Psychiatry and Clinical Neurosciences 2014; 68: 133–136
doi:10.1111/pcn.12099
Regular Article
New molecule in the etiology of schizophrenia: Urotensin II Feridun Bulbul, MD,1* Gokay Alpak, MD,1 Ahmet Unal, MD,1 Umit Sertan Copoglu, Mustafa Orkmez, MD,2 Osman Virit, MD,1 Mehmet Tarkcıoglu, PhD2 and Haluk A. Savas, PhD, MD1
MD,3
Departments of 1Psychiatry and 2Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep and 3Ceylanpinar State Hospital, Sanliurfa, Turkey
Aims: Urotensin II (U-II) is a cyclic peptide that was first isolated from the caudal neurosecretory system of goby fish. U-II receptors were detected in the vascular endothelium, brain and kidney cortex. Urotensin is by far the most powerful vasoconstrictor identified. U-II molecules were previously isolated from the brain of rats and were shown to have an impact on rat behavior. The aim of the present study was to measure the level of U-II molecule in schizophrenia patients and to investigate whether the U-II level is associated with the etiology of schizophrenia. Methods: Forty schizophrenia patients who were followed at Gaziantep University Faculty of Medicine Department of Psychiatry Psychotic Disorders Unit and 40 healthy volunteers were enrolled in this study. Blood samples were taken from the
CHIZOPHRENIA IS A chronic disease that causes the majority of disabilities among all psychiatric diseases, and its prevalence is 1%.1Positive, negative and cognitive signs and symptoms may be observed in schizophrenia.2 In the etiology of schizophrenia, genetic, biochemical, oxidative and environmental factors are involved.3 Urotensin II (U-II) is a cyclic peptide that was first isolated from the caudal neurosecretory system of the round goby fish in 1969.4 U-II consists of 11 aminoacids.5 U-II receptors have been detected in
S
*Correspondence: Feridun Bulbul, MD, Department of Psychiatry, Faculty of Medicine, Gaziantep University, 27310 S¸ahinbey, Gaziantep, Turkey. Email: [email protected] Received 19 April 2013; revised 10 June 2013; accepted 25 July 2013.
antecubital vein after 12-h fasting. U-II level was measured on ELISA.
Results: The U-II level in schizophrenia patients was significantly higher than in the control group. U-II level was not different with regard to gender in either group. U-II level was not different between subgroups of schizophrenia. No significant correlation was found between U-II level, Positive and Negative Syndrome Scale and Clinical Global Impression– Severity scale scores. Conclusion: U-II level was higher in schizophrenia patients, indicating that U-II level may be related to the etiology of the disease. Key words: new molecule, oxidative stress, pathogenesis, schizophrenia, urotensin II.
vascular endothelium, myocardium, smooth muscle and skeletal muscle, adrenal glands, thyroid and renal cortex.6 U-II is the most potent vasoconstrictor substance that has been described to date.7 U-II receptor activation acts via binding to the G protein Gq/11 family.7 Stimulation of the U-II receptor by U-II increases the intracellular inflow of Ca+2 by increasing the turnover of phosphoinositide.8 U-II and U-II receptors were isolated from the central nervous system of the rat.9 Immunoreactivity of the U-II receptor was detected in hippocampus, hypothalamus and thalamus.10 In rats, intracerebrovascular injection of U-II resulted in several behavioral, cardiovascular, motor and endocrine responses.9 In the rat, following the intracerebrovascular injection of U-II, plasma levels of thyroid-stimulating hormone and prolactin were increased but corticosterone level was not
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
133
134 F. Bulbul et al.
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
Table 1. Subject characteristics (mean ± SD)
Age (years) Sex (M/F) Duration of illness (years) PANSS CGI-S BMI
Schizophrenia
Control
P
37 ± 9.6 20/20 12.17 ± 9.25
37 ± 10 19/21
0.99
74.1 ± 35.57 4.48 ± 2.12 2.68 ± 0.85
BMI, body mass index; CGI-S, Clinical Global Impression–Severity scale; PANSS, Positive and Negative Syndrome Scale.
