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Neurosteroids: Synthesis and function in retinal degeneration
Poster session I
BIOL. PSYCHIATRY
SIS
1997;42:1~291S
between the two groups. These findings suggested that there are different psychophysiological backgrounds between the two groups.
114-1631 Cerebral asymmetry In mania and depression N.N. Nikolaenko, A.Y. Egorov. I.M. Sschenov Institute of Evolutionary Physiology. St Petersburg. Russia. Biochemistry, Russian Academy of SCiences. St. Petersburg, Russia The goal of the study was to Investigate the activation patterns of the right and left hemispheres separately in manic and depressed patients. Methods: To investigate changes of visual space structure we used an original test of mapping the visual field via drawing geometrical figures on Irregular 32 dot grid. Results: In depression (n = 42) the characteristic preference was for the left hemispace. The reduced activation of the left hemisphere associated with reciprocal hyperactivation of the right hemisphere was observed in depressed patients as well. In contrast, In mania (n 24) the high elaboration of right hemlspace (together with low elaboration of left hemispace up to left hemineglect) was observed. Theretore, a reduced activation ot the right hemisphere with reciprocal hyperactivation of the left one were found In mania.
=
114-1641 Neurophysiological mechanisms of Impaired facial emotion recognition In endogenous depression E.S. Mikhailova, I. Oleichik. Mental Health Researoh Center, Moscow, Russia The study was aimed at neurobiological basis of emotion recognition In depressed patients suffering from Major Depression (MD) and Schizotypal Personality (STP). Methods: Under recognition of centrally presented sad, laughing and neutral faces the timing of Nl80 wave of event-related potential was studied In successive topographic maps in two groups ot right·handed depressed patients (MD and STP) in comparison with matched healthy controls. Results: Under correct recognition the nonns revealed primary right hemisphere activation followed by involvement of left hemisphere with close correlation between peak latency of waves in symmetric points. In opposite, MD patients showed the right hemisphere dominance for all the timing ot Nl 80' while STP patients - the left hemisphere prevalence. Both groups demonstrated slower Interhemispheric transfer. Mered hemispheric and temporal pattems of Nl80 timing related with marked poor accuracy oJ emotion recognition. The revealed dissimilar hemispheric pattem of frontal activation In MD and STP may be argued in favor of different hemispheric mechanisms underiylng the Impaired recognition in these two groups of depressed patients.
114-1651 Neurosterolds: Synthesis and function In retinal degeneration P. Guameri 1, C. Cascio 2, D. Russo 3, G. De Leo·, F. Piccoli 2, R. Guamer1 1 • lIBS. CNR, Italy. 3/SMEDA, CNR, Italy. 2lnst. Neuropsychic., University of Palermo, Italy. ·Inst of Biology. University of Palermo, Italy The capability of CNS structures to synthesize neurosteroids is now well documented. However, the physiological relevance of CNS neurosteroido• genic activity remains to be elucidated. Previously, we observed that retina as well as other CNS structure synthesizes neurosteroids. The cytochrome P45Qscc enzyme involved in the synthesis of pregnenolone precursor is mainly located at retinal ganglion cells (Guameri et al. J. Neurochem., 64: 86, 1994). In addition, we showed that the synthesis Is modified by light and dark conditions (Guameri P. In: The brain: source and target for sex steroid honnones, Parthenon Publish., 1996) and by GABAA receptor activity (Guamert et aI. Brain Res., 683: 65, 1995) suggesting that neurosteroidoge• nesis may have a physiological role In visual function. In the present work, we observed that an excessive neurosteroidogenlc activity may contribute to retinal degeneration. When isolated retinae Incubated with pregnenolone metabolism Inhibitors were exposed to NMDA (1-100 I'M), an increase of pregnenolone and pregnenolone sulfate synthesis was reported. This effect depended on extracellular ea2+ and was reverted by MK801 or CCP. The cell viability assayed through LOH activity released In the bathing buffer, revealed that the maximal stimulatory effect corresponded to a little retinal damage. A larger cell damage and a reduction of activated neurosterold
synthesis were observed at higher NMDA concentrations or prolonged ex• posure. NMDA-induced stimulation of the synthesis was not further activated by the addition of musclmol which per 58 increased basal steroidogenic ac• tiVity, but was decreased when retinae were pre-InCUbated with bicucul/lne (10 j.lM). The GABAA receptor antagonist also reduced retinal cell damage caused by prolonged exposure to NMDA. Aminogluthetimide (0.76 mM), an inhibitor of P450scc enzyme, blocked steroidogenic actiVity and prevented NMDA-induced cell death. On the contrary, an histopathological pattem of retinal Inner nuclear and ganglion cell layers was produced when neures• terolds such as pregnenolone suKate (0.5-50 j.lM), THDOC and 3a,Sa·THP (SO j.lM) were exogenously applied. Considering the results, it is likely that neurosteroldogenesis is stimulated by the activation 01 NMDA receptors through GABAA receptors and is Involved in retinal neurodegeneration.
