Abstract
Background: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons.
Method: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. Results: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. Conclusion: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.Keywords: Fibroblast growth factor 2, schizophrenia, hyperbilirubinemia, Gunn rat, neuroinflammation, Unconjugated Bilirubin (UCB).
Graphical Abstract
[1]
Windebank KP. The cytokines are coming. Arch Dis Child 1990; 65(11): 1283-5.
[http://dx.doi.org/10.1136/adc.65.11.1283] [PMID: 2248547]
[http://dx.doi.org/10.1136/adc.65.11.1283] [PMID: 2248547]
[2]
Galvez-Contreras AY, Campos-Ordonez T, Lopez-Virgen V, Gomez-Plascencia J, Ramos-Zuniga R, Gonzalez-Perez O. Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders. Cytokine Growth Factor Rev 2016; 32: 85-96.
[http://dx.doi.org/10.1016/j.cytogfr.2016.08.004] [PMID: 27618303]
[http://dx.doi.org/10.1016/j.cytogfr.2016.08.004] [PMID: 27618303]
[3]
Nurjono M, Lee J, Chong SA. Review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci 2012; 10(2): 61-70.
[http://dx.doi.org/10.9758/cpn.2012.10.2.61] [PMID: 23431036]
[http://dx.doi.org/10.9758/cpn.2012.10.2.61] [PMID: 23431036]
[4]
Terwisscha van Scheltinga AF, Bakker SC, Kahn RS. Fibroblast growth factors in schizophrenia. Schizophr Bull 2010; 36(6): 1157-66.
[http://dx.doi.org/10.1093/schbul/sbp033] [PMID: 19429845]
[http://dx.doi.org/10.1093/schbul/sbp033] [PMID: 19429845]
[5]
Turner CA, Akil H, Watson SJ, Evans SJ. The fibroblast growth factor system and mood disorders. Biol Psychiatry 2006; 59(12): 1128-35.
[http://dx.doi.org/10.1016/j.biopsych.2006.02.026] [PMID: 16631131]
[http://dx.doi.org/10.1016/j.biopsych.2006.02.026] [PMID: 16631131]
[6]
Okada-Ban M, Thiery JP, Jouanneau J. Fibroblast growth factor-2. Int J Biochem Cell Biol 2000; 32(3): 263-7.
[http://dx.doi.org/10.1016/S1357-2725(99)00133-8] [PMID: 10716624]
[http://dx.doi.org/10.1016/S1357-2725(99)00133-8] [PMID: 10716624]
[7]
Hashimoto K, Shimizu E, Komatsu N, et al. Increased levels of serum basic fibroblast growth factor in schizophrenia. Psychiatry Res 2003; 120(3): 211-8.
[http://dx.doi.org/10.1016/S0165-1781(03)00186-0] [PMID: 14561432]
[http://dx.doi.org/10.1016/S0165-1781(03)00186-0] [PMID: 14561432]
[8]
Li XS, Wu HT, Yu Y, et al. Increased serum FGF2 levels in first-episode, drug-free patients with schizophrenia. Neurosci Lett 2018; 686: 28-32.
[http://dx.doi.org/10.1016/j.neulet.2018.08.046] [PMID: 30172685]
[http://dx.doi.org/10.1016/j.neulet.2018.08.046] [PMID: 30172685]
[9]
Miyaoka T, Seno H, Itoga M, Iijima M, Inagaki T, Horiguchi J. Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert’s syndrome). J Clin Psychiatry 2000; 61(11): 868-71.
[http://dx.doi.org/10.4088/JCP.v61n1110] [PMID: 11105741]
[http://dx.doi.org/10.4088/JCP.v61n1110] [PMID: 11105741]
[10]
Radhakrishnan R, Kanigere M, Menon J, Calvin S, Janish A, Srinivasan K. Association between unconjugated bilirubin and schizophrenia. Psychiatry Res 2011; 189(3): 480-2.
[http://dx.doi.org/10.1016/j.psychres.2011.03.003] [PMID: 21470692]
[http://dx.doi.org/10.1016/j.psychres.2011.03.003] [PMID: 21470692]
[11]
Hayashida M, Miyaoka T, Tsuchie K, et al. Hyperbilirubinemia-related behavioral and neuropathological changes in rats: a possible schizophrenia animal model. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(4): 581-8.
[http://dx.doi.org/10.1016/j.pnpbp.2009.02.013] [PMID: 19249333]
[http://dx.doi.org/10.1016/j.pnpbp.2009.02.013] [PMID: 19249333]
[12]
Gunn CK. Hereditary acholuric jaundice in the rat. Can Med Assoc J 1944; 50(3): 230-7.
[PMID: 20323028]
[PMID: 20323028]
[13]
Furuya M, Miyaoka T, Tsumori T, et al. Yokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat. J Neuroinflammation 2013; 10: 145.
