Clinical Neuroscience

[EFFECT OF LOCAL (INTRACEREBRAL AND INTRACEREBROVENTRICULAR) ADMINISTRATION OF TYROSINE HYDROXYLASE INHIBITOR ON THE NEUROENDOCRINE DOPAMINERGIC NEURONS AND PROLACTIN RELEASE]

BODNÁR Ibolya, HECHTL Dániel, SZÉKÁCS Dániel, OLÁH Márk, NAGY M. György

MARCH 20, 2007

Clinical Neuroscience - 2007;60(03-04)

[Background and purpose - Hypothalamic dopamine (DA), the physiological regulator of pituitary prolactin (PRL) secretion, is synthesized in the neuroendocrine DAergic neurons that projects to the median eminence and the neurointermediate lobe of the pituitary gland. The rate-limiting step of DA biosynthesis is catalyzed by the phosphorylated, therefore activated, tyrosine hydroxylase (TH) that produces L-3,4-dihydroxy- phenylalanine from tyrosine. The aims of our present study were to investigate 1. the effect of local inhibition of the DA biosynthesis in the hypothalamic arcuate nucleus on PRL release, and to get 2. some information whether the phosphorylated TH is the target of enzyme inhibition or not. Methods - A TH inhibitor, α-methyl-p-tyrosine was injected either intracerebro-ventricularly or into the arcuate nucleus of freely moving rats and plasma PRL concentration was measured. Immunohistochemistry, using antibodies raised against to native as well as phosphorylated TH were used to compare their distributions in the arcuate nucleus-median eminence region. Results - Intracerebro-ventricular administration of α-methyl-p-tyrosine has no effect, unlike the intra-arcuatus injection of enzyme inhibitor resulted in a slight but significant elevation in plasma PRL. Parallel with this, the level of DA and DOPAC were reduced in the neurointermediate lobe while no change in norepinephrine concentration can be detected indicating a reduced biosynthesis of dopamine following TH inhibition. On the other hand, systematic application of the α-methyl-p-tyrosine that inhibits TH activity located in DA terminals of the median eminence and the neurointermediate lobe, resulted in the most significant elevation of PRL. Conclusion - Our results suggest that α-methyl-p-tyrosine administered close to the neuroendocrine DAergic neurons was able to inhibit only a small proportion of the TH. Moreover, it also indicate that the majority of the activated TH can be found in the axon terminals of DAergic neurons, therefore, the DA released into the pituitary portal circulation is synthesized at this site.]

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Clinical Neuroscience

[OXYGEN-GLUCOSE DEPRIVATION-INDUCED CHANGES IN ORGANOTYPIC CULTURES OF THE RAT HIPPOCAMPUS]

BALI Balázs, NAGY Zoltán, KOVÁCS J. Krisztina

[Introduction - (-)Deprenyl is an irreversible inhibitor of type B monoamine oxidase (MAO-B), which is now used for treatment of Parkinson’s or Alzheimer’s diseases. Evidence suggests that the neuroprotective effect of deprenyl may not be related exclusively to the inhibition of the enzyme MAO-B. Methods - To test the impact of deprenyl on ischemiainduced changes in vitro, we followed the time course of propidium iodide (PI) uptake as an indicator of neuronal cell death as well as the expression of apoptotic factors in organotypic hippocampal slice cultures exposed to oxygen- glucose deprivation (OGD) for 45 min. Results - The first signs of neuronal death were detected 2 hours after OGD and were extended to all subfields of the hippocampus by 24 hours post-injury. Presence of deprenyl (10-9 M) significantly delayed the cell death induced by the insult. Exposure of control cultures to deprenyl significantly increased the abundance of Bcl-2 and Bcl-xl mRNAs as revealed by RT-PCR. OGD resulted in an elevation of anti-apoptotic factors, while the expression of pro-apoptotic bax remained unchanged. Conclusion - These data suggest that deprenyl is neuroprotective in an in vitro model of ischemia. Although deprenyl upregulates the expression of Bcl-2 under basal conditions, its effect on anti-apoptotic factors is not significantly manifested during OGD.]