affected.11 Behavioral effects of U-II are thought to generally result from cholinergic activation. Cholinergic regulation of U-II is suggested to be mediated by the mesopontine tegmentum region.12 In heart failure, renal failure, diabetes mellitus and hepatic disease, in the etiologies of which several oxidative and immunologic mechanisms are involved, plasma U-II level was found to be elevated.6,7,10 It has been shown that oxidative and immunological mechanisms can take a role in schizophrenia etiology.13,14 U-II molecules were previously isolated from the brain of the rat and were shown to have an impact on rat behavior. The aim of the present study was to measure U-II level in schizophrenia patients and to investigate whether U-II level is associated with the etiology of schizophrenia.
samples were collected from the antecubital vein following a 12-h fasting period. Blood samples collected in the serum separating tubes (SST) from the patients and from the controls were left for 1 h at room temperature up to coagulation, thereafter, they were centrifuged at 1000 g for 15 min and ultimately, the samples obtained were aliquoted and stored at −80°C until analysis. U-II level was measured on quantitative sandwich-type enzyme immunoassay (ELx 800 ELISA; Cusabio Biotech, Winooski, VT, USA).
Statistical analysis Statistical analysis was done using SPSS 18.0 for Windows (IBM, Chicago, IL, USA). P < 0.05 was considered as significant. Chi-squared test was used to compare dichotomous variables such as gender and rates. Assuming that the variables measured had a normal distribution, intergroup differences were evaluated using Student t-test. Spearman’s correlation analysis was used to evaluate correlations between variables.
RESULTS Patient sociodemographic and clinical data are listed in Table 1. Mean U-II level was 6.16 ± 5.63 pg/mL in the schizophrenia patients and 2.46 ± 2.91 pg/mL in the control group (Fig. 1). U-II level was significantly
30
METHODS 25 Urotensin II (pg/mL)
We enrolled a total of 40 patients aged >18 years old and who were diagnosed with schizophrenia according to DSM-IV-TR criteria, who were admitted to Gaziantep University, Faculty of Medicine, Department of Psychiatry, Psychotic Disorders Unit. The patients with mental retardation, hypertension, diabetes mellitus, malignancy, neurological disease, diagnosis of morbid obesity or those who could not provide an adequate blood sample were excluded. A sociodemographic data form, which was prepared by the authors for the present study, was completed. The participants or their relatives gave written informed consent. As a control group, 40 healthy people consisting of doctors, hospital staff and students were enrolled. The study was approved by Ethics Board of Gaziantep University, Faculty of Medicine. Blood
20 15 10 5 0 Schizophrenia
Controls
Figure 1. Urotensin II in schizophrenia and control subjects (pg/mL).
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
Urotensin II in schizophrenia 135
elevated in the schizophrenia patients compared to the control group (P < 0.001), but there were no differences with regard to gender in either group (P > 0.05). With regard to the schizophrenia subgroup, no difference was seen in U-II level (P = 0.697). No significant correlation was noted between U-II level and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression–Severity Scale (CGI-S) scores (P > 0.05). No difference in U-II level was found between smokers and non-smokers (P = 0.622). No significant difference of U-II level was detected between the patients with and without a history of electroconvulsive therapy (ECT; P = 0.769). No correlation was found between U-II level and body mass index and the duration of disease (P = 0.371, P = 0.539). There was no correlation between antipsychotic dose and U-II level (r = –0.29, P = 0.860).
