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Biomedical subjects

M Najimi

Publications and source records attributed to M Najimi.

At least 19 recordsLinked to original sources
PubMed2005

Liver cell transplantation.

Liver cell transplantation is an emerging procedure, consisting of infusing mature adult hepatocytes in the portal system of the recipient. It aims to correct inborn errors of liver metabolism, bridge unstable patients to transplantation, or even allow bridge to recovery in fulminant liver failure. The technique addresses ideally patients with inborn errors of metabolism, unstable but not sick enough for orthotopic transplantation. Best results have so far been obtained in metabolic diseases, such as urea cycle disorders, glycogenosis type I, Crigler Najjar, Refsum disease and factor VII deficiency. Cryopreserved hepatocytes can be used, allowing delay between cell isolation and patient's transplantation. The percentage of engraftment obtained can reach up 10%, with de novo expression of deficient enzyme activity. Better results of engraftment have been obtained in animal studies by different chemical or physical techniques, but not yet applied in humans. Because supply of human cells can be limited, research also aims to obtain transplantable cells from other sources, such as embryonic or adult stem cells, or liver progenitor cells that could be expanded in vitro. Careful progression in this field, and collaboration between centers are mandatory to validate further the technique for wider clinical use.

Adult↗
PubMed2002

Modulation Of [35S]-tert-butylbicyclophosphorothionate binding by somatostatin in rat hypothalamus.

1. The present study was designed to assess the effect of the tetradecapeptide somatostatin on the GABA(A) receptor complex in the rat hypothalamus. 2. GABA(A) receptors were labelled with [35S]-tert-butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel, and binding as assessed by in vitro quantitative autoradiography using a computer-assisted image analysis system. 3. Somatostatin inhibited the binding of [35S]-TBPS to the convulsant site of the hypothalamic GABA(A) receptor complex of rat slide-mounted hypothalamic structures in a concentration-dependent manner with an affinity in the micromolar range (10(-6) to 3 x 10(-6) mol/L). Somatostatin appeared to mimic the effects of the neurosteroid 5alpha-pregnane-3alpha ol-one (5alpha3alphaP), GABA and picrotoxin on [35S]-TBPS binding in the rat hypothalamus in all structures examined. Furthermore, GABA or muscimol (a GABA(A) receptor agonist), when added to the incubation medium, enhanced the capacity of somatostatin to inhibit [35S]-TBPS binding, with an IC50 of 10(-7) mol/L. However, incubation with bicuculline (a GABA(A) receptor antagonist) led to the abolition of the inhibitory effect of somatostatin on [35S]-TBPS specific binding in rat hypothalamus. 4. The present results demonstrate the presence of a modulatory effect of somatostatin on the GABA(A) receptor complex in rat hypothalamic structures. Furthermore, the data suggest that somatostatin allosterically modifies [35S]-TBPS binding through a mechanism similar to that of GABA. Taken together, these results provide evidence for the presence of somatostatin- GABA interactions in rat hypothalamus.

Animals↗
PubMed2001

Regional distribution of benzodiazepine binding sites in the human newborn and infant hypothalamus. A quantitative autoradiographic study.

Using in vitro quantitative autoradiography and [3H]flunitrazepam we examined the rostrocaudal distribution of benzodiazepine binding sites in the human neonate/infant hypothalamus. The autoradiographic analysis shows the presence of a heterogeneous distribution throughout the rostrocaudal extent of this brain structure. High [3H]flunitrazepam binding corresponds primarily to the diagonal band of Broca and the preoptic region. The labelling in the preoptic region showed a rostrocaudal increase, contrasting in that with the other hypothalamic structures. Intermediate densities were present in the septohypothalamic, suprachiasmatic, periventricular and paraventricular nuclei as well as in the mammillary complex. Low binding was observed in the other hypothalamic structures. The benzodiazepine binding sites analyzed belong mostly to type II receptors. In an attempt to unravel possible differences related to age, we compared the autoradiographic distribution in three postnatal age ranges. The topographical distribution of these binding sites was almost identical in each period analyzed. We found, however, that benzodiazepine binding is generally low in the neonatal period and a tendency in increasing densities is observed during development. Taken together, these results provide evidence for a large distribution of benzodiazepine binding sites in neonate/infant hypothalamus, suggesting their implication in the development of this brain structure and the maintenance of its various functions.

Age Factors↗
PubMed2001

Transcriptional regulation of the tyrosine hydroxylase gene by neurotensin in human neuroblastoma CHP212 cells.