Clinical Neuroscience

[ASSOCIATION OF APOLIPOPROTEIN E POLYMORPHISM WITH AGE-RELATED MACULAR DEGENERATION AND ALZHEIMER’S DISEASE IN SOUTH-WESTERN HUNGARY]

KOVÁCS Á. Katalin, PÁMER Zsuzsanna, KOVÁCS Attila, FEKETE Sándor, MISETA Attila, KOVÁCS Bálint, KOVÁCS L. Gábor

[Background - Age-related macular degeneration (AMD) and Alzheimer dementia (AD) show similarities (advanced age, formation of deposits of similar content). Recently apolipoprotein E 2 (apoE 2) has been associated with AMD, while apoE4 with AD. The question of coexistence, especially with respect to the genetic background has not been studied earlier. We investigated, therefore, the occurrence of AMD in AD patients and compared their lipid profile and apoE polymorphism. Methods - 49 AMD, 32 AD and 27 control patients were examined (risk factors, visual acuity, slit lamp biomicroscopy, fundoscopy). Following measurement of triglyceride, total and HDL cholesterol levels, apoE mutation analysis was performed. Results - AMD was found in 8% of the cooperating AD patients. The prevalence of the apoE 4 isoforms in the AMD, AD and the control patients was 2%, 47% and 22%, while that of apoE 2 was 17%, 6% and 7%, respectively. The prevalence of apoE 3 isoform was 82%, 41% and 71%, respectively. Triglyceride, total and HDL cholesterol were in the reference range; however, AD patients were characterized by a lower total cholesterol value. Conclusions - The new finding of this publication is the rare occurrence of AMD among AD patients. The higher frequency of apoE 4 among the AD population, and the higher frequency of apoE 2 among AMD patients in the South-Western region of Hungary confirms the findings of other investigators.]

Clinical Neuroscience

[SALSOLINOL AND THE PERIPHERAL SYMPATHETIC ACTIVITY: THE EFFECTS OF HYPOPHYSECTOMY, ADRENALECTOMY AND ADRENAL MEDULLECTOMY]

SZÉKÁCS Dániel, BODNÁR Ibolya, NAGY M. György, FEKETE I.K. Márton

[The endogenous isoquinoline salsolinol (SALS) is a recently identified prolactin (PRL) releasing factor, a selective and potent stimulator of PRL secretion both in vivo and in vitro. SALS decreased the peripheral tissue dopamine (DA) level dose dependently, consequently increased the NE/DA ratio, indicating reduced release of newly formed norepinephrine (NE) from sympathetic terminals. The aim of our study was to investigate the effect of adrenal medullectomy (MEDX), adrenalectomy (ADX) and hypophysectomy (HYPOX) on the action of SALS on the PRL secretion, and on the catecholamine concentration of the selected sympathetically innervated peripheral tissues (atrium, spleen, etc). The experiments were done in male rats of 200-300 g body weight kept in air conditioned room with regular lighting. We used high-pressure liquid chromatography with electrochemical detection (HPLC-EC) for measurement of NE and DA concentrations, and radioimmunoassay for prolactin measurement. In MEDX as well as in ADX rats, SALS (25 mg/kg i.p.) was able to reduce DA level and increase the NE/DA ratio. The changes of prolactin secretion (increase by SALS) were not affected either by ADX or MEDX. Therefore the presence of the adrenal gland is not required for the changes of prolactin secretion, nor for the reduction of peripheral sympathetic activity induced by SALS. Investigating the possible effect of pituitary hormones on the peripheral sympathetic system, the action of SALS has been tested in HYPOX rats. We have found that the effect of SALS on peripheral sympathetic terminals is not affected by HYPOX, consequently the role of pituitary hormones in the effect of SALS on the peripheral catecholamine metabolism may be excluded.]

Clinical Neuroscience

[HUMAN TRYPSIN(OGEN) 4-LIKE IMMUNOREACTIVITY IN THE WHITE MATTER OF THE CEREBRAL CORTEX AND THE SPINAL CORD]

GALLATZ Katalin, MEDVECZKY Péter, NÉMETH Péter, SZILÁGYI László, GRÁF László, PALKOVITS Miklós

[Human brain trypsin(ogen) 4-like (HT-4) immunoreactivity was localized in glial cells of human cerebral cortex and spinal cord. After a short post mortem delay (two hours), cortical and spinal cord regions were dissected, frozen or immersed into a fixative solution. Sections of 10 and 50 µm thickness were cut and immunostained by antibodies raised against recombinant human trypsin 4. HT-4-like immunoreactive glial cells and fibers were stained in the white matter, low to moderate levels of immunostaining were also observed in the matrix of the cerebral cortex and the spinal cord. To characterize HT-4-like immunopositive glial cells, alternate sections were immunostained for astrocytes and oligodendrocytes. HT-4 is present predominantly in astrocytes, but some of the oligodendrocytes and microglial cells may also contain this enzyme.]