and temporal regions and the hypofrontality previously detected in schizophrenia patients. In schizophrenia, a decrease in the white and gray matter volumes in the brain was observed.25 U-II could have played a role in the decrease of brain volume by leading to decreased blood flow in the brain. In contrast, it has been reported that in humans U-II activates NOS, and causes relaxation also.22 Moreover, it has been shown that the U-II relaxant response of endothelium-intact in human artery, such as internal mammary and radial artery, used for coronary bypass, is present.26 For this reason, the preservation of endothelium, by preventing vasospasm caused by U-II, in these grafts is important and provides more permanent coronary bypass.26 The exact function of U-II, however, is still unknown: that in the brain tissue of humans awaits clarification. In other studies, adrenomedullin level was found to be higher in schizophrenia patients than in controls, in contrast to the present study.27,28 Adrenomedullin has a vasodilator effect by altering NO and adenylate cyclase.29 Decreased blood flow in the frontal and temporal region of schizophrenia patients cannot be explained by elevated adrenomedullin level and its vasodilator effect. But UT-II, with its vasoconstrictor effect, is a more likely explanation for decreased blood flow in the frontal and temporal regions. In the present study, no correlation was found between disease onset age, duration of the disease, whether ECT was used hospitalization, PANSS and CGI-S scores and U-II level. This suggests that U-II level is not correlated with the severity of the disease. The main original point of the present study includes the fact that this been the first study to (i) investigate a biological molecule that may have an impact on behavior in schizophrenia; (ii) measure for the first time increased ROS in the brain in humans, which was first noted in animal studies; and (iii) detect a high level of a molecule that may play a role in the prospective etiology of schizophrenia. The limitations of the present study include (i) the small number of patients and the lack of knowledge on whether U-II level measured in the peripheral blood fully reflects the level in the brain; and (ii) the lack of investigation of the association between U-II and oxidative parameters or inflammatory mediators. Consequently, U-II may contribute to decreased blood flow in the frontal and temporal regions of the brain in schizophrenia. U-II may play a role in the probable etiology of schizophrenia by leading to increased ROS in the brain. Clarification of the role of
DISCUSSION The first of the present findings was the detection of a significantly elevated U-II level in the schizophrenia patients. The observation of increased U-II level in the schizophrenia patients compared to controls suggests that elevated U-II level can be associated with the disease. In a study performed on rats, it was observed that the intracerebroventricular injection of U-II to the brain resulted in an increase of reactive oxygen species (ROS) in the brain.15 In the present study, it was claimed that the elevation of U-II led to ROS formation in the brain. In many studies for schizophrenia, elevated ROS was detected in the patients.16,17 In postmortem studies, elevated levels of nitric oxide (NO) and nitric oxide synthase (NOS) in brain tissue of subjects with schizophrenia suggested that NOS may be activated in the illness.18,19 Similarly, it was shown that NO level in red blood cells is significantly increased in schizophrenia patients and that U-II is able to activate NOS.20–22 In the present study, the observation of elevated U-II level suggests that, in schizophrenia, elevated ROS level could be associated with U-II level. Further studies on the correlation between U-II and oxidative parameters and/or inflammatory mediators in psychiatric disorders are needed. In schizophrenia patients blood flow decreases in the frontal and temporal regions.23 In many studies, decreased blood flow in the frontal region was associated with hypofrontality.24 To the best of our knowledge, U-II is the most potent vasoconstrictor. Therefore, elevated U-II level may be one of the possible reasons for decreased blood flow in the frontal
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
136 F. Bulbul et al.
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
U-II in psychiatric disorders is needed. Further investigation should also be done on the association of U-II level with oxidative stress parameters and inflammatory mediators.
15. Lu N, Yu HY, Wang R, Zhu YC. Central reactive oxygen species mediate cardiovascular effects of urotensin II in spontaneously hypertensive rat. Sheng Li Xue Bao 2012; 64: 142–148. 16. Kohen R, Nyska A. Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol. Pathol. 2002; 30: 620–650. 17. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: An integrated approach. Neurosci. Biobehav. Rev. 2011; 35: 878–893. 18. Baba H, Suzuki T, Arai H, Emson PC. Expression of nNOS and soluble guanylate cyclase in schizophrenic brain. Neuroreport 2004; 15: 677–680. 19. Yao JK, Leonard S, Reddy RD. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr. Bull. 2004; 30: 923–934. 20. Herken H, Uz E, Ozyurt H, Akyol O. Red blood cell nitric oxide levels in patients with schizophrenia. Schizophr. Res. 2001; 52: 289–290. 21. Hindley S, Juurlink BH, Gysbers JW, Middlemiss PJ, Herman MA, Rathbone MP. Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. J. Neurosci. Res. 1997; 47: 427–439. 22. d’Emmanuele di Villa Bianca R, Cirino G, Mitidieri E et al. Urotensin II: A novel target in human corpus cavernosum. J. Sex. Med. 2010; 7: 1778–1786. 23. Malaspina D, Harkavy-Friedman J, Corcoran C et al. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol. Psychiatry 2004; 56: 931–937. 24. Andreasen NC, Rezai K, Alliger R et al. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch. Gen. Psychiatry 1992; 49: 943–958. 25. Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophr. Bull. 2013; 39: 1129–1138. 26. Chen ZW, Yang Q, Huang Y, Fan L, Li XW, He GW. Human urotensin II in internal mammary and radial arteries of patients undergoing coronary surgery. Vascul. Pharmacol. 2010; 52: 70–76. 27. Yilmaz N, Herken H, Cicek HK, Celik A, Yürekli M, Akyol O. Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med. Princ. Pract. 2007; 16: 137–141. 28. Zoroglu SS, Herken H, Yürekli M et al. The possible pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia. J. Psychiatr. Res. 2002; 36: 309–315. 29. Richards AM, Nichoils MG, Lewis L, Lainch-bury JG. Adrenomedullin. Clin. Sci. 1996; 91: 3–16.
