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F Hefti

Publications and source records attributed to F Hefti.

At least 145 records · Page 8Linked to original sources
PubMed1991

Nerve growth factor and Alzheimer's disease.

Clinical trials with cholinergic agents suggest that cholinergic hypertrophy may be beneficial in the treatment of Alzheimer's disease (AD). Recent findings substantiate the view that nerve growth factor (NGF) selectively acts on cholinergic neurons. In adult rats and primates, intraventricular administration of nerve growth factor produces trophic actions on cholinergic neurons and prevents age related neuronal atrophy. These findings suggest the possibility of the eventual development of pharmacological applications of nerve growth factor for the treatment of AD.

Alzheimer Disease↗
PubMed1991

Tyrosine hydroxylase mRNA expression by dopaminergic neurons in culture: effect of 1-methyl-4-phenylpyridinium treatment.

To enable us to study expression of tyrosine hydroxylase [TH; tyrosine 3-monooxygenase; L-tyrosine tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.2] as a measure of dopaminergic neuron function in future experiments, methods were developed to quantify TH mRNA levels in cultures of dopaminergic mesencephalic cells. The model of selective dopaminergic toxicity of 1-methyl-4-phenylpyridinium (MPP+) was used to verify the specificity of our methods. Fetal (embryonic day 15) rat ventral mesencephalic cell cultures were treated with 15 microM MPP+ for 48 h, conditions previously shown to reduce the number of TH-immunoreactive neurons, TH activity, and dopamine uptake to 5-10% of control values. This treatment decreased the number of neurons labeled by TH in situ hybridization to 9% of untreated controls and caused a strong reduction of the abundance of TH mRNA in Northern blots. Our findings establish TH mRNA expression as a parameter for future studies of toxic and trophic effects on cultured dopaminergic neurons, and they support the view that MPP+ destroys dopaminergic neurons.

1-Methyl-4-phenylpyridinium↗
PubMed1991

K-252b is a selective and nontoxic inhibitor of nerve growth factor action on cultured brain neurons.

K-252b is a kinase inhibitor structurally related to K-252a, which is known to abolish selectively the effects of nerve growth factor (NGF) on PC12 cells and PNS neurons. We tested whether K-252b, K-252a, and staurosporine, another related compound, are effective and selective inhibitors of NGF actions on CNS neurons. All three compounds, at appropriate concentrations, completely and selectively prevented the NGF-mediated activity increase of the cholinergic marker enzyme choline acetyltransferase in cultures of rat basal forebrain cells. The stimulatory effects of basic fibroblast growth factor and insulin on choline acetyltransferase in these cultures and on dopamine uptake in cultures of dissociated ventral mesencephalon were not affected. No signs of toxicity were observed in cultures treated with K-252b. In contrast, K-252a and staurosporine, at concentrations required to block the NGF actions on cholinergic cells, were cytotoxic and produced cell loss. In addition, K-252a, at higher concentrations and in the absence of growth factors, increased cell numbers. Our study suggests that K-252b is a selective and nontoxic inhibitor of NGF actions in the brain and may become a useful tool to study these actions in vivo.

Alkaloids↗
PubMed1991

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophage may lead to a better understanding of the mechanism of action of this class of drugs.

Acetylcholine↗
PubMed1991

Role of angiotensin II in injury-induced neointima formation in rats.

Angiotensin converting enzyme inhibition markedly suppresses neointima formation in response to balloon catheter-induced vascular injury of the rat carotid artery. To determine whether this effect was mediated through the vasoactive peptide angiotensin II (Ang II), two approaches were followed. First, the balloon model was used to compare the effects of continuous infusion of Ang II, with and without concurrent converting enzyme inhibition by cilazapril; second, the effects of the orally active nonpeptidic Ang II receptor antagonist DuP 753 were analyzed. Morphometric analysis was performed at 14 days after balloon injury. Animals that received continuous infusion of Ang II (0.3 micrograms/min/rat) were found to have significantly greater neointima formation in response to balloon injury than controls. Animals treated with cilazapril (10 mg/kg/day) had markedly reduced neointima formation, but in animals receiving infusion of Ang II, treatment with cilazapril did not suppress development of neointimal lesions. In the second group of experiments, DuP 753 (10 mg/kg twice daily) was as effective to prevent neointima formation as cilazapril. These data support the conclusions that converting enzyme inhibition prevents neointima formation after vascular injury through inhibition of Ang II generation.

