PubMed Health⌕ Search

Biomedical subjects

C E Van der Zee

Publications and source records attributed to C E Van der Zee.

18 recordsLinked to original sources
PubMed2001

A decrease in size and number of basal forebrain cholinergic neurons is paralleled by diminished hippocampal cholinergic innervation in mice lacking leukocyte common antigen-related protein tyrosine phosphatase activity.

The leukocyte common antigen-related (LAR) receptor, composed of an extracellular region with three immunoglobulin-like and eight fibronectin type III-like domains, and a cytoplasmic region containing two protein tyrosine phosphatase domains, is thought to play a role in axonal outgrowth and guidance during neural development. LAR mutant mice were generated completely lacking the two cytoplasmic protein tyrosine phosphatase domains, resulting in the loss of ability to bind intracellular associating proteins, but (may be) still containing the ability to perform extracellular functions. A reduction in size of basal forebrain cholinergic neurons and diminished hippocampal innervation reported for knockout mice that contain a leaky gene trap inserted into the 5' part of the LAR gene [Yeo T. T. et al. (1997) J. Neurosci. Res. 47, 348-360] warranted a computer-assisted quantitative image analysis throughout the basal forebrain and hippocampus of our LAR mutant mice. The total number, longest diameter and cell body area were calculated for the choline acetyltransferase-positive neurons in the medial septum and vertical diagonal band, and optical density measurements were performed to determine the extent of acetyl cholinesterase-positive fibre innervation of the different layers in the dentate gyrus. In LAR mutant mice, the number of cholinergic cells was significantly reduced (approximately 25%) in the vertical diagonal band. Also, the cross-sectional area of the cholinergic neurons in the medial septum and vertical diagonal band was reduced (5%). These findings were paralleled by a diminished cholinergic innervation of the supragranular (18%) and molecular (4%) layers of the dentate gyrus. Thus, LAR protein tyrosine phosphatase activity appears crucial for size, number and target projection of basal forebrain cholinergic neurons, further strengthening a role for LAR in CNS development.

Acetylcholine↗
PubMed1999

P75 nerve growth factor receptor is important for retrograde transport of neurotrophins in adult cholinergic basal forebrain neurons.

The role of the p75 nerve growth factor receptor in the retrograde transport of neurotrophins in the adult CNS was investigated by comparing the transport of 125I-labeled neurotrophins by normal and p75 nerve growth factor receptor-deficient cholinergic septohippocampal neurons. In control mice, nerve growth factor was selectively transported from the hippocampal formation to the cholinergic neurons in the septum. Nerve growth factor labeling was found in three to four times as many septal cholinergic neuronal cell bodies than labeling for neurotrophin-3 or neurotrophin-4/5, and transported brain-derived neurotrophic factor was barely detectable. Cells were considered as labeled when the number of grains per cell exceeded five times background. In p75 nerve growth factor receptor-deficient mice, the number of cholinergic neurons labeled with each of the neurotrophins was reduced by 85-95%. Retrograde labeling of septohippocampal neurons with Fluorogold was not obviously reduced in p75 nerve growth factor receptor-deficient mice, suggesting that general transport mechanisms were not impaired. Despite the reduced neurotrophin transport, cholinergic neurons of p75 nerve growth factor receptor-deficient mice were larger than controls and had an apparently normal density of immunostaining for choline acetyltransferase. Since nerve growth factor is reportedly involved in size regulation and choline acetyltransferase expression, this raises the possibility that the retrograde transport itself is not essential for these events. Thus, p75 nerve growth factor receptor plays an important, although not exclusive, role in the transport of neurotrophins by cholinergic basal forebrain neurons, and retrograde transport of nerve growth factor may not be needed for regulating certain cellular processes.

Animals↗
PubMed1998

p75NGFR mediates death of cholinergic neurons during postnatal development of the neostriatum in mice.

We have previously shown that p75 nerve growth factor receptor (p75NGFR) mediates apoptosis of approximately 25% of the cholinergic basal forebrain neurons in normal control mice between postnatal day 6 and 15, but only of cholinergic neurons that lacked the nerve growth factor receptor TrkA. Here, we investigated whether and when the cholinergic neurons of the neostriatum, which express TrkA and p75NGFR during early postnatal times, undergo p75NGFR-mediated death. The cholinergic neurons in the lateral neostriatal regions expressed choline acetyltransferase (ChAT) earlier (postnatal day 3-6) than those of the medial regions and TrkA appeared before ChAT in all regions. Between postnatal day 6 and 10, approximately 40% of the ChAT-positive neurons in the most lateral regions disappeared in control mice but not in p75NGFR-deficient mice. During this time, the neostriatum of control, but not p75NGFR-deficient, mice contained many apoptotic cells. This suggests that, similar to the cholinergic neurons of the basal forebrain, the neostriatal cholinergic neurons of control mice die and that this process is mediated by p75NGFR. However, the roles of p75NGFR and TrkA appear to be more complicated in the neostriatum where relatively few neurons express p75NGFR during the death phase (and predominantly in the lateral neostriatum where the neuronal loss is greatest), and TrkA-positive as well as TrkA-negative neurons may be lost.

