Decreased VEGF mRNA expression in the dorsolateral prefrontal cortex of schizophrenia subjects

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<ul><li><p>Schizophrenia Research 115 (2009) 372373</p><p>Contents lists available at ScienceDirect</p><p>nia</p><p>.e lswith an initial incubation at 55 C for 1200 s, then at 95 C for120 s followed by 35 cycles of 95 C for 15 s, 50 C for 30 s,72 C for 30 s and nal melting curve from 55 C to 95 C with</p><p>drugs, haloperidol and olanzapine, time-dependently reg-ulate VEGF protein levels in neurogenic area, hippocampus(Pillai and Mahadik, 2006). VEGF signaling has been shownLetter to the Editors</p><p>Decreased VEGF mRNA expression in the dorsolateralprefrontal cortex of schizophrenia subjects</p><p>Dear Editors,</p><p>In addition to the dysfunctional neural plasticity, changesin brain cellular energy metabolism and blood ow are alsoobserved in the prefrontal cortex of schizophrenia subjects(Hanson and Gottesman, 2005). Moreover, studies havefound that the various positive and negative symptomdimensions observed in subjects with schizophrenia areassociated with specic patterns of the regional blood ow(Andreasen et al., 1997; Wiser et al., 1998). Vascular en-dothelial growth factor (VEGF) is an angiogenetic factorinvolved in the regulation of blood ow and has neuro-trophic and neuroprotective properties (Greenberg and Jin,2005). A defect in VEGF gene expression would therefore beexpected to inuence the pathophysiology of schizophrenia.However, there is no previous report demonstrating theexpression of VEGF in schizophrenia subjects. In this study,we examined the mRNA levels of VEGF in the dorsolateralprefrontal cortex samples from schizophrenia and controlsubjects.</p><p>RNA samples from postmortem brain specimens, Brod-mann's area 46 (in the DLPFC), from 16 individuals withschizophrenia, and 18 psychiatrically normal controls wereobtained from the Stanley Array Collection. A description ofthe demographics is given in Supplementary Table 1. Real-time quantitative RT-PCR was performed on a SmartCycler(Cepheid, Sunnyvale, CA) using a SuperScript III PlatinumSYBR Green One-Step qRT-PCR kit (Invitrogen, Carlsbad, CA).Master mixes were prepared and used in the PCR amplica-tions. A typical reaction of a total volume of 25 l consisted of0.5 l Superscript III RT/Platinum Taq mix, 12.5 l 2X SYBRGreen Reaction Mix (includes 0.4 mM of each dNTP and6 mM MgSO4), 12.5 pMol of each of forward or reverseprimers and 5 l DEPC-treated water. Approximately 0.51.0 g RNAwas used as template. PCR amplicationwas done</p><p>Schizophre</p><p>j ourna l homepage: www0.2 C/s. The standard curve used for determining the relativequantity in each sample was constructed by the amplica-tion of serial dilutions of cDNA. Primer specicity wasconrmed by melting curve analysis and electrophoresis ofPCR products on a 2% agarose gel to conrm the presence of a</p><p>0920-9964/$ see front matter 2009 Elsevier B.V. All rights reserved.doi:10.1016/j.schres.2009.06.005single band of the predicted size. All measurements wereperformed in triplicates. The data were normalized to twocontrol genes (glyceraldehyde 3-phosphate dehydrogenase(GAPDH) and b-actin) and a geometric mean of these genes.Primers utilized are listed in Supplementary Table 2. Statis-tical analyses were conducted using Statistica (STATISTICA(data analysis software system) version 8.0 ( Forward stepwise multiple-regression ana-lyses were used for determining the contribution of demo-graphic, tissue- and disease-related variables to the geneexpression levels. Comparisons between diagnostic groupswere made using Student's t-test.</p><p>A signicant reduction in mean VEGF mRNA levels wasobserved in the schizophrenia (p=0.010) compared to thecontrol group (Fig. 1). Our analyses showed that alcohol usehistory was the only factor that signicantly correlated to thenormalized VEGF mRNA levels in these study subjects(Supplementary Table 3).