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F Hefti

Publications and source records attributed to F Hefti.

At least 73 records · Page 4Linked to original sources
PubMed1995

Immunohistochemical visualization of brain-derived neurotrophic factor in the rat brain.

A purified polyclonal antibody preparation was made against recombinant brain-derived neurotrophic factor (BDNF) in guinea pig and characterized for use in immunoassays and immunohistochemistry. The anti-BDNF antibodies specifically recognized BDNF in Western blots and immunoprecipitation. There was no cross-reactivity with the other known mammalian members of the neurotrophin family, nerve growth factor, neurotrophin-3 and neurotrophin-4/5. In immunohistochemical analysis, the anti-BDNF recognized exogenous BDNF injected into the brain of rats, whereas no signal was obtained with the other neurotrophins. Preabsorption with native BDNF abolished the immunoreactivity in brain sections. These studies identify the anti-BDNF as a tool for immunocytochemistry and the development of an immunoassay. Immunohistochemical analysis revealed widespread neuronal localization of BDNF in many brain areas. BDNF was localized in all subpopulations of hippocampal neurons. The distribution in the hippocampus suggests localization in the cytoplasm of cell bodies and dendrites.

Animals↗
PubMed1995

Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain.

Glial-cell-line-derived neurotrophic factor (GDNF) promotes survival of embryonic dopaminergic neurons in culture, and its expression pattern suggests a role as a transient target-derived trophic factor for dopaminergic neurons of the substantia nigra. These neurons participate in the control of motor activity, emotional status and cognition, and they degenerate in Parkinson's disease for unknown reasons. To test whether GDNF has a trophic effect on dopaminergic neurons in the adult brain, we used a rat model in which these neurons are induced to degenerate by transecting their axons within the medial forebrain bundle. We report here that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra. This loss was largely prevented by repeated injections of GDNF adjacent to the substantia nigra. Our findings suggest that GDNF or related molecules may be useful for the treatment of Parkinson's disease.

Animals↗
PubMed1995

Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy.

Cisplatin, a widely used chemotherapeutic agent, induces a sensory neuropathy with selective loss of vibration sense and proprioception. Here we demonstrate that neurotrophin-3 (NT-3), a member of the nerve growth factor family of neurotrophic factors, restored to normal levels the reduced H-reflex-related sensory nerve conduction velocity induced by cisplatin in rats. NT-3 treatment corrected an abnormal cytoplasmic distribution of neurofilament protein in large sensory neurons in dorsal root ganglia and the reduction in the numbers of myelinated fibers in sural nerves caused by cisplatin. The NT-3-dependent reversal of cisplatin neurotoxicity thus suggests the possible use of NT-3 in the treatment of peripheral sensory neuropathy.

Animals↗
PubMed1995

Retrograde transport of nerve growth factor from hippocampus and amygdala to trkA messenger RNA expressing neurons in paraventricular and reuniens nuclei of the thalamus.

We previously reported the presence of trkA messenger RNA expressing non-cholinergic neurons in the paraventricular anterior and reuniens nuclei, which are located in the thalamic midline. In the present study, retrograde labeling with iodinated (125I) nerve growth factor was used to identify the innervation target of these cells. Neurons in the paraventricular anterior and reuniens nuclei were labeled following injection of iodinated nerve growth factor into amygdala and hippocampus, but not into nucleus accumbens and entorhinal cortex, the two other main areas receiving strong innervation from the thalamic midline. Target ablation of hippocampus or amygdala failed to down-regulate trkA messenger RNA expression in the two thalamic nuclei, thus suggesting a role for nerve growth factor different from a critical survival factor. The thalamic paraventricular anterior and reuniens nuclei are part of the reticular formation which plays a role in general cortical activation, behavioral arousal and control of awareness. Retrograde transport of nerve growth factor by trkA messenger RNA expressing neurons in these nuclei suggests a physiological role of this trophic factor in the function of these cells.

Amygdala↗
PubMed1995

Differential regulation of catalytic and non-catalytic trkB messenger RNAs in the rat hippocampus following seizures induced by systemic administration of kainate.