Animals↗
PubMed1997

Nerve growth factor accelerates seizure development, enhances mossy fiber sprouting, and attenuates seizure-induced decreases in neuronal density in the kindling model of epilepsy.

Recurrent seizure activity induced during kindling has been reported to produce a functional synaptic reorganization of the mossy fibers in the hippocampus. To date, it is unclear whether this kindling-induced growth is secondary to decreases in hilar neuron density, which are presumed to reflect hilar neuronal cell loss, or whether it is related specifically to an activation-dependent plasticity. We recently demonstrated that blocking nerve growth factor (NGF) biological activity retards seizure development and inhibits the sprouting of mossy fibers. We now demonstrate that intraventricular administration of NGF itself accelerates the progression of kindling epileptogenesis, increases mossy fiber sprouting in the CA3 region and in the inner molecular layer (IML), but reduces seizure-induced decreases in hilar cell density. These findings provide support for a role of NGF in kindling and kindling-induced mossy fiber sprouting. In addition, the results dissociate this form of epileptogenesis from hilar cell loss or decreases in hilar cell density attributable to increases in hilar area, thereby supporting seizure-induced mossy fiber sprouting as being primarily attributable to the combined effects of neuronal activation and the activation-induced upregulation of growth factors.

Animals↗
PubMed1996

Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice.

The functions of the low-affinity p75 nerve growth factor receptor (p75(NGFR)) in the central nervous system were explored in vivo. In normal mice, approximately 25 percent of the cholinergic basal forebrain neurons did not express TrkA and died between postnatal day 6 and 15. This loss did not occur in p75(NGFR)-deficient mice or in normal mice systemically injected with a p75(NGFR)-inhibiting peptide. Control, but not p75(NGFR)-deficient, mice also had fewer cholinergic striatal interneurons. Apparently, p75(NGFR) mediates apoptosis of these developing neurons in the absence of TrkA, and modulation of p75(NGFR) can promote neuronal survival. Cholinergic basal forebrain neurons are involved in learning and memory.

Animals↗
PubMed1995

A nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy.

Kindling, an animal model of epilepsy wherein seizures are induced by subcortical electrical stimulation, results in the upregulation of neurotrophin mRNA and protein in the adult rat forebrain and causes mossy fiber sprouting in the hippocampus. Intraventricular infusion of a synthetic peptide mimic of a nerve growth factor domain that interferes with the binding of neurotrophins to their receptors resulted in significant retardation of kindling and inhibition of mossy fiber sprouting. These findings suggest a critical role for neurotrophins in both kindling and kindling-induced synaptic reorganization.

Animals↗
PubMed1995

NGF deprivation of adult rat brain results in cholinergic hypofunction and selective impairments in spatial learning.

Cholinergic hypofunction has often been correlated with a variety of behavioural impairments. In the present study, adult Wistar rats were intraventricularly infused with antibodies to nerve growth factor (anti-NGF) to examine the effects on cholinergic neurons of the basal forebrain, and on behavioural performance. Immunocytochemical techniques indicated that chronically infused anti-NGF penetrates into the basal forebrain, cortex, striatum, corpus callosum and hippocampus, confirming previous findings after a single injection. Treatment with anti-NGF for 1 or 2 weeks resulted in a significant decrease of 27-33% in density of choline acetyltransferase immunostaining of the cholinergic cell bodies in the medial septum and vertical diagonal band, and a 26% reduction in choline acetyltransferase enzyme activity in the septal area. An array of spatial learning Morris water maze tasks was used to distinguish between acquisition skills and the flexible use of learned information in novel tests. Rats subjected to the spatial learning paradigm received anti-NGF infusion for 2 weeks prior to and for another 2 weeks during the behavioural testing. The anti-NGF-treated animals were found to be no different from those receiving control serum in the Morris water maze acquisition task, either in the latency to find the platform or in the time spent searching in the training quadrant when the platform was removed. However, in consecutive extinction trials, anti-NGF rats continued to search in the empty training quadrant, suggesting the occurrence of perseveration; control rats expanded their search over other areas of the pool.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats.

