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M Palkovits

Publications and source records attributed to M Palkovits.

At least 37 records · Page 2Linked to original sources
PubMed2001

Serotonergic genes and suicidality.

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior. Studies have shown that the number of brain and platelet serotonin transporter binding sites are reduced in patients with depression and in suicide victims, and that the density of 5-HT2A receptors is increased in brain regions of depressed in suicide victims and in platelets of depressed suicidal patients. Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter, and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have thus been major candidate genes for association studies of suicide and suicidal behavior. Recent studies by our group and by others have shown that genetic variations in the serotonin-system-related genes might be associated with suicidal ideation and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1 (95% CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality supports the hypothesis that genetic factors can modulate suicide risk by influencing serotonergic activity.

Alleles↗
PubMed2001

Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain.

Apelin, a peptide recently isolated from bovine stomach tissue extracts, has been identified as the endogenous ligand of the human orphan APJ receptor. We established a stable Chinese hamster ovary (CHO) cell line expressing a gene encoding the rat apelin receptor fused to the enhanced green fluorescent protein, to investigate internalization and the pharmacological profile of the apelin receptor. Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. In contrast, the apelin fragments R10F (Arg8-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and G5F (Gly13-Pro-Met-Pro-Phe17) were inactive. The physiological role of apelin and its receptor was then investigated by showing for the first time in rodent brain: (i) detection of apelin neurons in the supraoptic and paraventricular nuclei by immunohistochemistry with a specific polyclonal anti-apelin K17F antibody; (ii) detection of apelin receptor mRNA in supraoptic vasopressinergic neurons by in situ hybridization and immunohistochemistry; and (iii) a decrease in vasopressin release following intracerebroventricular injection of K17F, or pE13F, but not R10F. Thus, apelin locally synthesized in the supraoptic nucleus could exert a direct inhibitory action on vasopressinergic neuron activity via the apelin receptors synthesized in these cells. Furthermore, central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure. Together, these results suggest that neuronal apelin plays an important role in the central control of body fluid homeostasis.

Adipokines↗
PubMed2001

Stressor specificity of central neuroendocrine responses: implications for stress-related disorders.

Despite the fact that many research articles have been written about stress and stress-related diseases, no scientifically accepted definition of stress exists. Selye introduced and popularized stress as a medical and scientific idea. He did not deny the existence of stressor-specific response patterns; however, he emphasized that such responses did not constitute stress, only the shared nonspecific component. In this review we focus mainly on the similarities and differences between the neuroendocrine responses (especially the sympathoadrenal and the sympathoneuronal systems and the hypothalamo-pituitary-adrenocortical axis) among various stressors and a strategy for testing Selye's doctrine of nonspecificity. In our experiments, we used five different stressors: immobilization, hemorrhage, cold exposure, pain, or hypoglycemia. With the exception of immobilization stress, these stressors also differed in their intensities. Our results showed marked heterogeneity of neuroendocrine responses to various stressors and that each stressor has a neurochemical "signature." By examining changes of Fos immunoreactivity in various brain regions upon exposure to different stressors, we also attempted to map central stressor-specific neuroendocrine pathways. We believe the existence of stressor-specific pathways and circuits is a clear step forward in the study of the pathogenesis of stress-related disorders and their proper treatment. Finally, we define stress as a state of threatened homeostasis (physical or perceived treat to homeostasis). During stress, an adaptive compensatory specific response of the organism is activated to sustain homeostasis. The adaptive response reflects the activation of specific central circuits and is genetically and constitutionally programmed and constantly modulated by environmental factors.

Adrenocorticotropic Hormone↗
PubMed2001

Gene expression of catecholamine synthesizing enzymes in A5 cell group and modulation of tyrosine hydroxylase mRNA by immobilization stress.

OBJECTIVE: The A5 group of noradrenergic neurons plays a key role in autonomic mechanisms like cardiovascular regulation, nociception and respiration. The aim of this work was to detect the gene expression of catecholamine synthesizing enzymes in A5 brain nuclei. METHODS: The gene expression of. tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyl-transferase (PNMT) in A5 brain nuclei was estimated. We also investigated various time intervals after the end of the single two-hour immobilization, as well as the effect of short-term repeated immobilization (120 min daily for 7 days) on tyrosine hydroxylase gene expression, the rate-limiting enzymes in catecholamines biosynthesis, in the A5 cell group. For all experiments, reverse transcription with subsequent polymerase chain reaction (RT-PCR) was used. RESULTS: As expected, we detected a clear signal for TH and DBH mRNA but no signal for PNMT mRNA. Both, single and repeated immobilization stress exposure increased significantly the gene expression of TH in A5 area. Maximal elevation in TH mRNA levels occurred after single immobilization for two hours and subsequent decapitation 24 hours later. CONCLUSIONS: In this study we detected for the first time the presence of DBH mRNA in micro dissected A5 cell group. We also showed how the gene expression of tyrosine hydroxylase changed with the function of time after the single immobilization exposure. Thus, TH mRNA in A5 cell group is modulated by immobilization stress in a time-dependent manner.

