- Email: [email protected]
S.04.01 The brain noradrenergic and serotonergic systems as unknown factors regulating the activity of cytochrome P450
S.04. Young Scientists Award symposium 1
S180
by pro-inflammatory cytokines such as Interferon-y or TumorNecrosis-Factor-a and is inhibited by anti-inflammatory cytokines. Inhibition or activation of IDO, however, lead to different products in the kynurenine metabolism, which are associated with an imbalance in the glutamatergic neurotransmission, contributing to an overweight of N-methyl-D-aspartate (NMDA) agonism in depression and of NMDA antagonism in schizophrenia. Conflict of interest: Honoraria: Affectis Pharmaceuticals; References
[1] Myint, A-M, Kim, Y.K., 2003. Cytolcine-serotonin interaction through 100: a neurodegeneration hypothesis of depression. Med. Hypotheses. 61, 519-525. [2] Miiller, N., Schwarz, M.J., 2007. The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J. Neural Transmission (Suppl. 72) 269-280. [3] Miiller, N., Schwarz, M.J., 2007. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol. Psychiatry 2007 1-13.
18.03.051 CNS infections during childhood and risk for schizophrenia: a historical-prospective study on 3,500 children hospitalised for CNS infections in childhood M. Weiser1 ., N. Werbe10ftl, A. Levine2 , G. Livni3 , S. Schreiber4, D. Halperin5 , M. Davidson5 . 1 Chaim Sheba Medical Center, Department of Psychiatry, Tel Hashomer, Israel; 2 Wolfton Medical Center, Pediatric Gastroenterology and Nutrition Unit, Holon, Israel; 3 Schneider Children Hospital, Pediatric Department Unit of Infectious Disease, Petach Tikua, Israel; 4 Tel-Aviv Sourasky Medical Center, Department ofPsychiatry, Tel Aviv, Israel; 5 Sheba Medical Center, Department of Psychiatry, Tel-Hashomer, Israel
s
Objective: The hypothesized role of CNS infection during childhood in increasing later risk of brain malfunction manifested as schizophrenia has been supported by some but not other studies. We sought to contribute to this debate by linking data on persons who had been hospitalized for meningitis as children, with a National Psychiatric Hospitalization Registry. Method: Data were gathered on 3,599 persons who had been hospitalized for a CNS infection before the age of 16, and 6,371 controls who had been hospitalized as children for gastroenteritis. Both groups were followed for later hospitalization for schizophrenia between 1970 and 2007 using the Israeli National Psychiatric Hospitalization Case Registry. Data were analyzed using Cox regression analyses. Results: The mean age of the subjects at hospitalization for a CNS infection was 3.4±3.6 years, mean age of the subjects at follow-up was 29.3±6.0 years. Compared to controls, hospitalization for any CNS infection during childhood was not associated with increased risk of later hospitalization for schizophrenia, adjusted HR=0.81, 95%CI: 0.5-1.32. However, a post-hoc subanalysis of children hospitalized for bacterial CNS infection between the ages of 2-5 years suggested increased risk of later hospitalization for schizophrenia (adjusted HR=4.35, 95%CI: 1.2-15.84). Conclusions: Overall there was no significant association between childhood CNS infection and schizophrenia. The association between bacterial CNS infections in 2-5 year olds and increased risk of schizophrenia later in life should be examined in an independent sample. These data do not support the presence of an infectious etiology of schizophrenia.
S.04. Young Scientists Award symposium 1 18.04.011 The brain noradrenergic and serotonergic systems as unknown factors regulating the activity of cytochrome P450 M. Kot 1 ., WA. Daniel 1 . 1Institute of Pharmacology Polish Academy ofSciences, Department ofPharmacokinetics and Drug Metabolism, Krakow, Poland The aim of the present study was to find out whether the brain noradrenergic or serotonergic system can affect the expression of liver CYP. Rats were injected intraperitoneally with one of the following neurotoxins: N-(2-chloroethyl)-N-ethyl2-bromobenzylarnine (DSP-4), a noradrenergic neurotoxin or p-chlorophenylalanine (pCPA) or p-chloroamphetamine (PCA), serotonergic neurotoxins. One week after the neurotoxin injection the levels of neurotansmitters in the brain and the activity and protein levels of CYP isoforms in the liver were measured. In the brain DSP-4 or PCA and PCPA selectively decreased noradrenaline or serotonin levels, respectively. The applied neurotoxins changed the activities and protein levels of CYP2B, CYP2C11, CYP3A (DSP-4, PCA, PCPA) and CYP1A isoform (PCA, PCPA) which are regulated by endogenous hormones. Since hormones regulating the above CYP isoforms remain under the control of the central nervous system, it is suggested that the brain noradrenergic and serotonergic systems are important to the physiological regulation of liver CYP expression.