Repeated subconvulsive electrical stimulation of certain areas of the forebrain leads to kindling, a progressive and permanent amplification of evoked epileptiform activity, which is a model for human temporal lobe epilepsy. Recent studies have shown that kindling induces synthesis of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in the hippocampus and cortex. Kindling also elicits mossy fiber sprouting and functional synaptogenesis in the supragranular layer, the hilus, and the CA3 region of the hippocampus. Intraventricular administration of antibodies to NGF has been shown to effectively block septohippocampal sprouting in the adult rat, and has been reported to retard amygdaloid kindling. In the present study, we have investigated the possible role of NGF in both kindling and kindling-associated sprouting. We have confirmed a kindling-induced sprouting of the mossy fibers into the stratum oriens of the CA3 region of the hippocampus, utilizing a new semiquantitative method of analysis based on Timm staining. Previous studies found no overt signs of hippocampal damage with this kindling paradigm, indicating that the increased Timm staining likely reflects a purely activity-induced sprouting. Intraventricular infusion of affinity-purified anti-NGF IgGs (which cross-react with NT-3 but not BDNF) resulted in both significant retardation of kindling and inhibition of the kindling-induced mossy fiber sprouting. The findings suggest a role for NGF in both these phenomena.

Animals↗
PubMed1993

Lesion-induced NADPH-diaphorase reactivity in neocortical pyramidal neurones.

Pyramidal neurones of the rat neocortex do not normally express NADPH-diaphorase reactivity. However, after stab lesions which extended through the entire depth of the neocortex, strong NADPH-diaphorase reactivity was observed in pyramidal neurones at 7 and 14 days post-lesion. At 3 and 21 days post-lesion fewer and less reactive pyramidal neurones were observed, and no reactive pyramidal neurones were seen at 2 and 26 days post-lesion. The great majority of reactive pyramidal neurones were in layers V and VI and most were situated medial to the lesion. The induction of NADPH-diaphorase implies that the capability to synthesize nitric oxide may be a component of the pyramidal neurones' response to traumatic injury.

Animals↗
PubMed1992

Antibody to NGF inhibits collateral sprouting of septohippocampal fibers following entorhinal cortex lesion in adult rats.

We have used an antiserum raised against mouse 2.5S NGF to examine the involvement of endogenous neurotrophins in the collateral sprouting of septohippocampal fibers in the adult rat brain. The antiserum was administered intraventricularly. Immunocytochemical techniques indicated that the injected antibodies penetrated into brain tissue that included the basal forebrain, cortex, striatum, corpus callosum, and hippocampus. Unilateral lesioning of the entorhinal cortex was done to evoke the sprouting of the cholinergic septohippocampal fibers. At 8 days postlesion, the sprouting was much advanced, as evidenced by an increase in density of the acetylcholinesterase (AChE) staining in the outer molecular layer (OML) of the dentate gyrus and by the associated increase in the absolute number of AChE-positive fibers in the OML. As well, there was a widening of the inner molecular layer (IML), interpreted as being due to sprouting of noncholinergic axons in that region. In rats injected daily with anti-NGF or anti-NGF Fab fragments, no increase in AChE density, or in the population of AChE-positive fibers, was observed in the OML. In contrast, the widening of the IML seemed to be unaffected by the anti-NGF treatment. No changes were observed in the AChE related parameters in the dentate gyrus of nonlesioned animals treated similarly for 8 days with anti-NGF; there was, however, a decrease of choline acetyltransferase (ChAT) immunostaining in the ChAT-positive cells of the basal forebrain. Our findings and the confirmation that our polyclonal anti-NGF also recognizes other members of the NGF neurotrophin family, specifically brain-derived neurotrophic factor and neurotrophin-3, indicate that at least one of these neurotrophins plays a key role in the collateral sprouting of the cholinergic septohippocampal fibers (but not that presumed to occur within the IML) following an entorhinal cortex lesion.

Acetylcholinesterase↗
PubMed1991

Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat.

1. In rats, recovery of sensory-motor function following a crush lesion of the sciatic or tibial nerve was monitored by measuring foot reflex withdrawal from a local noxious stimulation of the foot sole. 2. Putative neurotrophic compounds were tested on this functional recovery model: melanocortins (peptides derived from ACTH (corticotropin) and alpha-MSH (melanotropin], gangliosides and nimodipine were effective whereas isaxonine and TRH (thyrotropin releasing hormone) were not. 3. Structure-activity studies with melanocortins revealed a similar effectiveness of alpha-MSH, [N-Leu4, D-Phe7]-alpha-MSH, desacetyl-alpha-MSH and the ACTH analogue ORG 2766, questioning the validity of the previously suggested notion that the melanotrophic properties of these peptides are responsible for their neurotrophic effect. 4. As recovery of function after peripheral nerve damage follows a similar time course in hypophysectomized (five days post operation) and sham-operated rats, effective melanocortin therapy does not mimic an endogenous peptide signal in the repair process from pituitary origin. 5. Subcutaneous treatment with ORG 2766 (7.5 micrograms kg-1 48 h-1) facilitates recovery of function following peripheral nerve damage in young (6-7 weeks old), mature (5 month old) and old (20 month old) rats. 6. In view of the diversity in structure of the effective neurotrophic factors and the complexity of nerve repair, the present data support the notion that peripheral nerve repair may be facilitated by different humoral factors likely to be active on different aspects of the recovery process.