Animals↗
PubMed2000

Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation.

Various factors, including the orphan nuclear receptor Nurr1, have been implicated in dopamine biosynthesis, but many of the specific events involved in this process have to be determined. Using genetic manipulations in mice, the obligatory role for Nurr1 in dopamine (DA) biosynthesis has been documented; however, the mechanism remains unclear. DA biosynthetic enzymes, transporters and receptors are absent in the substantia nigra (SN) and the ventral tegmental area (VTA) of Nurr1-null neonates. The current study establishes that the loss of Nurr1 function does not affect the normal ventralization of neuroepithelial cells to the ventral midbrain, their differentiation into neurons, and their topographical pattern in the SN and VTA. Futhermore, the absence of Nurr1 does not affect the survival of these DA precursor cells in the ventral midbrain, as determined by quantitative analysis of cells, expressing the general neuronal nuclear marker (NeuN) and the TUNEL assay for apoptosis. These neurons express cholecystokinin (CCK), a co-transmitter of dopaminergic neurons in this area. The untranslated exon 1-2 of the Nurr1 gene, which remains intact after homologous recombination, revealed the presence of dopaminergic precursors in the ventral midbrain of the Nurr1-null mice. In addition, these neurons establish their nigrostriatal projections, as shown by axonal transport of a fluorescent tracer, DiI. These results provide evidence that Nurr1 is essential for terminal differentiation of the dopaminergic neurons in the ventral midbrain but does not affect the early steps of their neurogenesis, migration, survival and striatal projections. Our findings suggest that activation of Nurr1 might be therapeutically useful in Parkinson's disease.

Animals↗
PubMed2000

[The brain and the pain: neurotransmitters and neuronal pathways of pain perception and response].

The pain, an unpleasant feeling, induces several central nervous system mechanisms, like sensory-discriminative, motivational-affective activities, behavioral changes and it activates various responses, including antinociceptive actions. Accordingly, signals from the nociceptive neurons in the spinal cord and the sensory trigeminal nucleus ascend in various neuronal pathways and target several brain areas. Here, five ascending pain-conducting neuronal pathways and two spinal reflex routes are briefly summarized. The spinal and supraspinal antinociceptive mechanisms are described in more detail. During the past two decades, endogenous opioids, cannabinoids and their receptors have been discovered, localized and cloned. Five groups of endogenous opiates are known: beta-endorphin, enkephalins, dynorphins, endomorphins, and nociceptin. Two endogenous cannabinoids have already been described in the brain: the anandamide and the 2-arachidonyl-glycerol. The site of their antinociceptive (analgesic) actions in the brain are briefly summarized.

Afferent Pathways↗
PubMed2000

Increased c-Jun expression in neurons affected by lysolecithin-induced demyelination in rats.

The objective of this study was to investigate whether the expression of c-Jun is involved in the neuronal response to experimental demyelination. Lysolecithin-induced demyelination was generated in two distinct neural systems in rats: in the pontocerebellar and the septohippocampal pathways. Six days after the stereotaxic injections of lysolecithin, expression of the immediate early gene c-Jun was visualized by immunohistochemistry. Lesion-specific expression of the Jun protein was observed in neurons whose axons transverse the demyelinated area. Unlike the neural response to axotomy, lysolecithin treatment did not alter the expression of the neuropeptide galanin in the septohippocampal pathway. These results suggest that c-Jun protein expression might represent one step in the neuronal response to demyelination and that this response might be distinct in its downstream events from axotomy.

Animals↗
PubMed2000

Stress-induced expression of co-localized neuropeptides in hypothalamic and amygdaloid neurons.

This short review summarizes the effect of various stressful stimuli on the expression of neuropeptides which co-localize in corticotrophin releasing hormone (CRH)-synthesizing neurons in the hypothalamic paraventricular nucleus, as well as in oxytocin and vasopressin neurons in the supraoptic nucleus. Stress-induced changes failed to act on CRH neurons in the central amygdaloid nucleus but formalin-evoked pain enhanced galanin mRNA expression in the medial subdivision of this nucleus. Changes in the expression of enkephalin, galanin, dynorphin and cholecystokinin mRNA in response to restraint and formalin-induced pain are documented in hypothalamic and amygdaloid nuclei by in situ hybridization histochemical technique.