Angiotensin II↗
PubMed1991

Heparin and cilazapril together inhibit injury-induced intimal hyperplasia.

Both heparin and the angiotensin converting enzyme inhibitor cilazapril inhibit intimal thickening in rat carotid arteries injured by the passage of a balloon catheter. The purpose of this study was to determine if combinations of the two drugs were more effective than either drug alone and whether the effect could be accounted for by inhibition of smooth muscle cell proliferation. Heparin (0.1-0.3 mg/kg/hr) administered by continuous intravenous infusion with or without cilazapril (0-25 mg/kg/day p.o.) produced a dose-dependent inhibition of smooth muscle accumulation at 14 days after rat carotid ballooning. At the lower doses, the inhibitory effects of heparin and cilazapril were additive when the drugs were used together. This overall effect on growth was reflected in decreased smooth muscle cell proliferation at 2 and 7 days. A 7-day course of heparin combined with cilazapril, a regimen that might be applicable in the clinical setting, produced an 80% inhibition of intimal thickening at 28 days. These results provide evidence that heparin and cilazapril together might prove to be more effective than either drug alone in the control of intimal hyperplasia after arterial injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Vascular protection with cilazapril.

The hypertrophy of the media of coronary arteries associated with hypertension reduces cross-sectional area and limits vascular reserve. Cilazapril 10 mg/kg daily decreased cardiac hypertrophy, and decreased minimal coronary vascular resistance by 40% when administered to spontaneously hypertensive rats (SHR) at the onset of hypertension. After hypertension had developed, cilazapril restored arterial pressure to normal and increased the maximal coronary blood flow in isolated perfused hearts by 96%, which was probably a result of a marked decrease in medial hypertrophy of the coronary arteries. Similarly, cilazapril improved cerebral vascular reserve in the mesenteric and renal arteries of SHR. In the rat model of vascular injury produced by ballooning, cilazapril 10 mg/kg daily demonstrated a marked preventive effect on the myointimal proliferation that resulted in untreated controls, a phenomenon responsible for restenosis in humans after arterial angioplasty. Although this effect occurred with usual antihypertensive dosages in rats, it appeared to be independent of the decrease in arterial pressure since effective antihypertensive dosages of verapamil did not prevent neointima formation. In view of the clinical potential for preventing restenosis after coronary angioplasty, 2 multicentre trials of cilazapril are ongoing to test this hypothesis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

[Principles and pathogenesis of post-traumatic axial malalignment in the growth years].

Deviations of the axis or leg-length discrepancies after fractures in children and adolescents can be due to growth disturbances or can be the result of incomplete reduction of the fracture. We distinguish between four types of growth disturbances. In type I, the overall growth activity of the cartilage is increased; growth is then enhanced, which results in the affected bone being too long without deviation; this usually occurs after fractures of the metaphysis or diaphysis. In type II, activity, the epiphyseal cartilage is severely impaired or completely arrested. The direction of growth is unchanged. This results in shortening of the bone, usually due to severe damage to the germination zone of the growth cartilage after destruction of the vessels or infection. In type III, growth of the epiphyseal plate is partially stimulated. The consequence of this disturbance is deviation of the axis with overgrowth (this is in fractures of the proximal tibia). Type IV is characterized by an asymmetric arrest of growth. This results in deviation of the axis and shortening. The cause of such growth arrest can be epiphyseolysis or epiphyseal fracture. The defect in growth cartilage heals with a bone bridge. This is a very serious kind of growth disturbance, and it occurs in only 1% of all fractures before skeletal maturity. Correction after incomplete reduction of fractures during growth can be direct or indirect and specific or nonspecific. Direct corrections occur in combination with fracture healing; indirect corrections occur with physiological changes of the growing skeleton without association with the healing process.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Compensatory elevation of acetylcholine synthesis in vivo by cholinergic neurons surviving partial lesions of the septohippocampal pathway.

