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Biomedical subjects

F Hefti

Publications and source records attributed to F Hefti.

At least 199 records · Page 11Linked to original sources
PubMed1986

Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections.

Several findings obtained in recent years suggest that NGF, aside from its well-established function as a neurotrophic factor for peripheral sympathetic and sensory neurons, also has trophic influence on the cholinergic neurons of the basal forebrain. The present study assessed whether NGF was able to affect survival of central cholinergic neurons after axonal transections in adult rats. The septo-hippocampal pathway was transected unilaterally by cutting the fimbria, and animals were implanted with a cannula through which NGF or control solutions were injected intraventricularly over 4 weeks. The lesions reduced the number of large cell bodies, as visualized by Nissl staining in the medial septal nucleus and in the vertical limb of the diagonal band of Broca. Furthermore, in the same nuclei, they reduced the number of cell bodies positively stained for AChE after pretreatment with diisopropylfluorophosphate (a method known to result in reliable identification of cholinergic neurons in the septal area). On lesioned sides, the number of cholinergic cells in medial septal nucleus and the vertical limb of the diagonal band was reduced by 50 +/- 4%, as compared to the number on contralateral sides. On lesioned sides of animals chronically treated with NGF, the number of AChE-positive cells in these areas was reduced only by 12 +/- 6%, as compared to control levels. These findings suggest that fimbrial transections resulted in retrograde degeneration of cholinergic septo-hippocampal neurons and that NGF treatment strongly attenuated this lesion-induced degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

[Combined lateral ligament-plasty and calcaneus osteotomy in recurrent foot dislocation].

The risk of a supination trauma is particularly high in patients with pathological calcaneus varus as opposed to physiological calcaneus valgus. If in these patients only the lateral ligaments are operatively treated after a trauma, there is a high incidence of recurrence, as the abnormal position of the calcaneus means that the supinating forces acting laterally have a stronger effect than in normal cases. We therefore suggest a combination of fibulotalar syndesmoplasty with osteotomy of the calcaneus according to Dwyer in such cases. In the last 7 years we have carried out this operation eight times with no recurrence in any of these patients so far. In four patients, a gait analysis was performed. It was established that the abnormal floor reaction forces seen in the presence of calcaneus varus normalize following the operation.

Adolescent↗
PubMed1985

Implantation of PC12 cells into the corpus striatum of rats with lesions of the dopaminergic nigrostriatal neurons.

PC12 cells, which have the capacity to synthesize and release catecholamines, were implanted into the corpus striatum of adult rats with lesions of the dopaminergic nigrostriatal pathway. PC12 cells survived for 1-2 weeks in the host striatum and degenerated thereafter. The presence of these cells was associated with an attenuation of the apomorphine-induced circling behavior in rats with unilateral nigrostriatal lesions. These findings indicate that cells from a cell line are able, at least temporarily, to survive in the rat brain and to compensate functional deficits caused by lesions of specific neuronal systems. Cell lines might therefore be used for intracerebral grafting instead of neurons derived from fetal brains, if their survival can be prolonged and their proliferation in the host brain prevented.

Adrenal Gland Neoplasms↗
PubMed1985

Acetylcholine-rich transplants in the hippocampus: influence of intrinsic growth factors and application of nerve growth factor on choline acetyltransferase activity.

Three groups of rats received either unilateral fimbria-fornix lesions by aspiration through the overlying cingulate cortex (group I), a fimbria-fornix lesion followed by an intrahippocampal transplant of acetylcholine (ACh)-rich embryonic septal tissue (group II), or a similar septal transplant placed into the intact hippocampus, in the absence of the denervating lesion (group III). The 3 groups were subdivided into equal subgroups receiving 6 intrahippocampal injections of nerve growth factor (NGF) at 4-day intervals, control injections of cytochrome c, or no injections. On the 28th day all animals were sacrificed and the majority taken for biochemical analysis of hippocampal choline acetyltransferase (ChAT). The animals with intact hippocampi (group III) were given a denervating fimbria-fornix lesion 3 days prior to sacrifice in order to reveal graft-derived ChAT activity from intrinsic ChAT activity. The fimbria-fornix lesions (group I) depleted hippocampal ChAT activity to 15-20% of normal, which was not influenced by NGF injections. The ACh-rich grafts placed in the denervated hippocampus (group II) restored hippocampal ChAT activity to approximately 60% of the normal level, and this was promoted to approximately 84% of NGF, but not cytochrome c, injections into the hippocampus. Grafts placed into the intact hippocampus (group III) did not raise ChAT activity above the lesion-alone level, and this was not influenced by NGF injections. Acetylcholinesterase (AChE) histochemistry showed no difference in outgrowth from the grafts in the denervated hippocampus with or without NGF injections. The results are interpreted, in agreement with observations in tissue culture, as indicating that NGF enhances ChAT activity in grafted neurons, rather than promoting survival and growth per se.