Clinical Neuroscience

[ACTIVATED SOMATOSTATIN TYPE 2 RECEPTORS TRAFFIC IN VIVO FROM DENDRITES TO THE TRANS-GOLGI NETWORK]

CSABA Zsolt, PASCAL Dournaud

[Background and purpose - Understanding the trafficking of G-protein-coupled receptors is of particular importance. In the central nervous system, although some Gprotein- coupled receptors were reported to internalize in vivo, little is known about their trafficking downstream of the endocytic event. Methods - The distribution of the major somatostatin receptor subtype, the sst2, was monitored in the hippocampus using immunofluorescence from 10 minutes to seven days after in vivo injection of the receptor agonist octreotide. Results - From 10 min to 3 h after agonist injection, intensity of receptor immunoreactivity gradually decreased in the molecular layer of dentate gyrus and in the strata oriens and radiatum of CA1. Concomitantly, in the granular and pyramidal layers, small spherical immunofluorescent particles became apparent in perikarya, shortly after agonist stimulation (i.e. 30 min, 60 min). After longer survival times (i.e. 3 h, 6 h, 24 h), immunolabeling was confined to larger, intensely-stained intracytoplasmic vesicles. From 48 h to 7 d after agonist injection, distribution and intensity of sst2 receptor immunoreactivity became similar to that of control animals. The sst2 receptor labeling extensively colocalized with TGN38 and syntaxin 6 after OCT injection. Colocalization with trans-Golgi markers was observed as soon as 1 h after OCT injection and still present 24 h after. By contrast, colocalization with the endoplasmic reticulum marker PDI and the cis-Golgi marker GM130 was never observed. Conclusions - Our results suggest that upon agonist stimulation, dendritic receptors are retrogradely transported to a trans-Golgi network domain enriched in the t-SNARE syntaxin-6 and TGN38 proteins before recycling.]

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[SALSOLINOL AND THE PERIPHERAL SYMPATHETIC ACTIVITY: THE EFFECTS OF HYPOPHYSECTOMY, ADRENALECTOMY AND ADRENAL MEDULLECTOMY]

SZÉKÁCS Dániel, BODNÁR Ibolya, NAGY M. György, FEKETE I.K. Márton

[The endogenous isoquinoline salsolinol (SALS) is a recently identified prolactin (PRL) releasing factor, a selective and potent stimulator of PRL secretion both in vivo and in vitro. SALS decreased the peripheral tissue dopamine (DA) level dose dependently, consequently increased the NE/DA ratio, indicating reduced release of newly formed norepinephrine (NE) from sympathetic terminals. The aim of our study was to investigate the effect of adrenal medullectomy (MEDX), adrenalectomy (ADX) and hypophysectomy (HYPOX) on the action of SALS on the PRL secretion, and on the catecholamine concentration of the selected sympathetically innervated peripheral tissues (atrium, spleen, etc). The experiments were done in male rats of 200-300 g body weight kept in air conditioned room with regular lighting. We used high-pressure liquid chromatography with electrochemical detection (HPLC-EC) for measurement of NE and DA concentrations, and radioimmunoassay for prolactin measurement. In MEDX as well as in ADX rats, SALS (25 mg/kg i.p.) was able to reduce DA level and increase the NE/DA ratio. The changes of prolactin secretion (increase by SALS) were not affected either by ADX or MEDX. Therefore the presence of the adrenal gland is not required for the changes of prolactin secretion, nor for the reduction of peripheral sympathetic activity induced by SALS. Investigating the possible effect of pituitary hormones on the peripheral sympathetic system, the action of SALS has been tested in HYPOX rats. We have found that the effect of SALS on peripheral sympathetic terminals is not affected by HYPOX, consequently the role of pituitary hormones in the effect of SALS on the peripheral catecholamine metabolism may be excluded.]

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[PERSISTENT AKINETIC-RIGID SIDE EFFECTS OF NEUROLEPTICS MAY INDICATE WILSON'S DISEASE]

ASCHERMANN Zsuzsanna, SZALAY Ferenc, SCHMIDT Erzsébet, KOMOLY Sámuel, ILLÉS Zsolt

[Here we report two cases, where neuroleptic treatment provoked persistent akinetic-rigid symptoms resulting in the diagnosis of Wilson's disease. No liver function abnormalities suggested Wilson's disease in one of the cases. In both cases, the akinetic-rigid symptoms were originally attributed to side effects of neuroleptics, but symptoms persisted after discontinuation of treatment. In one of the cases, T2-weighted cranial MRI indicated bilateral hyperintense signals in the basal ganglia. Our cases suggest that in a subgroup of Wilson's disease, dopamin receptor antagonists may provoke akinetic-rigid neurological symptoms possibly due to the damage of dopaminergic neurons. Persistent akinetic-rigid side effects of neuroleptics in young patients thus require diagnostic tests to exclude Wilson's disease even in unsuspected cases.]

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