ACKNOWLEDGMENTS The authors report no conflicts of interest and declare that they received no financial grants to carry out the study.
REFERENCES 1. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008; 30: 67–76. 2. Tamminga CA, Holcomb HH. Phenotype of schizophrenia: A review and formulation. Mol. Psychiatry 2005; 10: 27–39. 3. Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr. Bull. 2009; 35: 528–548. 4. Onan D, Hannan RD, Thomas WG. Urotensin II: The old kid in town. Trends Endocrinol. Metab. 2004; 15: 175–182. 5. Coulouarn Y, Jégou S, Tostivint H, Vaudry H, Lihrmann I. Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett. 1999; 457: 28–32. 6. Ong KL, Lam KS, Cheung BM. Urotensin II: Its function in health and its role in disease. Cardiovasc. Drugs Ther. 2005; 19: 65–75. 7. McDonald J, Batuwangala M, Lambert DG. Role of urotensin II and its receptor in health and disease. J. Anesth. 2007; 21: 378–389. 8. Stirrat A, Gallagher M, Douglas SA et al. Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am. J. Physiol. Heart Circ. Physiol. 2001; 280: 925–928. 9. Jégou S, Cartier D, Dubessy C et al. Localization of the urotensin II receptor in the rat central nervous system. J. Comp. Neurol. 2006; 495: 21–36. 10. Watson AM, May CN. Urotensin II, a novel peptide in central and peripheral cardiovascular control. Peptides 2004; 25: 1759–1766. 11. Gartlon J, Parker F, Harrison DC et al. Central effects of urotensin-II following ICV administration in rats. Psychopharmacology (Berl) 2001; 155: 426–433. 12. de Lecea L, Bourgin P. Neuropeptide interactions and REM sleep: A role for urotensin II? Peptides 2008; 29: 845–851. 13. Virit O, Altindag A, Yumru M et al. A defect in the antioxidant defense system in schizophrenia. Neuropsychobiology 2009; 60: 87–93. 14. Müller N, Myint AM, Schwarz MJ. Inflammation in schizophrenia. Adv. Protein Chem. Struct. Biol. 2012; 88: 49–68.
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12099
Regular Article
New molecule in the etiology of schizophrenia: Urotensin II Feridun Bulbul, MD,1* Gokay Alpak, MD,1 Ahmet Unal, MD,1 Umit Sertan Copoglu, Mustafa Orkmez, MD,2 Osman Virit, MD,1 Mehmet Tarkcıoglu, PhD2 and Haluk A. Savas, PhD, MD1
MD,3
Departments of 1Psychiatry and 2Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep and 3Ceylanpinar State Hospital, Sanliurfa, Turkey
Aims: Urotensin II (U-II) is a cyclic peptide that was first isolated from the caudal neurosecretory system of goby fish. U-II receptors were detected in the vascular endothelium, brain and kidney cortex. Urotensin is by far the most powerful vasoconstrictor identified. U-II molecules were previously isolated from the brain of rats and were shown to have an impact on rat behavior. The aim of the present study was to measure the level of U-II molecule in schizophrenia patients and to investigate whether the U-II level is associated with the etiology of schizophrenia. Methods: Forty schizophrenia patients who were followed at Gaziantep University Faculty of Medicine Department of Psychiatry Psychotic Disorders Unit and 40 healthy volunteers were enrolled in this study. Blood samples were taken from the
CHIZOPHRENIA IS A chronic disease that causes the majority of disabilities among all psychiatric diseases, and its prevalence is 1%.1Positive, negative and cognitive signs and symptoms may be observed in schizophrenia.2 In the etiology of schizophrenia, genetic, biochemical, oxidative and environmental factors are involved.3 Urotensin II (U-II) is a cyclic peptide that was first isolated from the caudal neurosecretory system of the round goby fish in 1969.4 U-II consists of 11 aminoacids.5 U-II receptors have been detected in
S
*Correspondence: Feridun Bulbul, MD, Department of Psychiatry, Faculty of Medicine, Gaziantep University, 27310 S¸ahinbey, Gaziantep, Turkey. Email: [email protected] Received 19 April 2013; revised 10 June 2013; accepted 25 July 2013.