Ribonuclease protection analysis and quantitative in situ hybridization histochemistry were used to investigate the coordination and regional expression of catalytic and non-catalytic trkB messenger RNAs in the adult rat hippocampus following systemic kainate-induced seizures. Changes in trkB expression were compared with the messenger RNA expression of its neurotrophic ligands, brain-derived neurotrophic factor and neurotrophin-3. TrkB messenger RNA expression was increased in the dentate granule cells at 1-4 h following the onset of seizures, and returned to control levels 16-24 h thereafter. In addition, seizures also induced expression of trkB messenger RNA in putative non-neuronal cells at four to seven days in the molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1 region. Hybridization with probes specific for the non-catalytic trkB receptor and the catalytic trkB receptor revealed that the increases at four and seven days in the molecular layers of the hippocampus reflected an up-regulation of only the non-catalytic form of the receptor. Furthermore, the neuronal increases observed 1-4 h were due to an up-regulation of both trkB TK- and trkB TK+ messenger RNAs. It was established that systemic administration of kainate increased brain-derived neurotrophic factor messenger RNA levels in the pyramidal and granule cell regions of the hippocampus 1-4 h following the onset of behaviorally manifested seizure activity. Early changes in neuronal expression of trkB TK- and trkB TK+ messenger RNA paralleled changes in brain-derived neurotrophic factor messenger RNA in the dentate granule cell and CA1 pyramidal cell layers, but not in the CA3 subregion. These data suggest that concomitant regulation of brain-derived neurotrophic factor and its cognate receptor may play a role in the selective vulnerability of hippocampal subregions to kainate-induced neuropathology. Furthermore, these data suggest a dual function for trkB receptor expression in the hippocampus following kainate-induced seizures, possibly related to both the plastic and degenerative consequences of seizure induction by kainate.

Animals↗
PubMed1995

Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons.

Homozygous Igf1-/- mice at 2 months of age had reduced brain weights, with reductions evenly affecting all major brain areas. The gross morphology of the CNS was normal, but the size of white matter structures in brain and spinal cord was strongly reduced, owing to decreased numbers of axons and oligodendrocytes. Myelinated axons were more strongly reduced in number than unmyelinated axons. The volume of the dentate gyrus granule cell layer was reduced in excess of the decrease in brain weight. Among populations of calcium-binding protein-containing neurons, there was a selective reduction in the number of striatal parvalbumin-containing cells. Numbers of mesencephalic dopaminergic neurons, striatal and basal forebrain cholinergic neurons, and spinal cord motoneurons were unaffected. Cerebellar morphology was unaltered. Our findings suggest cell type- and region-specific functions for IGF-I and emphasize prominent roles in axon growth and maturation in CNS myelination.

Animals↗
PubMed1995

Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation.

REK7 is an Eph-related tyrosine kinase receptor expressed exclusively in the nervous system, predominantly in hippocampus and cortex. A soluble REK7-IgG fusion protein, produced to analyze the biological role of REK7, prevents axon bundling in cocultures of cortical neurons with astrocytes, a model of late stage nervous system development and differentiation. Using REK7-IgG as an affinity reagent, we purified and cloned a novel REK7 ligand called AL-1, a GPI-linked protein homologous to other members of an emerging ligand family. Membrane attachment of AL-1 appears necessary for receptor activation, since REK7 on cortical neurons is efficiently activated by transfected cells expressing GPI-linked AL-1, but not by soluble AL-1. Consistent with this, soluble AL-1 blocks axon bundling. Our findings, together with the observation that both molecules are expressed in the brain, suggest a role in the formation of neuronal pathways, a crucial feature of nervous system development and regeneration.

Amino Acid Sequence↗
PubMed1995

[Healing of ligaments and tendons].

Regeneration of ligaments and tendons is a slow process, compared with the healing of other connective tissues (e.g., bone). Healing starts from the surrounding soft tissues ("extrinsic healing"), but also from the ligament or tendon itself ("intrinsic healing"). Regeneration is poor when there is little surrounding soft tissue available, as is the case in the anterior cruciate ligament. Regeneration of the medial collateral ligament of the knee is examined best. Mechanical and ultrastructural properties are not completely normal even 1 year after dissection of the ligament irrespective of whether it was sutured or not. Our own experiments on rabbit anterior cruciate ligaments showed that there is no regeneration after complete transection of the ligament. After incomplete transection there is regeneration, but maximum load of the ligament reaches only about 3/4 of the values of the sham-operated contralateral side. An additional experiment showed that regeneration is significantly better with the application of continuous passive motion, and elongation of the ligament can be avoided. If the healing tissue is not loaded, regeneration results in unstructured scar tissue. Under functional load, the collagen fibers are oriented in a longitudinal direction and the mechanical properties are optimized. There are no fundamental differences in the healing process between tendons and ligaments.