[http://dx.doi.org/10.1186/1742-2094-10-145] [PMID: 24305622]
[http://dx.doi.org/10.1186/1742-2094-10-145] [PMID: 24305622]
[14]
Limoa E, Hashioka S, Miyaoka T, et al. Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat. J Neuroinflammation 2016; 13(1): 230.
[http://dx.doi.org/10.1186/s12974-016-0688-2] [PMID: 27590010]
[http://dx.doi.org/10.1186/s12974-016-0688-2] [PMID: 27590010]
[15]
Liaury K, Miyaoka T, Tsumori T, et al. Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model. J Neuroinflammation 2012; 9: 56.
[http://dx.doi.org/10.1186/1742-2094-9-56] [PMID: 22424389]
[http://dx.doi.org/10.1186/1742-2094-9-56] [PMID: 22424389]
[16]
Liaury K, Miyaoka T, Tsumori T, et al. Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: a possible hyperbilirubinemia-induced animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2014; 50: 184-90.
[http://dx.doi.org/10.1016/j.pnpbp.2013.12.017] [PMID: 24389395]
[http://dx.doi.org/10.1016/j.pnpbp.2013.12.017] [PMID: 24389395]
[17]
Tsuchie K, Miyaoka T, Furuya M, et al. The effects of antipsychotics on behavioral abnormalities of the Gunn rat (unconjugated hyperbilirubinemia rat), a rat model of schizophrenia. Asian J Psychiatr 2013; 6(2): 119-23.
[http://dx.doi.org/10.1016/j.ajp.2012.09.007] [PMID: 23466107]
[http://dx.doi.org/10.1016/j.ajp.2012.09.007] [PMID: 23466107]
[18]
Wesseling H, Want EJ, Guest PC, Rahmoune H, Holmes E, Bahn S. Hippocampal proteomic and metabonomic abnormalities in neurotransmission, oxidative stress, and apoptotic pathways in a chronic phencyclidine rat model. J Proteome Res 2015; 14(8): 3174-87.
[http://dx.doi.org/10.1021/acs.jproteome.5b00105] [PMID: 26043028]
[http://dx.doi.org/10.1021/acs.jproteome.5b00105] [PMID: 26043028]
[19]
Bachis A, Mallei A, Cruz MI, Wellstein A, Mocchetti I. Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons. Neuropharmacology 2008; 55(7): 1114-20.
[http://dx.doi.org/10.1016/j.neuropharm.2008.07.014] [PMID: 18682257]
[http://dx.doi.org/10.1016/j.neuropharm.2008.07.014] [PMID: 18682257]
[20]
Riva MA, Molteni R, Tascedda F, Massironi A, Racagni G. Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine. Neuropharmacology 1999; 38(7): 1075-82.
[http://dx.doi.org/10.1016/S0028-3908(99)00031-3] [PMID: 10428426]
[http://dx.doi.org/10.1016/S0028-3908(99)00031-3] [PMID: 10428426]
[21]
Detillieux KA, Sheikh F, Kardami E, Cattini PA. Biological activities of fibroblast growth factor-2 in the adult myocardium. Cardiovasc Res 2003; 57(1): 8-19.
[http://dx.doi.org/10.1016/S0008-6363(02)00708-3] [PMID: 12504809]
[http://dx.doi.org/10.1016/S0008-6363(02)00708-3] [PMID: 12504809]
[22]
Woodbury ME, Ikezu T. Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J Neuroimmune Pharmacol 2014; 9(2): 92-101.
[http://dx.doi.org/10.1007/s11481-013-9501-5] [PMID: 24057103]
[http://dx.doi.org/10.1007/s11481-013-9501-5] [PMID: 24057103]
[23]
Deguchi Y, Okutsu H, Okura T, et al. Internalization of basic fibroblast growth factor at the mouse blood-brain barrier involves perlecan, a heparan sulfate proteoglycan. J Neurochem 2002; 83(2): 381-9.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01129.x] [PMID: 12423248]
[http://dx.doi.org/10.1046/j.1471-4159.2002.01129.x] [PMID: 12423248]
[24]
Turner CA, Clinton SM, Thompson RC, Watson SJ Jr, Akil H. Fibroblast Growth Factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals. Proc Natl Acad Sci USA 2011; 108(19): 8021-5.
[http://dx.doi.org/10.1073/pnas.1103732108] [PMID: 21518861]
[http://dx.doi.org/10.1073/pnas.1103732108] [PMID: 21518861]
[25]
Yoshimura S, Takagi Y, Harada J, et al. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 2001; 98(10): 5874-9.
[http://dx.doi.org/10.1073/pnas.101034998] [PMID: 11320217]
[http://dx.doi.org/10.1073/pnas.101034998] [PMID: 11320217]
[26]
Werner S, Unsicker K. von Bohlen und Halbach O. Fibroblast growth factor-2 deficiency causes defects in adult hippocampal neurogenesis, which are not rescued by exogenous fibroblast growth factor-2. J Neurosci Res 2011; 89(10): 1605-17.