Amygdala↗
PubMed2000

Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues.

The human APJ receptor is a G protein-coupled receptor which functions as an efficient alternative co-receptor for a number of human immunodeficiency virus type 1 and simian immunodeficiency virus strains. We have cloned the rat APJ receptor, which we term B78/apj, and have mapped the mRNA distribution of both the receptor and its natural ligand apelin in rat tissues. Northern blot analysis showed a similar pattern of expression for B78/apj and apelin mRNAs with hybridising transcripts seen in the lung, heart, skeletal muscle, kidney, brain and liver. In situ hybridisation histochemistry studies revealed intense B78/apj gene expression in the parenchyma of the lung, a sub-population of glomeruli in the kidney, the corpora lutea of the ovary and isolated cells of the anterior lobe of the pituitary. B78/apj mRNA had a striking and unique distribution within the central nervous system (CNS) where receptor expression was found in cells within the meninges around the brain, in the posterior magnocellular and medial parvocellular areas of the hypothalamic paraventricular nucleus and in the supraoptic nucleus. This hypothalamic distribution offers a possible specific role of this receptor in mediating neuroendocrine responses in the CNS.

Amino Acid Sequence↗
PubMed2000

Septamer element-binding proteins in neuronal and glial differentiation.

Differentiation of progenitors into neurons and glia is regulated by interactions between regulatory DNA elements of neuron- and glia-specific genes and transcription factors that are differentially expressed by progenitors at progressive stages of neural development. We have identified a novel DNA regulatory element (TTTGCAT = septamer) present on the enkephalin (ENK), neuronal cell adhesion molecule, neurofilament of 68 kDa (NF68), growth-associated protein of 43 kDa, glial high-affinity glutamine transporter, tyrosine hydroxylase, etc., genes. When septamer function was blocked by introducing septamer competitor DNA into primary differentiating neural cultures, mRNA levels of ENK, NF68, and glial fibrillary acidic protein decreased by 50-80%, whereas no effect was seen using a control DNA. Septamer elements serve as binding sites for lineage-specific multimeric complexes assembled from three distinct nuclear proteins. Progenitors express a 16 kDa protein (p-sept) which binds to DNA as a homodimer (detected as the 32 kDa P-band). Cells that entered the neuronal lineage express an additional 29 kDa protein (n-sept) that binds to the homodimerized p-sept, and together they form a 62 kDa multimer (detected as N-band). Cells that entered the glial lineage express a distinct 23 kDa protein (g-sept), which along with the homodimerized p-sept form a 56 kDa multimer (observed as G-band). The binding of the distinct protein complexes (P, G, and N) to the septamer site causes a lineage-specific DNA bending (P = 53 degrees; G = 72 degrees; and N = 90 degrees ), which may contribute to the regulatory effect of the septamer interaction. In summary, septamer and its binding proteins represent novel protein-DNA interactions that may contribute to the regulation of neuroglial differentiation in the developing mammalian CNS.

Aging↗
PubMed2000

New members of the parathyroid hormone/parathyroid hormone receptor family: the parathyroid hormone 2 receptor and tuberoinfundibular peptide of 39 residues.

The parathyroid hormone (PTH) family currently includes three peptides and three receptors. PTH regulates calcium homeostasis through bone and kidney PTH1 receptors. PTH-related peptide, probably also through PTH1 receptors, regulates skeletal, pancreatic, epidermal, and mammary gland differentiation and bladder and vascular smooth muscle relaxation and has a CNS role that is under investigation. Tuberoinfundibular peptide of 39 residues (TIP39) was recently purified from bovine hypothalamus based on selective PTH2 receptor activation. PTH2 receptor expression is greatest in the CNS, where it is concentrated in limbic, hypothalamic, and sensory areas, especially hypothalamic periventricular neurons, nerve terminals in the median eminence, superficial layers of the spinal cord dorsal horn, and the caudal part of the sensory trigeminal nucleus. It is also present in a number of endocrine cells. Thus TIP39 and PTH2 receptor-influenced functions may range from pituitary and pancreatic hormone release to pain perception. A third PTH-recognizing receptor has been found in zebrafish.

Amino Acid Sequence↗
PubMed2000

Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia.

Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.

Animals↗
PubMed2000

Distribution of parathyroid hormone-2 receptor-like immunoreactivity and messenger RNA in the rat nervous system.