The present study characterized the effects of partial destruction of the cholinergic septohippocampal pathway on transmitter functions of surviving cholinergic neurons in the hippocampus. Partial and full fimbrial transections were performed, and 3 weeks after lesioning, cholinergic functions were assessed in vivo and in vitro. Hippocampal ChAT activity and the capacity of hippocampal slices to synthesize [3H]ACh in vitro decreased by 35% and 45%, respectively, following partial fimbrial lesions and by 68% and 85%, respectively, following full fimbrial lesions. [3H]ACh release from hippocampal slices in vitro was decreased by 57% and 87%, respectively, following partial and full fimbrial lesions. Partial lesions decreased high-affinity choline uptake into hippocampal synaptosomes by 52%. In contrast to the significant reductions in cholinergic parameters measured in vitro after partial fimbrial lesions, such partial lesions did not significantly alter in vivo measures of hippocampal cholinergic function. Levels of endogenous ACh and choline measured in the hippocampus following partial lesions were similar to that of control values. Also, the hippocampal content of newly synthesized [2H4]ACh and the [2H4]ACh synthesis rate were not significantly different from control values. However, following full fimbrial lesions, in vivo measures of hippocampal cholinergic function were decreased to a degree similar to that observed in vitro. Hippocampal levels of endogenous ACh and [2H4]ACh and the synthesis rate for [2H4]ACh were decreased by 73%, 72%, and 83%, respectively. These results suggest that, following partial destruction of afferent cholinergic fibers that innervate the hippocampal formation, residual cholinergic neurons are able to upregulate their capacity to synthesize and store ACh in vivo, thus compensating for lesion-induced losses of cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture.

Toxicity of 6-hydroxydopamine (6-OHDA) and dopamine were studied in cultures of dissociated fetal rat mesencephalic cells. To assess survival and function of dopaminergic cells we quantified the number of tyrosine hydroxylase-positive cells and measured dopamine uptake. Non-dopaminergic cells were monitored by counting the number of cells visible with phase-contrast microscopy and measuring GABA uptake. 6-OHDA, in contrast to MPP+, which selectively destroyed dopaminergic neurons, was found to be a non-selective neurotoxin in this culture system. Between 10 and 100 microM, dopaminergic and non-dopaminergic cells were destroyed. At concentrations higher than 100 microM, i.e., concentrations frequently used to lesion catecholaminergic neurons in vivo, 6-OHDA resulted in structural fixation and loss of viability of dopaminergic and non-dopaminergic cells. Dopamine produced the same actions at slightly higher concentrations. One hundred to 300 microM was toxic for all cell types, and concentrations above 300 microM resulted in fixation. The findings suggest that 6-OHDA cannot be considered a selective toxin for catecholaminergic neurons in vitro. The demonstrated toxicity of dopamine tends to support speculations that processes related to dopamine metabolism may play a role in the pathogenesis of Parkinson's disease.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Neuromelanin synthesis in rat and human substantia nigra.

A relation between neuromelanin synthesis and vulnerability of dopaminergic neurons is suggested by the fact that heavily pigmented cells are preferentially lost in aging and Parkinson's disease and that the dopaminergic neurotoxin MPP+ (1-methyl-4-phenyl-pyridine) binds to neuromelanin. To elucidate the mechanism of neuromelanin synthesis, we studied the formation of melanin in homogenates of human and rat substantia nigra tissue "in vitro". It was found that enzymatic processes accounted for 70% and 90% of the melanin formation in homogenates of human and rat tissue, respectively. The enzymatic synthesis was due to the activity of monoamine oxidase (MAO), since it was prevented by selective inhibitors of this enzyme. Both MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ inhibited melanin formation, probably due to their ability to inhibit MAO. No evidence was found for involvement of cytochrome P-450 monooxigenases, which have been postulated to exist in central catecholaminergic neurons. Proadifen reduced melanin formation, not necessarily because it is an inhibitor of P-450 monooxigenases, but rather as it is also a potent inhibitor of MAO. Some antioxidants like ascorbic acid, but not agents destroying hydrogen peroxide, inhibited melanin formation. The findings suggest that the formation of neuromelanin in the substantia nigra involves MAO and non-enzymatic oxidative processes.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium: selective toxicity of 1-methyl-4-(4'-acetamidophenyl)-pyridinium and 1-methyl-4-cyclohexylpyridinium for dopaminergic neurons in culture.

