H.; Kato, T.; Di Prospero, N.A.; Ness, S.; Beal, M.F.; Krams, M.; Chen, G. Impaired mitochondrial function in psychiatric
disorders. Nat. Rev. Neurosci,  2012, 13(5), 293-307.
[http://dx.doi.org/10.1038/nrn3229] [PMID: 22510887] 
[126] 
Sharma, R.K.; Candelario-Jalil, E.; Feineis, D.; Bringmann, G.; Fiebich, B.L.; Akundi, R.S. 1-trichloromethyl-1,2,3,4-tetrahydrobeta-
carboline (TaClo) alters cell cycle progression in human neuroblastoma
cell lines. Neurotox. Res,  2017, 32, 649-660.
[http://dx.doi.org/10.1007/s12640-017-9782-1] [PMID: 28721631] 
[127] 
Akundi, R.S.; Macho, A.; Munoz, E.; Lieb, K.; Bringmann, G.; Clement, H.W.; Hull, M.; Fiebich, B.L. 1-trichloromethyl-1,2,3,4-
tetrahydro-beta-carboline-induced apoptosis in the human neuroblastoma
cell line SK-N-SH. J. Neurochem,  2004, 91, 263-273.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02710.x] [PMID: 15447660] 
[128] 
Gash, D.M.; Rutland, K.; Hudson, N.L.; Sullivan, P.G.; Bing, G.; Cass, W.A.; Pandya, J.D.; Liu, M.; Choi, D.Y.; Hunter, R.L.; Gerhardt, G.A.; Smith, C.D.; Slevin, J.T.; Prince, T.S. Trichloroethylene: parkinsonism and complex I mitochondrial neurotoxicity. Ann. Neurol,  2008, 63, 184-192.
[http://dx.doi.org/10.1002/ana.21288] [PMID: 18157908] 
[129] 
Leemans, J.C.; Cassel, S.L.; Sutterwala, F.S. Sensing damage by
the NLRP3 inflammasome. Immunol. Rev.,  2011, 243(1), 152-62.
[http://dx.doi.org/10.1111/j.1600-065X.2011.01043.x] [PMID: 21884174] 
[130] 
Su, W.J.; Zhang, Y.; Chen, Y.; Gong, H.; Lian, Y.J.; Peng, W.; Liu, Y.Z.; Wang, Y.X.; You, Z.L.; Feng, S.J.; Zong, Y.; Lu, G.C.; Jiang, C.L. NLRP3 gene knockout blocks NF-κB and MAPK signaling
pathway in CUMS-induced depression mouse model. Behav. Brain.
Res.,  2017, 322(Pt A), 1-8.
[http://dx.doi.org/10.1016/j.bbr.2017.
01.018] [PMID: 28093255] 
[131] 
Iwata, M.; Ota, K.T.; Li, X.Y.; Sakaue, F.; Li, N.; Dutheil, S.; Banasr, M.; Duric, V.; Yamanashi, T.; Kaneko, K.; Rasmussen, K.; Glasebrook, A.; Koester, A.; Song, D.; Jones, K.A.; Zorn, S.; Smagin, G.; Duman, R.S. Psychological stress activates the inflammasome
via release of adenosine triphosphate and stimulation
of the purinergic type 2 × 7 receptor. Biol. Psychiatry,  2016, 80(1), 12-22.
[http://dx.doi.org/10.1016/j.biopsych. 2015.11.026] [PMID: 26831917] 
[132] 
Tan, S.; Wang, Y.; Chen, K.; Long, Z.; Zou, J. Ketamine alleviates
depressive-like behaviours via down-regulating inflammatory cytokines
induced by chronic restrain stress in mice. Biol. Pharm.
Bull,  2017, 40(8), 1260-67.
[http://dx.doi.org/10.1248/bpb.b17-
00131] [PMID: 28769008] 
[133] 
Chang, Y.; Lee, J.J.; Hsieh, C.Y.; Hsiao, G.; Chou, D.S.; Sheu, J.R. Inhibitory effects of ketamine on lipopolysaccharide-induced microglial
activation. Mediators Inflamm,  2009, 2009, 705379.
[http://dx.doi.org/10.1155/2009/705379] [PMID: 19343193] 
[134] 
Chang, H.C.; Lin, K.H.; Tai, Y.T.; Chen, J.T.; Chen, R.M. Lipoteichoic
acid-induced TNF-α and IL-6 gene expressions and oxidative
stress production in macrophages are suppressed by ketamine
through downregulating Toll-like receptor 2-mediated activation of
ERK1/2 and NFκB. Shock,  2010, 33, 485-92.
[http://dx.doi.org/10.1097/SHK.0b013e3181c3cea5] [PMID: 19823118] 
[135] 
Yuhas, Y.; Ashkenazi, S.; Berent, E.; Weizmann, A. Immunomodulatory
activity of ketamine in human astroglial A172 cells:
possible relevance to its rapid antidepressant activity. J. Neuroimmunol,  2015, 282, 33-38.
[http://dx.doi.org/10.1016/j.jneuroim.
2015.03.012] [PMID: 25903726] 
[136] 
Sadatomi, D.; Nakashioya, K.; Mamiya, S.; Honda, S.; Kameyama, Y.; Yamamura, Y.; Tanimura, S.; Takeda, K. Mitochondrial function
is required for extracellular ATP-induced NLRP3 inflammasome
activation. J. Biochem,  2017, 161(6), 503-12.
[http://dx.doi.org/10.1093/jb/mvw098] [PMID: 28096454] 
[137] 
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria
in NLRP3 inflammasome activation. Nature,  2011, 469(7329), 221-5.