The parathyroid hormone-2 receptor is a member of the secretin family of guanine nucleotide-binding protein-coupled receptors. The human parathyroid hormone-2 receptor is activated by parathyroid hormone and a recently purified hypothalamic polypeptide, tubero-infundibular peptide of 39 residues, while the rat parathyroid hormone-2 receptor is poorly activated by parathyroid hormone and is potently activated by tubero-infundibular peptide of 39 residues. In order to provide a foundation for studies on the physiological role of the parathyroid hormone-2 receptor and tubero-infundibular peptide of 39 residues, we investigated the cellular distribution of the parathyroid hormone-2 receptor in the rat CNS using both immunohistochemistry and in situ hybridization histochemistry. The receptor is found in discrete groups of neurons in many regions. It is present in scattered small cells throughout the cerebral cortex, in small and medium-sized cells in the striatum, and is quite abundant in the septum and the midline thalamic nuclei. Its expression is high in the hypothalamus, particularly in the periventricular and arcuate nuclei. Fibers and terminals in the external zone of the median eminence, and in the superficial layers of the caudal spinal trigeminal tract and the spinal cord dorsal horn, are strongly and dramatically labeled by a parathyroid hormone-2 receptor-selective antibody. The localization of parathyroid hormone-2 receptor suggests a role in the regulation of pituitary hormone secretion, sensory information processing and homeostatic regulation.

Animals↗
PubMed2000

Axonal changes in chronic demyelinated cervical spinal cord plaques.

Imaging and pathomorphological studies in multiple sclerosis suggest that axonal injury and axonal loss are playing a crucial role in those with persistent disability and long-standing disease. Although the existence of axonal injury in multiple sclerosis is proven, especially in the zone of active inflammation, the effect of chronic inflammation on the axons remains elusive. The aim of this study was to perform a quantitative morphometrical analysis, estimating axonal loss and evaluating axonal degenerative changes in cervical spinal cord samples of patients suffering from secondary progressive multiple sclerosis. Completely demyelinated plaques, normal appearing white matter (NAWM) and control material from anatomically identical regions of the cord have been compared. Neurofilament immunostaining was used for identification of the axons. We observed a significant reduction of axonal density (number of axons/mm(2)) in multiple sclerosis, both in the plaque and in the NAWM compared with the control cases. Axons under approximately 3.3 microm diameter seemed to be more affected. The intensity of the immunostaining was significantly reduced in the plaque compared with either NAWM or control. Our results on the cervical cord combined with other observations support the concept of slow axonal degeneration rather than acute damage as a cause of chronic disability in multiple sclerosis.

Adult↗
PubMed2000

Fine topography of brain areas activated by cold stress. A fos immunohistochemical study in rats.

Neuronal activity in response to acute cold exposure was mapped in the central nervous system of adult rats using Fos immunostaining. A single, 3-hour exposure to cold elicited strong Fos-like immunoreactivity in the medial preoptic nucleus that is known as the thermoregulatory center of the brain. By this technique, pontine and medullary thermosensitive areas have been first localized and outlined anatomically. The medullary thermosensitive neurons occupy well-demarcated areas immediately ventral and dorsal to the spinal trigeminal nucleus, termed peritrigeminal and paratrigeminal nuclei, respectively. Cold-sensitive neurons were present in the dorsal part of the pontine reticular formation. Topographically, this area corresponds to the 'pontine thermoregulatory area', named on the basis of neurophysiological observations. In addition, thermosensitive neurons were found in the rostral thalamus and zona incerta. Several cell groups that showed strong Fos-like immunoreactivity in our previous pain-related stress experiments were also activated by cold exposure. The midline thalamic, hypothalamic dorsomedial, supramamillary and lateral parabrachial nuclei were targets of cold stress-induced noxious stimuli. Fos-positive neurons established specific topographical patterns in the paraventricular, arcuate, central amygdaloid nuclei, and the nucleus of the solitary tract. The possible involvement of central noradrenergic neurons in stress response to acute cold exposure was investigated by double immunostaining for tyrosine hydroxylase (TH) and Fos. None of the tyrosine hydroxylase positive neurons in the brain stem established Fos-like immunoreactivity, suggesting that the central noradrenergic system may have a minor, if any, role in cold-induced stress responses. Based on the topographical distribution of Fos-activated neurons, this study suggests that in addition to the hypothalamo-pituitary-adrenal axis, some other stress effector systems may play an important role in the maintenance of homeostasis during cold stress.

Animals↗