114-1661 Plasma dehydroeplandrosterone sulfate and cortisol measurements In major depression M. Takebayashi 1.2, A. Kagaya 1, Y. Uchitoml 3 , A. Kugaya 3 , M. Fukue 1, N. Yokota', J. Horiguchi 1, S. Yamawakl'. 1 Department of Psychiatry and Neurosciences. Hiroshima University School of Medicine, Japan. 2 Senogawa Hospital, Hiroshima. Japan, 3 Psycho-Oncology Division, National Cencer Center Institute. East, Japan Recent studies demonstrate that not only classical steroids, such as cortisol, but also neurosterolds, acting at neuronal cell membrane directly through non-genomic effect, play an Important role on several neuronal physiological functions. We investigated the association between dehydroeplandrosterone sulfate (DHEAS), one of neurosterold, and major depression. Method: Unmediated depressed out-patients (6 female, 6 male) and 12 healthy controls were studied. They gave inlonned consent for this study and blood samples were drawn before treatment and 4 weeks after the pharmacotherapy. Results: There were significant Increases In both DHEAS and cortisol In depression before treatment, as compared to healthy control. 4 weeks after treatment, there was no difference of DHEAS and cortisol from the control. These results provide a possibility that the neurosterold Is associated with the phase of major depression.
114-1671 Genetic and biochemical study of depression-associated alteration In G protein signaling F. Karege 1, C. Buresi 1, P. Bovier M. Leboyer 2 • J. Mallet 2, " A. Malafosse '. 1 Geneva University Hospitals, Division of Neuropsychiatry; Geneva. Suisse, 2 Sa/~tri8re Hospital, Paris, Ftance Major depression was postulated to be associated to an lmpainnent In the membrane receptor and post-receptor signaling. Due to the central position of GTP-binding proteins (G proteins) in this signaling cascade, we have Undertaken a combined molecular genetics and biochemical study of the main G protein subunits. Methods: G protein levels were measured using the method of Westem Immunoblot both in blood platelet and In mononuclear leukocytes (MNL) membranes. Association study was performed by using amplifiable bi-allelic polymorphism In the exon-5 of Gas subunit (restriction site Fok-1). New mutations were searched in exons 8-9 by the SSCP method. Clinical diagnosis was assessed by the DIGS interview. Results: Biochemical study Indicated a depression-assoclated Increase in platelet Gal, Gaq and GfJ and MNL Gas (45 kDa). Genetic approactlshowed that the allelic frequencies In BP patients are not significantly different from those in controls. However, in a preliminary experiment, searching for mutation In the Gas exons 8-9, a difference In the migration of the bands (sequences amplified by PCR) was observed. In conclusion, the observed alteration in G protein and Its pivotal position along the signaling cascade make it a good candidate for a genetically detennined impainnent in BP disorder, since this disease has a tligh heritability. This work was supported by the Swiss Foundation for Sclentific Research, Grant No: 32-37531.93.