Animals↗
PubMed1985

Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs.

In rats with partial, unilateral lesions of the dopaminergic nigrostriatal pathway, synthesis of dopamine (DA) per surviving neurone was assessed by measuring the ratio of DOPA accumulated after inhibition of aromatic amino acid decarboxylase to dopamine (DOPA/DA ratio). Release of DA per surviving neurone was assessed by measuring the ratios of the concentrations of 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) to DA. In striata ipsilateral to the lesion, the DOPA/DA ratio was elevated 4-fold, and the DOPA/DA and HVA/DA ratios were elevated 2-fold as compared to values in contralateral striata. Administration of gamma-butyrolacetone (750 mg/kg, 30 min), i.e. of a drug which accelerates synthesis of DA, further increased the DOPA/DA ratio in lesioned striata to levels 37 times higher than those measured on the control side of saline-injected controls. Morphine (20 mg/kg, 30 min) and haloperidol (2.5 mg/kg, 60 min), i.e. drugs known to accelerate the turnover and release of DA, further elevated the DOPAC/DA and HVA/DA ratios in lesioned striata to levels approx. 5 times higher than the ratios measured on contralateral sides of saline-treated controls. The data indicate that dopaminergic neurones surviving partial lesions of the nigrostriatal pathway synthesize and release DA at an elevated but submaximal rate. Synthesis and release of DA can be further enhanced to a large extent by drugs.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Striatal acetylcholinesterase-containing interneurons innervate hippocampal tissue in co-cultured slices.

Co-cultures of hippocampal and striatal slices were prepared from 7-day-old rats. After a month in vitro they were examined by histochemical and electrophysiological techniques. Acetylcholinesterase-positive fibers, originating in presumed cholinergic local circuit neurons of the striatum, invaded the adjacent hippocampus, resulting in a functional innervation displaying the characteristics of muscarinic inputs. These observations demonstrate that interneurons, when offered an appropriate target, are capable of mimicking projection neurons. Such a target-induced change in growth characteristics can take place even during relatively advanced phases of their development.

Acetylcholinesterase↗
PubMed1985

Behavioural and neurochemical effects of chronic intraventricular injections of nerve growth factor in adult rats with fimbria lesions.

Rats received bilateral lesions of the fimbria. These lesions impaired their ability to learn a radial maze. Rats given repeated intraventricular injections of nerve growth factor (NGF, 10 micrograms twice weekly during 4 weeks after the lesion) learned the maze problem more rapidly than rats with the same injury but treated with a control protein (cytochrome c). When retested after a period of 6 weeks without NGF treatment, the performance of NGF-treated and cytochrome c-treated rats with fimbria lesions did not differ. Whereas our previous study showed an increase in choline acetyltransferase (ChAT) activity in the septum and the hippocampus 4 days after the last NGF injection, the present study found that after the retest period (i.e. 10 weeks after the last NGF injection) ChAT activity was increased in the septum but not in the hippocampus. The relationship between the NGF-induced changes in ChAT activity and behaviour is discussed.

Animals↗
PubMed1985

Nerve growth factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons.