antecubital vein after 12-h fasting. U-II level was measured on ELISA.
Results: The U-II level in schizophrenia patients was significantly higher than in the control group. U-II level was not different with regard to gender in either group. U-II level was not different between subgroups of schizophrenia. No significant correlation was found between U-II level, Positive and Negative Syndrome Scale and Clinical Global Impression– Severity scale scores. Conclusion: U-II level was higher in schizophrenia patients, indicating that U-II level may be related to the etiology of the disease. Key words: new molecule, oxidative stress, pathogenesis, schizophrenia, urotensin II.
vascular endothelium, myocardium, smooth muscle and skeletal muscle, adrenal glands, thyroid and renal cortex.6 U-II is the most potent vasoconstrictor substance that has been described to date.7 U-II receptor activation acts via binding to the G protein Gq/11 family.7 Stimulation of the U-II receptor by U-II increases the intracellular inflow of Ca+2 by increasing the turnover of phosphoinositide.8 U-II and U-II receptors were isolated from the central nervous system of the rat.9 Immunoreactivity of the U-II receptor was detected in hippocampus, hypothalamus and thalamus.10 In rats, intracerebrovascular injection of U-II resulted in several behavioral, cardiovascular, motor and endocrine responses.9 In the rat, following the intracerebrovascular injection of U-II, plasma levels of thyroid-stimulating hormone and prolactin were increased but corticosterone level was not
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
133
134 F. Bulbul et al.
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
Table 1. Subject characteristics (mean ± SD)
Age (years) Sex (M/F) Duration of illness (years) PANSS CGI-S BMI
Schizophrenia
Control
P
37 ± 9.6 20/20 12.17 ± 9.25
37 ± 10 19/21
0.99
74.1 ± 35.57 4.48 ± 2.12 2.68 ± 0.85
BMI, body mass index; CGI-S, Clinical Global Impression–Severity scale; PANSS, Positive and Negative Syndrome Scale.
affected.11 Behavioral effects of U-II are thought to generally result from cholinergic activation. Cholinergic regulation of U-II is suggested to be mediated by the mesopontine tegmentum region.12 In heart failure, renal failure, diabetes mellitus and hepatic disease, in the etiologies of which several oxidative and immunologic mechanisms are involved, plasma U-II level was found to be elevated.6,7,10 It has been shown that oxidative and immunological mechanisms can take a role in schizophrenia etiology.13,14 U-II molecules were previously isolated from the brain of the rat and were shown to have an impact on rat behavior. The aim of the present study was to measure U-II level in schizophrenia patients and to investigate whether U-II level is associated with the etiology of schizophrenia.
samples were collected from the antecubital vein following a 12-h fasting period. Blood samples collected in the serum separating tubes (SST) from the patients and from the controls were left for 1 h at room temperature up to coagulation, thereafter, they were centrifuged at 1000 g for 15 min and ultimately, the samples obtained were aliquoted and stored at −80°C until analysis. U-II level was measured on quantitative sandwich-type enzyme immunoassay (ELx 800 ELISA; Cusabio Biotech, Winooski, VT, USA).