Mesencephalic cells in culture were exposed to various compounds which we hypothesized to be selective toxins for dopaminergic neurons. The culture system was previously shown suitable for assessing selective dopaminergic neurotoxicity, since 1-methyl-4-phenyl-pyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium, destroyed dopaminergic neurons without affecting other cells. Some compounds tested were selected to fulfill two criteria believed to underly the selective dopaminergic neurotoxicity of MPP+, i.e., to be a potential substrate for the uptake carrier for dopamine and to possess a strong delocalized positive charge to inhibit the mitochondrial respiratory system. Other compounds were chosen on the basis of clinical or anecdotal evidence linking them to Parkinson's disease. Among the tested compounds two pyridinium analogs, 1-methyl-4-(4'-acetamidophenyl)pyridinium (MACPP+) and 1-methyl-4-cyclohexylpyridinium (MCP+) were found to be selectively toxic toward dopaminergic neurons. Incubation of cultures with both MACPP+ and MCP+ produced a dramatic reduction in the number of tyrosine hydroxylase-positive cells and the uptake of [3H]dopamine without reducing the number of cells visualized by phase-contrast microscopy or the uptake of [3H]aminobutyric acid. Besides MACPP+ and MCP+ none of the tested compounds exhibited any selective dopaminergic neurotoxicity. Together with earlier findings, these data suggest that the structural requirements are rather strict for a chemical to be a selective dopaminergic neurotoxin and make it unlikely that there is a wide spectrum of environmental dopaminergic toxins.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Trophic actions of recombinant human nerve growth factor on cultured rat embryonic CNS cells.

NGF is a neurotrophic factor for basal forebrain cholinergic neurons and may serve to counteract the cholinergic deficits that are observed in Alzheimer's disease. Prior to the introduction of clinical trials, it is essential that recombinant human NGF (rhNGF) be produced and that its actions on target cells in the CNS be demonstrated. We prepared rhNGF and examined its actions on fetal rat brain neurons in culture including, in particular, the cholinergic neurons of the basal forebrain. rhNGF was more potent in increasing choline acetyltransferase (ChAT) activity in septal cultures than NGF purified from mouse salivary glands (mNGF). ED50s of the beta-NGF dimers were 4.9 pM for rhNGF and 12.4 pM for mNGF. The maximal ChAT activity response was achieved at approximately 35 pM with both NGFs and their efficacies were not significantly different. The two NGFs were not additive in effect. Identical to the results with mNGF, rhNGF strongly enhanced the intensity of ChAT immunostaining in septal cultures. Neither rhNGF nor mNGF affected the appearance of the cultures under phase-contrast illumination. Survival of cells at very low plating density on polyornithine/laminin-coated culture dishes was not affected by rhNGF or mNGF. Protein content and the uptake of GABA were also unaffected. At concentrations of up to 10 micrograms/ml, rhNGF did not significantly increase uptake of dopamine into cultures of ventral mesencephalon. We conclude that rhNGF produces potent and selective actions on cholinergic neurons of the basal forebrain as previously shown for mNGF.

Animals↗
PubMed1990

Long-term administration of mouse nerve growth factor to adult rats with partial lesions of the cholinergic septohippocampal pathway.