Neurons dissociated from the septal area of fetal rat brains were grown in culture. Cholinergic neurons were identified by immunocytochemical visualization of choline acetyltransferase and cytochemical demonstration of acetyl cholinesterase. Choline acetyltransferase immunocytochemistry stained cell bodies and proximal processes while acetylcholinesterase cytochemistry visualized the entire neuron. Choline acetyltransferase-positive neurons could only be identified in cultures grown under conditions that produced the maximal choline acetyltransferase activity, measured biochemically. All of the choline acetyltransferase-positive neurons were double stained for acetylcholinesterase while only 6% of the acetylcholinesterase-positive cells were choline acetyltransferase negative in these cultures. These results indicate that acetylcholinesterase is a reliable marker for cholinergic cells in cultures of dissociated septal neurons. Being the more sensitive method, acetylcholinesterase staining was therefore used to identify cholinergic cells in cultures with choline acetyltransferase levels insufficient for immunocytochemical visualization of this enzyme. Addition of nerve growth factor or antibodies to nerve growth factor to the medium did not affect the number of cholinergic neurons surviving in culture. Furthermore, nerve growth factor and anti-nerve growth factor failed to influence the general morphological appearance and the number of processes of these neurons. However, nerve growth factor elevated the biochemically measured activity of choline acetyltransferase up to two-fold. The nerve growth factor-mediated increase in choline acetyltransferase activity was dose dependent with an ED50 of 10 ng/ml (4 X 10(-10) M). The increase was highly specific for nerve growth factor. It was blocked by anti-nerve growth factor, and epidermal growth factor, insulin and other control proteins failed to exert a similar effect. Nerve growth factor had to be present for at least 3 days in the culture medium to increase choline acetyltransferase activity, suggesting that the increase was due to an elevated choline acetyltransferase synthesis rather than to an activation of the enzyme.

Acetylcholinesterase↗
PubMed1985

Gangliosides alter morphology and growth of astrocytes and increase the activity of choline acetyltransferase in cultures of dissociated septal cells.

Administration of gangliosides has been reported to stimulate regeneration of motoneurons and of central dopaminergic and cholinergic neurons. To shed light on the mechanism by which gangliosides mediate the effects on cholinergic neurons, we studied their actions on cultures of cells dissociated from the septal area of fetal rat brains. These cultures contain cholinergic neurons, which, in vivo, give rise to the cholinergic septo-hippocampal pathway. Gangliosides produced prominent changes in the morphological appearance of the cultures. In contrast to control cultures, which contained many process-bearing cells and a confluent layer of flat cells, there were no flat cells in cultures grown in the presence of gangliosides (0.2 to 0.8 mg/ml of medium). Using immunocytochemical visualization of the astrocytic marker glial fibrillary acid protein, it was shown that all astrocytes in cultures grown in the presence of gangliosides exhibited the morphology of process-bearing cells, whereas in control cultures astrocytes represented the majority of the flat cells. Furthermore, gangliosides attenuated astrocytic proliferation. The effects of gangliosides apparently were not mediated by cAMP, since they could be differentiated from actions of forskolin, an activator of adenylate cyclase. Astrocytic growth and morphology were affected by ganglioside mixtures of various sources and composition and also by the pure gangliosides GM1 and GD1a, whereas lipid and carbohydrate components of gangliosides were ineffective. In contrast to the prominent effects on astrocytes, gangliosides failed to significantly alter survival or fiber growth of cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Growth of dissociated neurons in culture dishes coated with synthetic polymeric amines.

Polyornithine and polylysine, the most commonly used coating materials in the preparation of neuronal cultures, can be replaced by polyethyleneimine (PEI) and other synthetic polymeric amines. PEI supports attachment and growth of neurons from fetal rat brain equally well as polyornithine. Furthermore, differentiation of the cultured neurons, as judged by the expression of choline acetyltransferase and of binding sites for substance P, was very similar in cultures grown in dishes coated with PEI or polyornithine.

Animals↗
PubMed1984

Acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduces dopamine and serotonin but accelerates norepinephrine metabolism in the rat brain. Effect of chronic pretreatment with MPTP.