18.04.021 M- and T-tropic HIVs cause apoptosis in rat neuronal cell culture
F. Biggio 1 ., A. Bachis2 , I. Mocchetti2 .
1 University of Cagliari, Department of Exp. Biology, Monserrato (Cagliari), Italy; 2 Georgetown University, Department of Neuroscience, Washington (D.c.), USA
Human immunodeficiency virus type 1 (HIV-1) causes neuronal degeneration and, at a late stage, creates HIV-associated dementia (HAD). We have previously demonstrate that gpIIIB, a tropic (X4) strain, causes neuronal apoptosis through activation of the chemokine receptor CXCR4 both in vitro and in vivo. Our experiments were performed in Cortical neurons and Cerebellar granule cells prepared from 1 day old and 8 days old Sprague Dawley rat pups, respectively. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-I, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCRS co-receptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in celllysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCRS receptor inhibitor D-Alapeptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the NMDA receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors. Our data suggest that HIV-1 neurotoxicity can be initiated by the viral protein
S180
by pro-inflammatory cytokines such as Interferon-y or TumorNecrosis-Factor-a and is inhibited by anti-inflammatory cytokines. Inhibition or activation of IDO, however, lead to different products in the kynurenine metabolism, which are associated with an imbalance in the glutamatergic neurotransmission, contributing to an overweight of N-methyl-D-aspartate (NMDA) agonism in depression and of NMDA antagonism in schizophrenia. Conflict of interest: Honoraria: Affectis Pharmaceuticals; References
[1] Myint, A-M, Kim, Y.K., 2003. Cytolcine-serotonin interaction through 100: a neurodegeneration hypothesis of depression. Med. Hypotheses. 61, 519-525. [2] Miiller, N., Schwarz, M.J., 2007. The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J. Neural Transmission (Suppl. 72) 269-280. [3] Miiller, N., Schwarz, M.J., 2007. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol. Psychiatry 2007 1-13.
18.03.051 CNS infections during childhood and risk for schizophrenia: a historical-prospective study on 3,500 children hospitalised for CNS infections in childhood M. Weiser1 ., N. Werbe10ftl, A. Levine2 , G. Livni3 , S. Schreiber4, D. Halperin5 , M. Davidson5 . 1 Chaim Sheba Medical Center, Department of Psychiatry, Tel Hashomer, Israel; 2 Wolfton Medical Center, Pediatric Gastroenterology and Nutrition Unit, Holon, Israel; 3 Schneider Children Hospital, Pediatric Department Unit of Infectious Disease, Petach Tikua, Israel; 4 Tel-Aviv Sourasky Medical Center, Department ofPsychiatry, Tel Aviv, Israel; 5 Sheba Medical Center, Department of Psychiatry, Tel-Hashomer, Israel
s
Objective: The hypothesized role of CNS infection during childhood in increasing later risk of brain malfunction manifested as schizophrenia has been supported by some but not other studies. We sought to contribute to this debate by linking data on persons who had been hospitalized for meningitis as children, with a National Psychiatric Hospitalization Registry. Method: Data were gathered on 3,599 persons who had been hospitalized for a CNS infection before the age of 16, and 6,371 controls who had been hospitalized as children for gastroenteritis. Both groups were followed for later hospitalization for schizophrenia between 1970 and 2007 using the Israeli National Psychiatric Hospitalization Case Registry. Data were analyzed using Cox regression analyses. Results: The mean age of the subjects at hospitalization for a CNS infection was 3.4±3.6 years, mean age of the subjects at follow-up was 29.3±6.0 years. Compared to controls, hospitalization for any CNS infection during childhood was not associated with increased risk of later hospitalization for schizophrenia, adjusted HR=0.81, 95%CI: 0.5-1.32. However, a post-hoc subanalysis of children hospitalized for bacterial CNS infection between the ages of 2-5 years suggested increased risk of later hospitalization for schizophrenia (adjusted HR=4.35, 95%CI: 1.2-15.84). Conclusions: Overall there was no significant association between childhood CNS infection and schizophrenia. The association between bacterial CNS infections in 2-5 year olds and increased risk of schizophrenia later in life should be examined in an independent sample. These data do not support the presence of an infectious etiology of schizophrenia.
S.04. Young Scientists Award symposium 1 18.04.011 The brain noradrenergic and serotonergic systems as unknown factors regulating the activity of cytochrome P450 M. Kot 1 ., WA. Daniel 1 . 1Institute of Pharmacology Polish Academy ofSciences, Department ofPharmacokinetics and Drug Metabolism, Krakow, Poland The aim of the present study was to find out whether the brain noradrenergic or serotonergic system can affect the expression of liver CYP. Rats were injected intraperitoneally with one of the following neurotoxins: N-(2-chloroethyl)-N-ethyl2-bromobenzylarnine (DSP-4), a noradrenergic neurotoxin or p-chlorophenylalanine (pCPA) or p-chloroamphetamine (PCA), serotonergic neurotoxins. One week after the neurotoxin injection the levels of neurotansmitters in the brain and the activity and protein levels of CYP isoforms in the liver were measured. In the brain DSP-4 or PCA and PCPA selectively decreased noradrenaline or serotonin levels, respectively. The applied neurotoxins changed the activities and protein levels of CYP2B, CYP2C11, CYP3A (DSP-4, PCA, PCPA) and CYP1A isoform (PCA, PCPA) which are regulated by endogenous hormones. Since hormones regulating the above CYP isoforms remain under the control of the central nervous system, it is suggested that the brain noradrenergic and serotonergic systems are important to the physiological regulation of liver CYP expression.
18.04.021 M- and T-tropic HIVs cause apoptosis in rat neuronal cell culture
F. Biggio 1 ., A. Bachis2 , I. Mocchetti2 .
1 University of Cagliari, Department of Exp. Biology, Monserrato (Cagliari), Italy; 2 Georgetown University, Department of Neuroscience, Washington (D.c.), USA
Human immunodeficiency virus type 1 (HIV-1) causes neuronal degeneration and, at a late stage, creates HIV-associated dementia (HAD). We have previously demonstrate that gpIIIB, a tropic (X4) strain, causes neuronal apoptosis through activation of the chemokine receptor CXCR4 both in vitro and in vivo. Our experiments were performed in Cortical neurons and Cerebellar granule cells prepared from 1 day old and 8 days old Sprague Dawley rat pups, respectively. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-I, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCRS co-receptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in celllysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCRS receptor inhibitor D-Alapeptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the NMDA receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors. Our data suggest that HIV-1 neurotoxicity can be initiated by the viral protein