Nerve growth factor (NGF), a neurotrophic factor acting on cholinergic neurons of the basal forebrain, has been proposed as a treatment for Alzheimer's disease. Experimental support for its pharmacological use is derived from short-term studies showing that intraventricular administration of NGF during 2-4 weeks protects cholinergic cell bodies from lesion-induced degeneration, stimulates synthesis of choline acetyltransferase, and improves various behavioral impairments. To investigate the consequences of long-term NGF administration, we tested whether cholinergic cell bodies are protected from lesion-induced degeneration and whether cholinergic axons are stimulated to regrow into the denervated hippocampus following fimbrial transections. We found that intraventricular injections of NGF twice a week for 5 months to adult rats resulted in extended protection of cholinergic cell bodies from lesion-induced degeneration and did not produce obvious detrimental effects on the animals. NGF treatment mildly stimulated growth of cholinergic neurites within the 2-mm area directly adjacent to the fimbrial lesion but it failed to induce significant homotypic growth of cholinergic neurites into the deafferented hippocampus.

Acetylcholinesterase↗
PubMed1990

The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition.

Smooth muscle cell (SMC) proliferation and formation of extracellular matrix in the intima of muscular arteries are major processes that can lead to vascular stenosis in arteriosclerosis or after coronary angioplasty. These processes are also seen in the proliferative response to balloon catheter-induced vascular injury of the rat carotid artery, and result in marked neointima formation by 14 days after catheterization. We have shown recently that the angiotensin-converting enzyme (ACE) inhibitor cilazapril strongly suppressed this development of neointima. In this report, we show that the beneficial effects on neointima formation persist for at least 8 weeks after stopping treatment with cilazapril, and that continuous treatment may have additional inhibitory effects during the late phases of vascular remodeling after injury. To investigate further the possible mechanisms, we examined several vasoactive compounds in this model. Another ACE inhibitor of a different chemical class, captopril, reduced neointima formation as strongly as cilazapril (67 and 78%, respectively), but the calcium antagonist verapamil was not active as an inhibitor of neointima formation, despite similar lowering of blood pressure. Hydralazine and a new calcium antagonist, Ro 40-5967, partially suppressed neointima formation (36%, p less than 0.005 and 33%, p less than 0.05, respectively). In vitro, neither cilazapril nor its active metabolite, cilazaprilate, had any effect on SMC proliferation in response to serum or PDGF. To characterize further the role of angiotensin II (Ang II), we tested in cell culture the effects of Ang II and cilazaprilate on mRNA levels of several proteins potentially involved in regulating the SMC response.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1990

Toxicity of 1-methyl-4-phenylpyridinium for rat dopaminergic neurons in culture: selectivity and irreversibility.

Cultures of dissociated embryonic rat mesencephalic cells were exposed to 10 microM 1-methyl-4-phenylpyridinium (MPP+), a concentration shown earlier to result in loss of greater than 85% of tyrosine hydroxylase (TH)-positive neurons without affecting the total number of cells observed by phase-contrast microscopy. To characterize better the selectivity of the toxic action of MPP+, other parameters were measured reflecting survival and function of dopaminergic or nondopaminergic neurons. Exposure of cultures to 10 microM MPP+ for 48 h reduced TH activity to 11% of control values without reducing protein levels. [3H]Dopamine uptake was reduced to less than 4% of control values, whereas the uptake of gamma-[3H]aminobutyric acid ([3H]GABA) was not affected in these cultures. This same treatment failed to reduce the number of cholinergic cells visualized in septal cultures and did not affect either choline acetyltransferase activity or high-affinity choline uptake. To assess for possible recovery of dopaminergic neurons, cultures were exposed to 10, 1.0, or 0.1 microM MPP+ for 48 h and then kept for up to 6 days in MPP(+)-free medium. After exposure to 10 microM MPP+, the number of TH-positive neurons, their neurite density, TH activity, and [3H]dopamine uptake remained at constant, reduced levels throughout the period of observation after termination of exposure, whereas GABA uptake remained normal. Treatment with lower concentrations of MPP+, i.e., 1.0 and 0.1 microM, induced less pronounced dopaminergic toxic effects. However, no recovery was seen after posttreatment incubation in toxin-free medium. These findings provide evidence that MPP+ treatment results in highly selective and irreversible toxicity for cultured dopaminergic neurons.

1-Methyl-4-phenylpyridinium↗