Animals↗
PubMed1995

The influence of heregulins on human Schwann cell proliferation.

The use of Schwann cell (SC) autotransplantation to influence neural repair in humans is dependent upon identifying mitogens that will effectively expand human Schwann cells (SCs) in culture. The recent purification and molecular cloning of glial growth factor (GGF), a potent mitogen for rat Schwann cells, has led to the recognition that a family of proteins (GGF/HRG/NDF/ARIA) are alternatively spliced products of a single gene. The heregulins (HRGs) have been characterized with respect to their influence on human breast cancer cell lines; here we examined whether the HRGs have mitogenic activity for human SCs. Using DNA synthesis assays and serial passaging of cells in culture, we demonstrate that HRG is an effective mitogen for human SCs and that, in the presence of agents that elevate cAMP, it is possible to expand these cells over multiple passages without overwhelming fibroblast contamination. One putative target for this family of proteins is p185erbB2, and EGF-like receptor tyrosine kinase that is encoded by the erbB2 protooncogene. In this report we also demonstrate that the erbB2/3/4 messages as well as the erbB2/3 receptor proteins are present within cultured human SCs. The addition of HRG to human SCs results in tyrosine phosphorylation of a 185 kDa protein. In the presence of stimulatory concentrations of HRG, a blocking monoclonal antibody (2C4) to p185erbB2 is capable of significantly inhibiting phosphorylation of a 185 kDa protein as well as the subsequent incorporation of 3H-thymidine within the human SC. These latter results implicate an important role for p185erbB2 in mediating the mitogenic response of human SCs to HRGs.

Adenylyl Cyclases↗
PubMed1995

[Langerhans cell histiocytosis].

Langerhans cell histiocytosis is a non-neoplastic granulomalike lesion of unknown origin; it is characterized by proliferation of reticulohistiocytic structures, polynuclear eosinophils, neutrophils, lymphocytes, plasma cells, multinucleate giant cells and Langerhans cells. In recent years, the older terms "eosinophilic granuloma" and "histiocytosis X" have been replaced by the more precise expression "Langerhans cell histiocytosis". The granuloma can be solitary and multifocal, with or without soft-tissue involvement. A specific entity is Hand-Schüller-Christian disease. Characteristic lesions in the skull are combined with exophthalmus and diabetes insipidus. These symptoms occur because of the involvement of the hypophysis. A clinically malignant form of the disease is Letterer-Siwe disease. This syndrome occurs in very small children. Dysfunction of various organs causes early death of the individual. The etiology of Langerhans cell histiocytosis is probably a dysfunction of the immune system. In the 130 cases registered at the Swiss bone tumor reference center the lesions were localized in almost all bones. The mandibula, skull, ribs and femur were the most frequently involved bones. Eighty-three patients (64%) were male, 43 (36%) female. Seventy-five percent of the lesions occurred in the first three decades of life. Ninety-three lesions were monostotic and 24 polyostotic; in 5 cases there was soft-tissue involvement, 7 had Hand-Schüller-Christian, and 1 Letterer-Siwe disease. Treatment of osseous lesions should be purely surgical; there is no need for chemotherapy in such cases. If soft-tissue involvement is diagnosed, chemotherapy should be considered. Alternatively, cortisone or interferone therapy can be administered. In our opinion there is no place for radiation therapy.

Adolescent↗
PubMed1994

Neurotrophin-4/5 promotes survival and differentiation of rat striatal neurons developing in culture.