The human neuroblastoma cell line CHP212 was found to express functional high affinity neurotensin (NTS-1) receptor subtype. Based on the functional interactions between neurotensin and dopamine transmission, we have used this cell line to investigate the short- and long-term modulation of tyrosine hydroxylase gene expression by the stable neurotensin agonist JMV 449. After exposure of the cells to 1 microM JMV 449 for 5 or 72 h, tyrosine hydroxylase protein and mRNA levels were significantly increased as detected by western blot analysis and quantitative RT-PCR, respectively. Transfection of CHP212 cells with a plasmid containing the luciferase reporter gene under the control of a limited proximal region of the cloned tyrosine hydroxylase promoter, revealed that the effect of JMV 449 results from an increase in the transcriptional activity of the TH gene. These results indicate that modulation of tyrosine hydroxylase gene expression may constitute one of the mechanisms involved in the control of dopamine transmission by neurotensin. Such neurotensin-mediated changes in tyrosine hydroxylase expression may also participate in multiple adaptation processes within the central nervous system to environmental conditions where neurotensin is released such as stress and food intake.

Blotting, Western↗
PubMed2001

Allosteric modulation of the GABA(A) receptor in rat hypothalamus by somatostatin is altered by stress.

1. This autoradiographic study was conducted to investigate somatostatin modulation of GABA(A) receptor binding in hypothalamic structures of immobilization-stressed rats. 2. GABA(A) receptor binding was labelled with [35S]-t- butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel. 3. Several structures of the rat hypothalamus (i.e. the peri- and paraventricular nuclei) display an increase in [35S]-TBPS binding as well as an alteration of the modulatory effect of somatostatin on the GABA(A) receptor complex under stress. Furthermore, these results demonstrate for the first time that somatostatin is particularly effective in modifying [35S]-TBPS binding to the GABA(A) receptor in rat hypothalamus.

Allosteric Regulation↗
PubMed2001

Modulation of the neuronal dopamine transporter activity by the metabotropic glutamate receptor mGluR5 in rat striatal synaptosomes through phosphorylation mediated processes.

There is considerable evidence that the activity of the neuronal dopamine transporter (DAT) is dynamically regulated and a putative implication of its phosphorylation in this process has been proposed. However, there is little information available regarding the nature of physiological stimuli that contribute to the endogenous control of the DAT function. Based on the close relationship between glutamatergic and dopaminergic systems in the striatum, we investigated the modulation of the DAT activity by metabotropic glutamate receptors (mGluRs). Short-term incubations of rat striatal synaptosomes with micromolar concentrations of the group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine were found to significantly decrease the DAT capacity and efficiency. This alteration was completely prevented by a highly selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). The effect of (S)-3,5-dihydroxyphenylglycine was also inhibited by staurosporine and by selective inhibitors of protein kinase C and calcium calmodulin-dependent protein kinase II. Co-application of okadaic acid prolonged the transient effect of the agonist, supporting a critical role for phosphorylation in the modulation of the DAT activity by mGluRs. In conclusion, we propose that striatal mGluR5 contribute to the control of the DAT activity through concomitant activation of both protein kinase C and calcium calmodulin-dependent protein kinase II.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Immunohistochemical distribution of DSIP immunoreactivity in the human hypothalamus during the first postnatal year. A preliminary report.

The distribution of DSIP-IR cell bodies and fibers was investigated in the normal human hypothalamus during the first postnatal year using the indirect immunofluorescence technique. The analysis of the immunohistochemical patterns obtained in the seven cases analyzed showed regional differences in the localization of cell bodies and fibers. Immunoreactive perikarya were relatively few, and were mostly scattered throughout the anterior and the mediobasal hypothalamus. DSIP-IR fibers and terminal-like structures were observed throughout the rostro-caudal extent of the hypothalamic region. In the present study, we noticed qualitative changes in the density of DSIP immunoreactivity in several hypothalamic structures such as the preoptic area and the median eminence with respect to age. These postnatal differences observed for DSIP could be related to neuronal maturation processes occurring at this period in the central nervous system as well as other physiological processes controlling the evolution of DSIP concentrations. These data are compatible with the proposed role of the neuropeptide in the regulation of many postnatal physiological functions.

Aging↗
PubMed2001

Allosteric modulation of GABAA receptor by somatostatin is altered under stress in rat brainstem.