[http://dx.doi.org/10.1002/jnr.22680] [PMID: 21800348]
[http://dx.doi.org/10.1002/jnr.22680] [PMID: 21800348]
[27]
Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302(5651): 1760-5.
[http://dx.doi.org/10.1126/science.1088417] [PMID: 14615545]
[http://dx.doi.org/10.1126/science.1088417] [PMID: 14615545]
[28]
Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther 2012; 19(7): 724-33.
[http://dx.doi.org/10.1038/gt.2011.126] [PMID: 21918553]
[http://dx.doi.org/10.1038/gt.2011.126] [PMID: 21918553]
[29]
Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 2007; 27(31): 8309-13.
[http://dx.doi.org/10.1523/JNEUROSCI.1781-07.2007] [PMID: 17670977]
[http://dx.doi.org/10.1523/JNEUROSCI.1781-07.2007] [PMID: 17670977]
[30]
Jin K, LaFevre-Bernt M, Sun Y, et al. FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 2005; 102(50): 18189-94.
[http://dx.doi.org/10.1073/pnas.0506375102] [PMID: 16326808]
[http://dx.doi.org/10.1073/pnas.0506375102] [PMID: 16326808]
[31]
Seubert JM, Darmon AJ, El-Kadi AO, D’Souza SJ, Bend JR. Apoptosis in murine hepatoma hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin. Mol Pharmacol 2002; 62(2): 257-64.
[http://dx.doi.org/10.1124/mol.62.2.257] [PMID: 12130676]
[http://dx.doi.org/10.1124/mol.62.2.257] [PMID: 12130676]
[32]
Qaisiya M, Coda Zabetta CD, Bellarosa C, Tiribelli C. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal 2014; 26(3): 512-20.
[http://dx.doi.org/10.1016/j.cellsig.2013.11.029] [PMID: 24308969]
[http://dx.doi.org/10.1016/j.cellsig.2013.11.029] [PMID: 24308969]
[33]
Inta D, Lang UE, Borgwardt S, Meyer-Lindenberg A, Gass P. Microglia activation and schizophrenia: lessons from the effects of minocycline on postnatal neurogenesis, neuronal survival and synaptic pruning. Schizophr Bull 2017; 43(3): 493-6.
[PMID: 27352782]
[PMID: 27352782]
[34]
Trépanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP. Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review. Mol Psychiatry 2016; 21(8): 1009-26.
[http://dx.doi.org/10.1038/mp.2016.90] [PMID: 27271499]
[http://dx.doi.org/10.1038/mp.2016.90] [PMID: 27271499]
[35]
Baron O, Ratzka A, Grothe C. Fibroblast growth factor 2 regulates adequate nigrostriatal pathway formation in mice. J Comp Neurol 2012; 520(17): 3949-61.
[http://dx.doi.org/10.1002/cne.23138] [PMID: 22592787]
[http://dx.doi.org/10.1002/cne.23138] [PMID: 22592787]
[36]
Grothe C, Timmer M. The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system. Brain Res Brain Res Rev 2007; 54(1): 80-91.
[http://dx.doi.org/10.1016/j.brainresrev.2006.12.001] [PMID: 17229467]
[http://dx.doi.org/10.1016/j.brainresrev.2006.12.001] [PMID: 17229467]
[37]
Thompson JL, Pogue-Geile MF, Grace AA. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr Bull 2004; 30(4): 875-900.
[http://dx.doi.org/10.1093/oxfordjournals.schbul.a007139] [PMID: 15954196]
[http://dx.doi.org/10.1093/oxfordjournals.schbul.a007139] [PMID: 15954196]
[38]
Fontan A, Rojo A, Sanchez Pernaute R, et al. Effects of fibroblast growth factor and glial-derived neurotrophic factor on akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates. Parkinsonism Relat Disord 2002; 8(5): 311-23.
[http://dx.doi.org/10.1016/S1353-8020(02)00005-6] [PMID: 15177060]
[http://dx.doi.org/10.1016/S1353-8020(02)00005-6] [PMID: 15177060]
[39]
Ohkubo Y, Uchida AO, Shin D, Partanen J, Vaccarino FM. Fibroblast growth factor receptor 1 is required for the proliferation of hippocampal progenitor cells and for hippocampal growth in mouse. J Neurosci 2004; 24(27): 6057-69.
[http://dx.doi.org/10.1523/JNEUROSCI.1140-04.2004] [PMID: 15240797]
[http://dx.doi.org/10.1523/JNEUROSCI.1140-04.2004] [PMID: 15240797]
[40]
van den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 2010; 36(2): 246-70.
[http://dx.doi.org/10.1093/schbul/sbp132] [PMID: 19900963]
[http://dx.doi.org/10.1093/schbul/sbp132] [PMID: 19900963]