Statistical analysis Statistical analysis was done using SPSS 18.0 for Windows (IBM, Chicago, IL, USA). P < 0.05 was considered as significant. Chi-squared test was used to compare dichotomous variables such as gender and rates. Assuming that the variables measured had a normal distribution, intergroup differences were evaluated using Student t-test. Spearman’s correlation analysis was used to evaluate correlations between variables.
RESULTS Patient sociodemographic and clinical data are listed in Table 1. Mean U-II level was 6.16 ± 5.63 pg/mL in the schizophrenia patients and 2.46 ± 2.91 pg/mL in the control group (Fig. 1). U-II level was significantly
30
METHODS 25 Urotensin II (pg/mL)
We enrolled a total of 40 patients aged >18 years old and who were diagnosed with schizophrenia according to DSM-IV-TR criteria, who were admitted to Gaziantep University, Faculty of Medicine, Department of Psychiatry, Psychotic Disorders Unit. The patients with mental retardation, hypertension, diabetes mellitus, malignancy, neurological disease, diagnosis of morbid obesity or those who could not provide an adequate blood sample were excluded. A sociodemographic data form, which was prepared by the authors for the present study, was completed. The participants or their relatives gave written informed consent. As a control group, 40 healthy people consisting of doctors, hospital staff and students were enrolled. The study was approved by Ethics Board of Gaziantep University, Faculty of Medicine. Blood
20 15 10 5 0 Schizophrenia
Controls
Figure 1. Urotensin II in schizophrenia and control subjects (pg/mL).
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
Urotensin II in schizophrenia 135
elevated in the schizophrenia patients compared to the control group (P < 0.001), but there were no differences with regard to gender in either group (P > 0.05). With regard to the schizophrenia subgroup, no difference was seen in U-II level (P = 0.697). No significant correlation was noted between U-II level and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression–Severity Scale (CGI-S) scores (P > 0.05). No difference in U-II level was found between smokers and non-smokers (P = 0.622). No significant difference of U-II level was detected between the patients with and without a history of electroconvulsive therapy (ECT; P = 0.769). No correlation was found between U-II level and body mass index and the duration of disease (P = 0.371, P = 0.539). There was no correlation between antipsychotic dose and U-II level (r = –0.29, P = 0.860).
and temporal regions and the hypofrontality previously detected in schizophrenia patients. In schizophrenia, a decrease in the white and gray matter volumes in the brain was observed.25 U-II could have played a role in the decrease of brain volume by leading to decreased blood flow in the brain. In contrast, it has been reported that in humans U-II activates NOS, and causes relaxation also.22 Moreover, it has been shown that the U-II relaxant response of endothelium-intact in human artery, such as internal mammary and radial artery, used for coronary bypass, is present.26 For this reason, the preservation of endothelium, by preventing vasospasm caused by U-II, in these grafts is important and provides more permanent coronary bypass.26 The exact function of U-II, however, is still unknown: that in the brain tissue of humans awaits clarification. In other studies, adrenomedullin level was found to be higher in schizophrenia patients than in controls, in contrast to the present study.27,28 Adrenomedullin has a vasodilator effect by altering NO and adenylate cyclase.29 Decreased blood flow in the frontal and temporal region of schizophrenia patients cannot be explained by elevated adrenomedullin level and its vasodilator effect. But UT-II, with its vasoconstrictor effect, is a more likely explanation for decreased blood flow in the frontal and temporal regions. In the present study, no correlation was found between disease onset age, duration of the disease, whether ECT was used hospitalization, PANSS and CGI-S scores and U-II level. This suggests that U-II level is not correlated with the severity of the disease. The main original point of the present study includes the fact that this been the first study to (i) investigate a biological molecule that may have an impact on behavior in schizophrenia; (ii) measure for the first time increased ROS in the brain in humans, which was first noted in animal studies; and (iii) detect a high level of a molecule that may play a role in the prospective etiology of schizophrenia. The limitations of the present study include (i) the small number of patients and the lack of knowledge on whether U-II level measured in the peripheral blood fully reflects the level in the brain; and (ii) the lack of investigation of the association between U-II and oxidative parameters or inflammatory mediators. Consequently, U-II may contribute to decreased blood flow in the frontal and temporal regions of the brain in schizophrenia. U-II may play a role in the probable etiology of schizophrenia by leading to increased ROS in the brain. Clarification of the role of