BIOL. PSYCHIATRY
SIS
1997;42:1~291S
between the two groups. These findings suggested that there are different psychophysiological backgrounds between the two groups.
114-1631 Cerebral asymmetry In mania and depression N.N. Nikolaenko, A.Y. Egorov. I.M. Sschenov Institute of Evolutionary Physiology. St Petersburg. Russia. Biochemistry, Russian Academy of SCiences. St. Petersburg, Russia The goal of the study was to Investigate the activation patterns of the right and left hemispheres separately in manic and depressed patients. Methods: To investigate changes of visual space structure we used an original test of mapping the visual field via drawing geometrical figures on Irregular 32 dot grid. Results: In depression (n = 42) the characteristic preference was for the left hemispace. The reduced activation of the left hemisphere associated with reciprocal hyperactivation of the right hemisphere was observed in depressed patients as well. In contrast, In mania (n 24) the high elaboration of right hemlspace (together with low elaboration of left hemispace up to left hemineglect) was observed. Theretore, a reduced activation ot the right hemisphere with reciprocal hyperactivation of the left one were found In mania.
=
114-1641 Neurophysiological mechanisms of Impaired facial emotion recognition In endogenous depression E.S. Mikhailova, I. Oleichik. Mental Health Researoh Center, Moscow, Russia The study was aimed at neurobiological basis of emotion recognition In depressed patients suffering from Major Depression (MD) and Schizotypal Personality (STP). Methods: Under recognition of centrally presented sad, laughing and neutral faces the timing of Nl80 wave of event-related potential was studied In successive topographic maps in two groups ot right·handed depressed patients (MD and STP) in comparison with matched healthy controls. Results: Under correct recognition the nonns revealed primary right hemisphere activation followed by involvement of left hemisphere with close correlation between peak latency of waves in symmetric points. In opposite, MD patients showed the right hemisphere dominance for all the timing ot Nl 80' while STP patients - the left hemisphere prevalence. Both groups demonstrated slower Interhemispheric transfer. Mered hemispheric and temporal pattems of Nl80 timing related with marked poor accuracy oJ emotion recognition. The revealed dissimilar hemispheric pattem of frontal activation In MD and STP may be argued in favor of different hemispheric mechanisms underiylng the Impaired recognition in these two groups of depressed patients.
114-1651 Neurosterolds: Synthesis and function In retinal degeneration P. Guameri 1, C. Cascio 2, D. Russo 3, G. De Leo·, F. Piccoli 2, R. Guamer1 1 • lIBS. CNR, Italy. 3/SMEDA, CNR, Italy. 2lnst. Neuropsychic., University of Palermo, Italy. ·Inst of Biology. University of Palermo, Italy The capability of CNS structures to synthesize neurosteroids is now well documented. However, the physiological relevance of CNS neurosteroido• genic activity remains to be elucidated. Previously, we observed that retina as well as other CNS structure synthesizes neurosteroids. The cytochrome P45Qscc enzyme involved in the synthesis of pregnenolone precursor is mainly located at retinal ganglion cells (Guameri et al. J. Neurochem., 64: 86, 1994). In addition, we showed that the synthesis Is modified by light and dark conditions (Guameri P. In: The brain: source and target for sex steroid honnones, Parthenon Publish., 1996) and by GABAA receptor activity (Guamert et aI. Brain Res., 683: 65, 1995) suggesting that neurosteroidoge• nesis may have a physiological role In visual function. In the present work, we observed that an excessive neurosteroidogenlc activity may contribute to retinal degeneration. When isolated retinae Incubated with pregnenolone metabolism Inhibitors were exposed to NMDA (1-100 I'M), an increase of pregnenolone and pregnenolone sulfate synthesis was reported. This effect depended on extracellular ea2+ and was reverted by MK801 or CCP. The cell viability assayed through LOH activity released In the bathing buffer, revealed that the maximal stimulatory effect corresponded to a little retinal damage. A larger cell damage and a reduction of activated neurosterold
synthesis were observed at higher NMDA concentrations or prolonged ex• posure. NMDA-induced stimulation of the synthesis was not further activated by the addition of musclmol which per 58 increased basal steroidogenic ac• tiVity, but was decreased when retinae were pre-InCUbated with bicucul/lne (10 j.lM). The GABAA receptor antagonist also reduced retinal cell damage caused by prolonged exposure to NMDA. Aminogluthetimide (0.76 mM), an inhibitor of P450scc enzyme, blocked steroidogenic actiVity and prevented NMDA-induced cell death. On the contrary, an histopathological pattem of retinal Inner nuclear and ganglion cell layers was produced when neures• terolds such as pregnenolone suKate (0.5-50 j.lM), THDOC and 3a,Sa·THP (SO j.lM) were exogenously applied. Considering the results, it is likely that neurosteroldogenesis is stimulated by the activation 01 NMDA receptors through GABAA receptors and is Involved in retinal neurodegeneration.