This study was conducted to investigate somatostatin modulation of GABAA receptor binding in several rat brainstem structures, located principally in the mesencephalon, after exposure to acute immobilization stress (single 1-hour session). Animals were randomly assigned to either control or stress conditions and changes in specific binding of the GABAA receptor as labelled with TBPS were assessed by in vitro quantitative autoradiography with the aid of a computer-assisted image analysis system. Exposure to immobilization stress led to a significant increase in [35S]TBPS binding site density in the SN of stressed rats compared to controls. In the other brainstem structures analysed, specific binding of [35S]TBPS remained unchanged in stressed rats. Furthermore, the results of the present in vitro study demonstrate an alteration of the modulatory effect of somatostatin on the GABAA receptor complex in the SN of stressed rats as compared to controls. This apparent alteration of allosteric effects of GABA receptor-somatostatin in the SN of stressed rats was eliminated in the presence of 1 micromolar concentration of GABA. Taken together, these data provide the first evidence of stress-induced alteration of allosteric effects of GABA-somatostatin in the rat mesencephalon. Furthermore, they also demonstrate that the tetradecapeptide somatostatin is particularly effective in modifying the [35S]TBPS binding to the GABAA receptor in this cerebral region.

Allosteric Regulation↗
PubMed2001

Distribution of delta sleep-inducing peptide in the newborn and infant human hypothalamus: an immunohistochemical study.

The distribution of delta sleep-inducing peptide immunoreactive cell bodies, fibers, and terminal-like structures was investigated in the normal human hypothalamus during the first postnatal year, using immunohistofluorescence and peroxidase anti-peroxidase techniques. Immunolabeled perikarya were relatively few and were mostly scattered through the anterior (preoptic) and mediobasal regions (infundibular nucleus) of the hypothalamus. DSIP-immunoreactive fibers and terminal-like fibers were observed throughout the entire rostrocaudal extent of the hypothalamus. They exhibit high densities in the preoptic region, the organum vasculosum of lamina terminalis, infundibular nucleus and median eminence. Moderate to low densities of DSIP-immunoreactive fibers were observed in the other hypothalamic structures, located in the anterior and mediobasal regions of hypothalamus, such as periventricular, paraventricular, suprachiasmatic, ventromedial, dorsomedial and parafornical nuclei. In the present study, the analysis of the immunohistochemical pattern of DSIP-immunoreactive neuronal elements in the human infant hypothalamus during the first postnatal year provided evidence of the presence of several differences. We have found qualitative age-related changes in the density of DSIP immunoreactivity in several hypothalamic structures such as the anterior region and the median eminence.

Delta Sleep-Inducing Peptide↗
PubMed2000

Evidence for the dual coupling of the rat neurotensin receptor with pertussis toxin-sensitive and insensitive G-proteins.

We previously demonstrated the functional coupling of the rat neurotensin receptor NTS1 with G-proteins on transfected CHO cell homogenates by showing modulation of agonist affinity by guanylyl nucleotides and agonist-mediated stimulation of [(35)S]GTP gamma S binding. In the present study, we observed that G(i/o)-type G-protein inactivation by pertussis toxin (PTx) resulted in a dramatic reduction of the NT-induced [(35)S]GTP gamma S binding whereas the effect of guanylyl nucleotide was almost not affected. As expected, NT-mediated phosphoinositide hydrolysis and intracellular calcium mobilization were not altered after PTx treatment. This suggests the existence of multiple signaling cascades activated by NT. Accordingly, using PTx and the PLC inhibitor U-73122, we showed that both signaling pathways contribute to the NT-mediated production of arachidonic acid. These results support evidence for a dual coupling of the NTS1 with PTx-sensitive and insensitive G-proteins.

Animals↗
PubMed1999

Benzodiazepine binding sites in the human hypothalamus. Autoradiographic study.

Using in vitro labelling and autoradiographic techniques, we have analyzed the fine and the detailed distribution of benzodiazepine binding sites in the post-mortem human hypothalamus. Binding sites were labelled in mounted tissue sections from adult brains, using the selective high affinity ligand [3H]-Flunitrazepam. A heterogeneous distribution of benzodiazepine binding sites was found throughout the rostrocaudal extent of human hypothalamus. The autoradiographic labelling was shown in the three hypothalamic parts, i.e., anterior, mediobasal and posterior levels. At the anterior level, the highest densities were present in the diagonal band of Broca, the preoptic area (medial and lateral parts) and the septohypothalamic nucleus. At the mediobasal hypothalamic level, the highest densities were mainly localized in the ventromedial nucleus, whereas the other structures were moderately labelled with [3H]-Flunitrazepam. The mammillary complex as well as the posterior hypothalamic area represented the most heavily labelled structures in the posterior hypothalamus. The results obtained in this study, indicate the presence of a large and heterogeneous distribution of benzodiazepine binding sites in human adult hypothalamus. This could support their implication in the control of distinct neural functions (like neuroendocrine role).