Cultures of dissociated striatal neurons from fetal rats were prepared, and were grown in the presence of neurotrophin-4/5 (NT-4/5) as well as the other known neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We found that acute administration of NT-4/5 to 7-day-old cultures stimulates the hydrolysis of phosphatidylinositol, an event involved in neurotrophin signal transduction. Growth of striatal cultures in the presence of NT-4/5 resulted in increased cell survival, as indicated by elevations in cell number, protein content, and a measure of mitochondrial enzyme activity (MTT assay). NT-4/5 increased GABA uptake and staining intensity in these cultures, as indicated by GABA immunocytochemistry, indicating a trophic action on GABAergic neurons, the predominant neuron type in the striatum. To further identify responsive cell populations we analysed for calretinin, a calcium-binding protein known to colocalize with GABA in a number of neuronal cells. In cultures prepared from rats of embryonic day 15, NT-4/5 strongly increased the number of calretinin-positive cells as well as calretinin levels, as determined by Western blot analysis. When the cultures were prepared from embryonic day 18 rats, NT-4/5 very strongly increased the morphological differentiation of calretinin-positive cells, whereas the increase in cell number was less prominent. All effects produced by NT-4/5 were mimicked by BDNF with similar potency. NT-3 was less effective than NT-4/5 and BDNF, and its effects were limited to cultures prepared from embryonic day 15 rats, suggesting a role in the regulation of cell survival at early developmental stages. NGF did not affect any of the measured parameters. Our findings identify NT-4/5 as potent neurotrophic factor for striatal neurons, able to promote their survival and differentiation.

Animals↗
PubMed1994

Deafferentation removes calretinin immunopositive terminals, but does not induce degeneration of calbindin D-28k and parvalbumin expressing neurons in the hippocampus of adult rats.

Unilateral combined transections of the fimbriafornix and angular bundle in adult Fischer 344 rats were used to study the effects of deafferentation on hippocampal expression of calretinin, calbindin D-28k, and parvalbumin. Reflecting the widespread degeneration of synaptic contacts, immunostaining for glial fibrillary acidic protein 6 days after the lesions was increased in lacunosum-molecular and oriens layers of CA1, 2, and 3 in ipsi- and contralateral hippocampus and in the ipsilateral dentate gyrus outer molecular layer. At 21 days the immunoreactivity had decreased to control levels except for a still slightly increased signal in the oriens layer of CA1-3. At 6 and 21 days after the combined lesions the numbers of hippocampal neurons containing calretinin, parvalbumin, and calbindin D-28k was unaltered. The combined lesions abolished calretinin containing terminals in the dentate gyrus inner molecular layer on the deafferentated side. This could be reproduced by single unilateral fimbria-fornix transections, suggesting that the axons of these calretinin positive terminals project to the hippocampus through the fimbria-fornix. The most likely origin of the calretinin positive terminals are neurons in the supramammillary hypothalamic nucleus. Our findings demonstrate that the extensive lesion-induced synaptic rearrangements in the adult hippocampus do not induce degeneration of hippocampal neurons expressing calretinin, calbindin D-28k, and parvalbumin, but do remove calretinin containing terminals which reach their targets in the hippocampus through the fimbria-fornix.

Animals↗
PubMed1994

Stimulation of GABAergic neuron differentiation by NT-4/5 in cultures of rat cerebral cortex.

Primary cultures of fetal rat cortical cells were used to investigate trophic effects of neurotrophin-4/5 (NT-4/5) on GABAergic neurons. Chronic administration of NT-4/5 resulted in a significant increase in high-affinity GABA uptake and in a stronger immunohistochemical staining pattern and bigger cells size of neurons visualized by GABA immunohistochemistry. Brain-derived neurotrophic factor (BDNF) exerted similar actions. These effects were observed in cultures prepared from rat fetuses from embryonic day (ED) 15 and ED18. The total number of cells was marginally increased in ED15 but not ED18 cultures. NT-4/5 did not elevate uptake of excitatory amino acids. Administration of NT-4/5 and BDNF resulted in higher levels of the calcium binding protein, calbindin, in these cultures. Our findings suggest that subpopulations of cortical GABAergic and calbindin-expressing neurons respond to NT-4/5 during development.

Animals↗
PubMed1994

6-Hydroxydopamine lesions reduce BDNF mRNA levels in adult rat brain substantia nigra.