114-1661 Plasma dehydroeplandrosterone sulfate and cortisol measurements In major depression M. Takebayashi 1.2, A. Kagaya 1, Y. Uchitoml 3 , A. Kugaya 3 , M. Fukue 1, N. Yokota', J. Horiguchi 1, S. Yamawakl'. 1 Department of Psychiatry and Neurosciences. Hiroshima University School of Medicine, Japan. 2 Senogawa Hospital, Hiroshima. Japan, 3 Psycho-Oncology Division, National Cencer Center Institute. East, Japan Recent studies demonstrate that not only classical steroids, such as cortisol, but also neurosterolds, acting at neuronal cell membrane directly through non-genomic effect, play an Important role on several neuronal physiological functions. We investigated the association between dehydroeplandrosterone sulfate (DHEAS), one of neurosterold, and major depression. Method: Unmediated depressed out-patients (6 female, 6 male) and 12 healthy controls were studied. They gave inlonned consent for this study and blood samples were drawn before treatment and 4 weeks after the pharmacotherapy. Results: There were significant Increases In both DHEAS and cortisol In depression before treatment, as compared to healthy control. 4 weeks after treatment, there was no difference of DHEAS and cortisol from the control. These results provide a possibility that the neurosterold Is associated with the phase of major depression.
114-1671 Genetic and biochemical study of depression-associated alteration In G protein signaling F. Karege 1, C. Buresi 1, P. Bovier M. Leboyer 2 • J. Mallet 2, " A. Malafosse '. 1 Geneva University Hospitals, Division of Neuropsychiatry; Geneva. Suisse, 2 Sa/~tri8re Hospital, Paris, Ftance Major depression was postulated to be associated to an lmpainnent In the membrane receptor and post-receptor signaling. Due to the central position of GTP-binding proteins (G proteins) in this signaling cascade, we have Undertaken a combined molecular genetics and biochemical study of the main G protein subunits. Methods: G protein levels were measured using the method of Westem Immunoblot both in blood platelet and In mononuclear leukocytes (MNL) membranes. Association study was performed by using amplifiable bi-allelic polymorphism In the exon-5 of Gas subunit (restriction site Fok-1). New mutations were searched in exons 8-9 by the SSCP method. Clinical diagnosis was assessed by the DIGS interview. Results: Biochemical study Indicated a depression-assoclated Increase in platelet Gal, Gaq and GfJ and MNL Gas (45 kDa). Genetic approactlshowed that the allelic frequencies In BP patients are not significantly different from those in controls. However, in a preliminary experiment, searching for mutation In the Gas exons 8-9, a difference In the migration of the bands (sequences amplified by PCR) was observed. In conclusion, the observed alteration in G protein and Its pivotal position along the signaling cascade make it a good candidate for a genetically detennined impainnent in BP disorder, since this disease has a tligh heritability. This work was supported by the Swiss Foundation for Sclentific Research, Grant No: 32-37531.93.