</p><p>This is the rst time report on the expression of VEGF,a key mediator in angiogenesis and neurogenesis, in schizo-phrenia. Endogenous VEGF production is important forthe maintenance of the vasculature in various physiologicaland pathological processes (Greenberg and Jin, 2005).VEGF immunoreactivity is primarily associated with astro-cytes, which serve as a source of VEGF to promote prolifera-tion and activation of endothelial cells and therebyangiogenesis (Pillai and Mahadik, 2006). But, it is still notclear whether alterations in blood ow cause changes inneuronal-glial function or vice versa. It has been suggestedthat the increased neuronal ring alter the demand foroxygen and glucose, which then trigger/stimulate vasodila-tion and increased cerebral blood ow (Villringer andDirnagl, 1995). Although there are not many studies doneso far investigating the direct visualization of the vascularsystem in schizophrenia, one study has reported atypicallysimplied angioarchitecture and failure of normal arboriza-tion of brain vessels in schizophrenia (Senitz and Winkel-mann, 1991).</p><p>Our earlier study in rats has shown that antipsychotic</p><p>Research</p><p>ev ie locate /schresto mediate the antidepressant actions in rodents (Warner-Schmidt and Duman, 2007). Furthermore, both antipsycho-tics and antidepressants are known to increase proliferationof neuronal as well as endothelial cells (Newton and Duman,2007). Thus, the potential of VEGF signaling to increase</p></li><li><p>References</p><p>Andreasen, N.C., O'Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., BolesPonto, L.L., Hichwa, R.D., 1997. Hypofrontality in schizophrenia: dis-tributed dysfunctional circuits in neuroleptic-nave patients. Lancet 349,17301734.</p><p>Greenberg, D.A., Jin, K., 2005. From angiogenesis to neuropathology. Nature438, 954959.</p><p>Hanson, D.R., Gottesman, I.I., 2005. Theories of schizophrenia: a genetic-inammatory-vascular synthesis. BMC Med. Genet. 6, 7.</p><p>Newton, S.S., Duman, R.S., 2007. Neurogenic actions of atypical antipsychoticdrugs and therapeutic implications. CNS Drugs 21 (9), 715725.</p><p>Pillai, A., Mahadik, S.P., 2006. Differential effects of haloperidol andolanzapine on levels of vascular endothelial growth factor andangiogenesis in rat hippocampus. Schizophr. Res. 87, 4859.</p><p>Senitz, D., Winkelmann, E., 1991. Neuronal structure abnormality in theorbito-frontal cortex of schizophrenics. J. Hirnforsch. 32, 149158.</p><p>Villringer, A., Dirnagl, U., 1995. Coupling of brain activity and cerebral bloodow: basis of functional neuroimaging. Cerebrovasc. Brain Metab. Rev.7 (3), 240276 Fall.</p><p>Warner-Schmidt, J.L., Duman, R.S., 2007. VEGF is an essential mediator of theneurogenic and behavioral actions of antidepressants. Proc. Natl. Acad.Sci. U. S. A. 104, 46474652.</p><p>Wiser, A.K., Andreasen, N.C., O'Leary, D.S., Watkins, G.L., Boles Ponto, L.L.,Hichwa, R.D., 1998. Dysfunctional cortico-cerebellar circuits causecognitive dysmetria in schizophrenia. Neuroreport 9, 18951899.</p><p>Fig. 1. VEGF expression in the dorsolateral prefrontal cortex of control andschizophrenia subjects. VEGF mRNA, measured by qRTPCR (quantitativereverse transcription-PCR) and normalized to the geometric mean of twohousekeeping transcripts (-actin, GAPDH), is decreased in subjects withschizophrenia. Values are expressed as meanSEM. The number ofindividuals per sample is indicated within each bar.</p><p>373Letter to the Editorstarget for psychiatric disorders such as schizophrenia anddepression.</p><p>Role of funding sourceNone.</p><p>ContributorsPillai designed the research. Fulzele performed the research. Pillai and</p><p>Fulzele analyzed the data and Pillai wrote the paper.</p><p>Conict of interestNone.</p><p>AcknowledgmentsRNA samples were donated by The Stanley Medical Research Institute's</p><p>brain collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J.Webster, and Robert H. Yolken.</p><p>Appendix A. Supplementary data</p><p>Supplementarydata associatedwith this article canbe found,in the online version, at doi:10.1016/j.schres.2009.06.005.Sadanand FulzeleDepartment of Orthopedic Surgery,</p><p>Medical College of Georgia, Augusta, GA, USA</p><p>Anilkumar PillaiDepartment of Psychiatry and Health Behavior,</p><p>Medical College of Georgia and Medical Research Service Line,Veterans Affairs Medical Center, Augusta, GA, USA</p><p>Corresponding author. Department of Psychiatry and HealthBehavior, Medical College of Georgia,</p><p>997 St. Sebastian Way, Augusta, GA 30912, USA.Tel.: +1 706 721 7793; fax: +1 706 823 3949.</p><p>E-mail address:</p><p>8 April 2009both angiogenesis and neurogenesis make it as a novel drug</p><p>Decreased VEGF mRNA expression in the dorsolateral prefrontal cortex of schizophrenia subjectsRole of funding sourceContributorsConflict of interestAcknowledgmentsSupplementary dataReferences</p></li></ul>


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