Adult↗
PubMed1998

Activation of receptor gene transcription is required to maintain cell sensitization after agonist exposure. Study on neurotensin receptor.

Neurotensin (NT) acts through specific G protein-coupled receptors to induce effects in the central nervous system and periphery. In this study we have shown that in the human neuroblastoma cell line CHP 212, an NT agonist, JMV 449, induced high affinity neurotensin receptor (NTR) gene activation. 125I-NT binding of cells challenged with JMV 449 rapidly decreased then reappeared and subsequently stabilized at 50% of the control values after 48 h of agonist exposure. These receptors, which reappeared at the cell surface, are as active as those found in control cells as demonstrated by Ca2+ mobilization. Furthermore, the tyrosine hydroxylase (TH) gene, a known NT target gene, remained activated after prolonged NT agonist exposure in this cell line. In the murine neuroblastoma cell line, N1E-115, NT did not stimulate NTR gene activation but induced NTR mRNA destabilization after long term agonist exposure. In this cell line, NT binding dropped to 15% of control values and remained at this value after agonist treatment. The TH expression, which was originally activated upon NT agonist exposure, decreased to control values after prolonged agonist exposure. These observations combined with the data obtained from a complementary study with HT-29 cells (Souazé, F., Rostène, W., and Forgez, P. (1997) J. Biol. Chem. 272, 10087-10094) revealed the crucial role of agonist-induced receptor gene transcription in the maintenance of cell sensitivity. A model for G protein-coupled receptor regulation induced by prolong and intense agonist stimulation is proposed.

Animals↗
PubMed1994

Localization and developmental pattern of vasoactive intestinal polypeptide binding sites in the human hypothalamus.

Using a quantitative in vitro autoradiographic approach, vasoactive intestinal polypeptide (VIP) binding site densities were compared in the post-mortem hypothalamus of human neonate/infant and adult. The densities were similar during development in most of the hypothalamic nuclei and areas examined underlying the stability of 125I-VIP binding sites in the post-mortem hypothalamus of young and adult individuals. However, the ventral part of the medial preoptic area, the medial, lateral, and supramammillary nuclei were characterized by an increase of 125I-VIP binding with age. In young and adult individuals, the highest densities of hypothalamic 125I-VIP binding sites were detected in the supraoptic and infundibular nuclei; the ependyma; the organum vasculosum of the lamina terminalis; the horizontal limb of the diagonal band of Broca; the ventral part of the medial preoptic area (in adult); the suprachiasmatic, paraventricular, and periventricular nuclei; and the medial and lateral mammillary nuclei in adult. Moderate densities were found in the vertical limb of the diagonal band of Broca, the bed nucleus of the stria terminalis, the ventral part of the medial preoptic area in neonate/infant, the medial and lateral mammillary nuclei in neonate/infant, the supramammillary nucleus in adult, the dorsal hypothalamic area, and the ventromedial nucleus. Low to moderate binding site densities were observed in the other hypothalamic regions of young or adult individuals. The nonspecific binding ranged from 15% of the total binding in the anterior hypothalamus to 20% in the mediobasal and posterior hypothalamic levels. Taken together, these results provide evidence for a large distribution of VIP binding sites in neonate/infant and adult human hypothalamus suggesting the implication of VIP in the development of this brain structure and the maintenance of its various functions.

Adult↗
PubMed1992

Evidence for a substance P containing subpopulation in the primate suprachiasmatic nucleus.

Immunohistochemical detection of substance P (SP) in the suprachiasmatic nucleus (SCN) of the Old World monkey, Macaca fascicularis, was performed using two different rabbit polyclonal antisera. Immunostaining revealed a large population of neurons located in the dorsal subdivision of the nucleus identified by Nissl stain. This neuronal group represents the only cluster of SP-like immunoreactive (SP-IR) perikarya observed within the hypothalamus. In contrast with our present finding in the macaque, earlier studies only reported a few scattered SP-IR neurons in the SCN of other mammalian species. In agreement with previous descriptions of neuropeptides in the SCN, the topographical distribution of SP-IR neurons in the monkey confirms that cellular segregation is a significant feature of the mammalian SCN. This particular peptidergic subpopulation may represent a characteristic of the monkey circadian pacemaker. Together with other anatomical data previously reported in monkey and man, this finding also relates to the anatomical evolution of the circadian system from non-primates to humans. Although convincing data support the implication of SP in cyclic neuroendocrine regulations, the role of this tachykinin in circadian rhythmicity remains to be elucidated.