Acute administration of MPTP (a synthetic heroin substitute) at 10-30 mg/kg (s.c.) produced 'Straub tail' phenomena, piloerection and reduced pelvis elevation in rats. The same dose decreased the concentrations of dopamine metabolites and reduced the rate of dopamine synthesis in the striatum. MPTP also reduced the metabolism of serotonin but accelerated that of norepinephrine in their corresponding terminal areas. The effects on central monoamines probably were not due to an agonistic action of MPTP on dopaminergic and serotonergic receptors, since MPTP only exhibited micromolar affinity to the corresponding binding sites. Furthermore, MPTP failed to induce rotational behavior in animals with unilateral nigrostriatal lesions. Chronic treatment of rats with MPTP (10 mg/kg s.c., daily for 3 weeks) did not result in massive degenerative changes in the nigrostriatal system. Histochemical analysis showed intact dopaminergic neurons. Striatal dopamine levels only were reduced by 10%. Dopaminergic neurons in rats chronically treated with MPTP responded normally to a pharmacological stimulus increasing their transmitter synthesis. Chronic treatment did not affect their response to an acute injection of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions.

Nerve growth factor (NGF) was injected intraventricularly during 4 weeks into adult rats with unilateral partial lesions of the cholinergic septo-hippocampal pathway. On the lesioned side, NGF treatment elevated choline acetyltransferase (ChAT) activity up to 60% above the activity measured on the lesioned side of cytochrome c-treated controls. On the unlesioned side, NGF treatment increased ChAT activity only to an insignificant degree. ChAT activity in the septum of NGF-treated animals was increased by 60% as compared to controls. The NGF-induced increases on the lesioned side and in the septum were not accompanied by elevations in acetylcholinesterase (AChE) activity. Furthermore, histochemical analysis revealed no difference in AChE staining pattern or intensity between NGF-treated and control animals. The lack of effect on AChE strongly suggests that the increases in ChAT activity in hippocampus and septum are due to an elevation of ChAT activity within cholinergic neurons surviving the lesion rather than to a promotion of sprouting of cholinergic fibers.

Animals↗
PubMed1984

Guidance of acetylcholinesterase-containing fibres by target tissue in co-cultured brain slices.

Slices of various brain regions were prepared from newborn and from 7-day old rats and co-cultured in different combinations. In the majority of co-cultures of septal and hippocampal slices, acetylcholinesterase-positive fibres originating in the septal nuclei invaded the adjacent hippocampal slice. A similar pattern of hippocampal ingrowth by acetylcholinesterase-positive fibres occurred with slices prepared from the nucleus basalis of Meynert and from spinal cord. Septal neurones also projected to cortical slices, an effect which even occurred in the presence of their natural target tissue. In contrast to these massive projections to brain areas which in situ receive cholinergic inputs, no significant acetylcholinesterase-positive fibre ingrowth was observed in tissues which lack major cholinergic afferents in situ (hypothalamus, substantia nigra and cerebellum). These results indicate that under our culture conditions, acetylcholinesterase-positive fibres selectively invade cholinergic target areas. This effect is independent of the brain area from which the cholinergic neurones were derived.

Acetylcholinesterase↗
PubMed1984

Suppression of L-dopa-induced circling in rats with nigral lesions by blockade of central dopa-decarboxylase: implications for mechanism of action of L-dopa in parkinsonism.

Dopamine (DA) elevations in rat striatum produced by combined administration of L-dopa and carbidopa were abolished when L-dopa was injected with NSD-1015, an inhibitor of central dopa-decarboxylase. In all rats with unilateral 6-OH-DA nigral lesions, L-dopa-induced contraversive circling occurred after carbidopa, but was totally abolished (in 60%) or markedly suppressed after pretreatment with NSD-1015. Administration of the DA metabolites DOPAC and HVA systemically and of 3-methoxytyramine intrastriatally evoked no circling in animals with 6-OH-DA lesions. In rats with unilateral nigrotomies, the direction of L-dopa-induced circling was reversed and became ipsiversive after DA receptors were reduced by the addition of kainic acid lesions in ipsilateral striata. Findings provide evidence that circling in rats--and by analogy, efficacy in parkinsonians--requires the decarboxylation of exogenous L-dopa and interaction of the formed DA with DA receptors in striatum.

Animals↗