[http://dx.doi.org/10.1038/nature09663] [PMID: 21124315] 
[138] 
Tannahill, G.M.; Curtis, A.M.; Adamik, J.; Palsson-McDermott, E.M.; McGettrick, A.F.; Goel, G.; Frezza, C.; Bernard, N.J.; Kelly, B.; Foley, N.H.; Zheng, L.; Gardet, A.; Tong, Z.; Jany, S.S.; Corr, S.C.; Haneklaus, M.; Caffrey, B.E.; Pierce, K.; Walmsley, S.; Beasley, F.C.; Cummins, E.; Nizet, V.; Whyte, M.; Taylor, C.T.; Lin, H.; Masters, S.L.; Gottlieb, E.; Kelly, V.P.; Clish, C.; Auron, P.E.; Xavier, R.J.; O'Neill, L.A. Succinate is an inflammatory signal that
induces IL-1β through HIF-1α. Nature,  2013, 496(7444), 238-42.
[http://dx.doi.org/10.1038/nature11986] [PMID: 23535595] 
[139] 
Lepine, J.P.; Briley, M. The increasing burden of depression. Neuropsychiatr.
Dis. Treat.,  2011, 7(Suppl 1), 3-7.
[http://dx.doi.org/10.2147/NDT.S19617] [PMID: 21750622] 
[140] 
Levy, M.; Faas, G.C.; Saggau, P.; Craigen, W.J.; Sweatt, J.D. Mitochondrial
regulation of synaptic plasticity in the hippocampus J.
Biol. Chem,  2003, 278(20), 17727-34.
[http://dx.doi.org/10.1074/
jbc.M212878200] [PMID: 12604600] 
[141] 
Kleinridders, A.; Cai, W.; Cappellucci, L.; Ghazarian, A.; Collins, W.R.; Vienberg, S.G.; Pothos, E.N.; Kahn, C.R. Insulin resistance
in brain alters dopamine turnover and causes behavioural disorders. Proc. Natl. Acad. Sci. U.S.A.,  2015, 112(11), 3463-8.
[http://dx.doi.org/10.1073/pnas1500877112] [PMID: 25733901] 
[142] 
Koizumi, S.; Shigemoto-Mogami, Y.; Nasu-Tada, K.; Shinozaki, Y.; Ohsawa, K.; Tsuda, M.; Joshi, B.V.; Jacobson, K.A.; Kohsaka, S.; Inoue, K. UDP acting at P2Y6 receptors is a mediator of microglial
phagocytosis. Nature,  2007, 446(7139), 1091-5.
[http://dx.doi.org/10.1038/nature05704] [PMID: 17410128] 
[143] 
Haynes, S.E.; Hollopeter, G.; Yang, G.; Kurpius, D.; Dailey, M.E.; Gan, W.B.; Julius, D. The P2Y12 receptor regulates microglial activation
by extracellular nucleotides. Nat. Neurosci,  2006, 9(12), 1512-9.
[http://dx.doi.org/10.1038/nn1805] [PMID: 17115040] 
[144] 
Xia, M.; Zhu, Y. Signaling pathways of ATP-induced PGE2 release
in spinal cord astrocytes are EGFR transactivation-dependent. Glia,  2011, 59(4), 664-74.
[http://dx.doi.org/10.1002/glia.21138] [PMID: 21294165] 
[145] 
Cavaliere, F.; Florenzano, F.; Amadio, S.; Fusco, F.R.; Viscomi, M.T.; D’Ambrosi, N.; Vacca, F.; Sancesario, G.; Bernardi, G.; Molinari, M.; Volonte, C. Upregulation of P2X2, P2X4 receptor
and ischemic cell death: prevention by P2 antagonists. Neuroscience,  2003, 120(1), 85-98.
[http://dx.doi.org/10.1016/S0306-
4522(03)00228-8] [PMID: 12849743] 
[146] 
Verma, R.; Cronin, C.G.; Hudobenko, J.; Venna, V.R.; McCullough, L.D.; Liang, B.T. Deletion of P2X4 receptor is neuroprotective
acutely.; but induces a depressive phenotype during
recovery from ischemic stroke. Brain Behav. Immun, 2017.
[http://dx.doi.org/10.1016/j.bbi.2017.07.155] [PMID: 28751018] 
[147] 
Kaster, M.P.; Machado, N.J.; Silva, H.B.; Nunes, A.; Ardais, A.P.; Santana, M.; Baqi, Y.; Müller, C.E.; Rodrigues, A.L.; Porciúncula, L.O.; Chen, JF.; Tomé, Â.R.; Agostinho, P.; Canas, P.M.; Cunha, R.A. Caffeine acts through neuronal adenosine A2A receptors to
prevent mood and memory dysfunction triggered by chronic stress. Proc. Natl. Acad. Sci. U.S.A.,  2015, 112(25), 7833-8.
[http://dx.doi.org/10.1073/ pnas.1423088112] [PMID: 26056314] 
[148] 
Gonçalves, F.M.; Neis, V.B.; Rieger, D.K.; Lopes, M.W.; Heinrich, I.A.; Costa, A.P.; Rodrigues, A.L.S.; Kaster, M.P.; Leal, R.B. Signaling
pathways underlying the antidepressant-like effect of inosine
in mice. Purinergic. Signal,  2017, 13(2), 203-14.
[http://dx.doi.org/10.1007/s11302-016-9551-2] [PMID: 27966087] 
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DOI https://dx.doi.org/10.2174/1570159X16666180302120322	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

Mitochondria: A Connecting Link in the Major Depressive Disorder Jigsaw

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