Animals↗
PubMed1992

Quantitative autoradiographic study of somatostatin and neurotensin binding sites in medulla oblongata of SIDS.

Quantitative autoradiography analysis of neurotensin (NT) and somatostatin (SS) binding sites was performed on coronal sections of the medulla oblongata from 2 fetuses, 6 controls and 7 victims of Sudden Infant Death Syndrome (SIDS). Throughout the first postnatal year, mean SS binding site density was similar in controls and SIDS in all structures of the medulla oblongata. The density of neurotensin binding sites was significantly higher in the nucleus of tractus solitarius (NTS) of SIDS than in controls, but there was no significant differences in the other areas of the medulla oblongata. Our findings suggest an immature developmental pattern of increased NT binding sites the NTS of SIDS. This alteration may be related to an abnormal central cardiorespiratory and arousal control which is thought to be present in SIDS.

Autoradiography↗
PubMed1992

Ontogeny of peptides in human hypothalamus in relation to sudden infant death syndrome (SIDS).

The brains of mammals are not mature at birth, in particular in humans. Growth and brain development are influenced by the hormonal state in which the hypothalamus plays the major regulatory role. The maturation of the hormonal patterns leads to the physiological establishment of chronological variations as revealed by the circadian variations of both hypothalamic peptides and pituitary hormones (as illustrated for hypothalamic-pituitary-thyroid axis by the determination of thyro-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) circadian rhythms in the rat (Jordan et al., 1989)). It has been established that hypothalamic peptide variations are regulated by hormonal feed-back and amine systems, with the maturation of the latter also being dependent upon the whole functional maturation of the brain. Though these systems have been studied in the rat, very little information is currently available with regard to the human brain. The only biochemical or immunohistochemical information published to date concerns either the fetus or the adult. We have studied four main peptidergic systems (somatostatin-releasing inhibiting factor (SRIF), thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LHRH) and delta sleep inducing peptide (DSIP) in post-mortem adults and infants and in sudden infant death syndrome (SIDS) brains either by autoradiography and/or immunochemistry of radioimmunology. From a technical point of view, human brain studies display certain pitfalls not present in animal studies. These may be divided into two subclasses: ante- and post-mortem. Ante-mortem problems concern mainly sex, laterality, nutritional and treatment patterns while post-mortem problems concern post-mortem delay and conditions before autopsy and hypothalamic dissection. This might induce dramatic changes in morphological, immunochemical and autoradiographic evaluations. The matching of pathological subjects with controls is particularly difficult in the case of SIDS because of the rapid changes which take place in physiological regulatory processes during the first year of life. Thus, the treatment of hypothalamic tissue samples both for immunochemistry, radioimmunology and autoradiographic studies required techniques which must be rigorously controlled. For example, SRIF studies were carried out with three different antibodies, which gave similar results. The use of different technical procedures as well as different antibodies is discussed. These types of differences might explain, at least in part, the discrepancy observed until now. As previously described in the fetus (Bugnon et al., 1977b; Bouras et al., 1987), we confirmed that in the infant hypothalamic SRIF immunoreactive cell bodies are present in the paraventricular and suprachiasmatic nuclei and in the periventricular area.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Autoradiographic distribution of TRH binding sites in the human hypothalamus.

Using in vitro quantitative autoradiography and [3H]3MeTRH, a selective high affinity radioligand, we examined the rostrocaudal distribution of TRH binding sites in both the infant and the adult human hypothalamus. The saturation curve shows that the [3H]3MeTRH binds with high affinity to a single class of TRH binding sites and is saturable, the apparent constant of dissociation is in the namomolar range. TRH binding sites showed a wide distribution, principally in the anterior and mediobasal levels of the hypothalamus. TRH binding site concentration was highest within the diagonal band of Broca, the lateral preoptic area, the infundibular and the tuberal nuclei. TRH binding site concentration was moderate in the ventromedial nucleus and the medial preoptic area, whereas we observed low densities in the periventricular, paraventricular and mammillary nuclei. The distribution in the infant and the adult is generally similar. However, it is noteworthy that the infant tuberal nuclei displayed a lower binding site density when compared to the adult. On the other hand, the diagonal band of Broca is relatively more labeled in infant. The analysis of the whole hypothalamus allows us to ascertain the absence of lateral asymmetric distribution both in the infant and the adult. No significant difference is noticed when considering as parameters of variation age, sex or post mortem delay.

Adult↗