Expression of brain-derived neurotrophic factor (BDNF) in the ventral mesencephalon has been assayed by mRNA in situ hybridization in adult rats with unilateral injections of 6-hydroxydopamine in the substantia nigra. On contralateral control sides, a specific hybridization signal was detected in the substantia nigra pars compacta (A9), ventral tegmental area (A10) and substantia nigra pars lateralis (A8). Cellular levels of BDNF mRNA were lower than those in BDNF expressing cortical and hippocampal neurons. The 6-hydroxydopamine injections completely abolished BDNF mRNA labeling in the pars compacta of the substantia nigra, whereas many labeled neurons remained in the ventral tegmental area and pars lateralis. The results strongly suggest that BDNF is expressed by nigral dopaminergic neurons.

Animals↗
PubMed1994

Neurotrophic factor therapy for nervous system degenerative diseases.

The ability of neurotrophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases. Solid rationales exist for the use of NGF and neurotrophin-3 in the treatment of neuropathies of the peripheral sensory system, insulin-like growth factor and ciliary neurotrophic factor in motor neuron atrophy, and NGF in Alzheimer's disease. Growth factors have been identified for neurons affected in Parkinson's disease, Huntington's disease, and acute brain and spinal cord injury. Various strategies are actively pursued to deliver neurotrophic factors to the brain, and develop therapeutically useful molecules that mimic neurotrophic factor actions or stimulate their production or receptor mechanisms.

Animals↗
PubMed1994

Development of effective therapy for Alzheimer's disease based on neurotrophic factors.

Neurotrophic factors play a major role in brain development and function. Because administration of these factors can attenuate degeneration of neurons and behavioral deficits in animals, such molecules may become useful in the treatment of AD. At the present time, a solid rationale can be made for clinical trials with NGF, given the pronounced trophic effect of NGF on forebrain cholinergic neurons and the cholinergic atrophy occurring in AD. Future research in the following areas will be crucial toward development of successful neurotrophic factor therapy: (a) New research should focus on identifying new neurotrophic factors, which protect other vulnerable neurons in AD, in particular hippocampal and cortical neurons; (b) Multiple available strategies should be pursued to find ways to deliver neurotrophic proteins across the blood-brain barrier. In addition, a broadly based effort to establish a small-molecule pharmacology of neurotrophic factors is likely to lead to clinically useful drugs; (c) Regulatory guidance is necessary to establish ethically acceptable designs for clinical trials to unequivocally establish efficacy of drugs that attenuate the progression of AD.

Alzheimer Disease↗
PubMed1994

Intrastriatal infusion of nerve growth factor after quinolinic acid prevents reduction of cellular expression of choline acetyltransferase messenger RNA and trkA messenger RNA, but not glutamate decarboxylase messenger RNA.

Excitotoxic striatal lesions induced by quinolinic acid, a model for Huntington's disease, were used to test for neuroprotective actions of nerve growth factor on striatal cholinergic and GABAergic neurons. Expressions of the trkA receptor for nerve growth factor, choline acetyltransferase and glutamate decarboxylase were analysed by messenger RNA in situ hybridization in adult rats following quinolinic acid lesion (150 nmol) and daily striatal administration of nerve growth factor (1 microgram) or control protein (cytochrome C) for one week. One week after toxin administration, the numbers of cells expressing trkA or choline acetyltransferase messenger RNAs were decreased when compared with unlesioned animals. Moreover, the surviving cells showed a strong down-regulation of these messenger RNAs as deduced from grain count analysis of sections processed for emulsion autoradiography. Daily intrastriatal nerve growth factor administration for one week completely prevented the reduction in the number of cells expressing either of the two markers. Nerve growth factor treatment increased the cellular expression of choline acetyltransferase messenger RNA three times above control levels and restored the levels of trk A messenger RNA expression to control levels. In contrast to the protective effects on cholinergic cells, nerve growth factor treatment failed to attenuate the quinolinic acid-induced decrease in glutamate decarboxylase messenger RNA levels. Optical density measurements of the entire striatum on autoradiographs of brain sections from quinolinic acid-lesioned animals revealed a reduction of the glutamate decarboxylase messenger RNA-specific hybridization signal, which was unaltered by infusion of nerve growth factor or control protein. Our findings strongly suggest that in both the intact and the quinolinic acid-lesioned adult rat striatum, nerve growth factor action is confined to trk A-expressing cholinergic neurons. Striatal glutamate decarboxylase messenger RNA-expressing GABAergic neurons which degenerate in Huntington's disease are not responsive to nerve growth factor.

Animals↗