DISCUSSION The first of the present findings was the detection of a significantly elevated U-II level in the schizophrenia patients. The observation of increased U-II level in the schizophrenia patients compared to controls suggests that elevated U-II level can be associated with the disease. In a study performed on rats, it was observed that the intracerebroventricular injection of U-II to the brain resulted in an increase of reactive oxygen species (ROS) in the brain.15 In the present study, it was claimed that the elevation of U-II led to ROS formation in the brain. In many studies for schizophrenia, elevated ROS was detected in the patients.16,17 In postmortem studies, elevated levels of nitric oxide (NO) and nitric oxide synthase (NOS) in brain tissue of subjects with schizophrenia suggested that NOS may be activated in the illness.18,19 Similarly, it was shown that NO level in red blood cells is significantly increased in schizophrenia patients and that U-II is able to activate NOS.20–22 In the present study, the observation of elevated U-II level suggests that, in schizophrenia, elevated ROS level could be associated with U-II level. Further studies on the correlation between U-II and oxidative parameters and/or inflammatory mediators in psychiatric disorders are needed. In schizophrenia patients blood flow decreases in the frontal and temporal regions.23 In many studies, decreased blood flow in the frontal region was associated with hypofrontality.24 To the best of our knowledge, U-II is the most potent vasoconstrictor. Therefore, elevated U-II level may be one of the possible reasons for decreased blood flow in the frontal
© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology
136 F. Bulbul et al.
Psychiatry and Clinical Neurosciences 2014; 68: 133–136
U-II in psychiatric disorders is needed. Further investigation should also be done on the association of U-II level with oxidative stress parameters and inflammatory mediators.
15. Lu N, Yu HY, Wang R, Zhu YC. Central reactive oxygen species mediate cardiovascular effects of urotensin II in spontaneously hypertensive rat. Sheng Li Xue Bao 2012; 64: 142–148. 16. Kohen R, Nyska A. Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol. Pathol. 2002; 30: 620–650. 17. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: An integrated approach. Neurosci. Biobehav. Rev. 2011; 35: 878–893. 18. Baba H, Suzuki T, Arai H, Emson PC. Expression of nNOS and soluble guanylate cyclase in schizophrenic brain. Neuroreport 2004; 15: 677–680. 19. Yao JK, Leonard S, Reddy RD. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr. Bull. 2004; 30: 923–934. 20. Herken H, Uz E, Ozyurt H, Akyol O. Red blood cell nitric oxide levels in patients with schizophrenia. Schizophr. Res. 2001; 52: 289–290. 21. Hindley S, Juurlink BH, Gysbers JW, Middlemiss PJ, Herman MA, Rathbone MP. Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. J. Neurosci. Res. 1997; 47: 427–439. 22. d’Emmanuele di Villa Bianca R, Cirino G, Mitidieri E et al. Urotensin II: A novel target in human corpus cavernosum. J. Sex. Med. 2010; 7: 1778–1786. 23. Malaspina D, Harkavy-Friedman J, Corcoran C et al. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol. Psychiatry 2004; 56: 931–937. 24. Andreasen NC, Rezai K, Alliger R et al. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch. Gen. Psychiatry 1992; 49: 943–958. 25. Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophr. Bull. 2013; 39: 1129–1138. 26. Chen ZW, Yang Q, Huang Y, Fan L, Li XW, He GW. Human urotensin II in internal mammary and radial arteries of patients undergoing coronary surgery. Vascul. Pharmacol. 2010; 52: 70–76. 27. Yilmaz N, Herken H, Cicek HK, Celik A, Yürekli M, Akyol O. Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med. Princ. Pract. 2007; 16: 137–141. 28. Zoroglu SS, Herken H, Yürekli M et al. The possible pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia. J. Psychiatr. Res. 2002; 36: 309–315. 29. Richards AM, Nichoils MG, Lewis L, Lainch-bury JG. Adrenomedullin. Clin. Sci. 1996; 91: 3–16.
ACKNOWLEDGMENTS The authors report no conflicts of interest and declare that they received no financial grants to carry out the study.
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