Adrenocorticotropic Hormone↗
PubMed1989

Beneficial effect of Org 2766 in treatment of peripheral neuropathy in streptozocin-induced diabetic rats.

An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in rats. In such rats the values of motor nerve conduction velocity and sensory nerve conduction velocity were decreased compared with the values obtained in nondiabetic controls from 3 wk after STZ injection onward. In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage. This article documents the beneficial effect of the peptide Org 2766, an ACTH-(4-9) analogue, in diabetic peripheral neuropathy. Chronic subcutaneous treatment of diabetic rats with Org 2766 results in a significant enhancement of both motor and sensory nerve conduction velocity compared with saline-treated diabetic rats. Histological analysis of cross sections of the sural nerve showed no difference in the total number of nerve fibers in saline- or peptide-treated diabetic rats. In contrast, a difference in fiber size distribution was demonstrated; i.e., the sural nerves of diabetic rats contained fewer thick myelinated fibers. Treatment with Org 2766 resulted in a normal distribution. Apparently, the peptide Org 2766 has a protective action on nerve fibers and nerve function during STZ-induced diabetes.

Adrenocorticotropic Hormone↗
PubMed1989

Expression of growth-associated protein B-50 (GAP43) in dorsal root ganglia and sciatic nerve during regenerative sprouting.

Recently it has been shown that B-50 is identical to the neuron-specific, growth-associated protein GAP43. The present study reports on the fate of B-50/GAP43 mRNA and B-50/GAP43 protein, determined by radioimmunoassay, in a rat model of peripheral nerve regeneration (sciatic nerve crush) over a period of 37 and 312 d, respectively. Moreover, the effects of repeated subcutaneous injection of the neurotrophic peptide Org.2766 (an ACTH4-9 analog) and of a conditioning lesion on B-50/GAP43 protein levels in the regenerating nerve and dorsal root ganglia (DRG) were investigated. Both treatments enhanced the functional recovery as evidenced by a foot-flick withdrawal test. Immunocytochemical analysis using antineurofilament antibodies revealed a peptide-induced increase in the number of outgrowing sprouts in the sciatic nerve. Both the peptide and the conditioning lesion amplified the crush lesion-induced increase in B-50 protein content in the nerve as determined by radioimmunoassay. B-50 protein levels seem to correlate proportionally with the number of sprouts. In the DRG of the crushed sciatic nerve, the time course of B-50 expression was studied. B-50 mRNA was quantified from Northern blots. A linear increase up to 10 times the basal level of B-50 mRNA was observed 2 d postsurgery, followed by a gradual decline to normal levels at day 37. The first significant rise in B-50 mRNA level became apparent between 8 and 16 hr after placement of the crush lesion. The first significant rise in B-50 protein level occurred 40 hr after the crush lesion, reaching a plateau of 3 times the basal level between day 6 and 20. B-50 protein levels in DRG cell bodies remained elevated up to 60 d after crush, a period much longer than that observed for B-50 mRNA. Thus, during a later phase of peripheral axonal regeneration, the presence of B-50 appears to be prolonged, probably by an increase in half-life and not so much by enhanced transcription. Treatment with Org.2766 did not affect the B-50/GAP43 levels in DRG cell bodies during the first 6 d following crush. Conditioning lesion resulted in a DRG B-50/GAP43 protein amount at the same level as in rats 14 d after the test lesion. B-50/GAP43 levels in DRG are probably influenced by the rapid axonal transport of the protein, as has been reported by others.

Adrenocorticotropic Hormone↗
PubMed1988

alpha-MSH and Org.2766 in peripheral nerve regeneration: different routes of delivery.

The efficacy of melanocortins (alpha-MSH and an ACTH-(4-9) analog, Org.2766) in accelerating functional recovery from sciatic nerve damage following various types of subcutaneous and oral administration was assessed in the rat. Furthermore, the effectiveness of the local delivery of melanocortins to the site of injury was examined. An accelerated recovery was evident following subcutaneous constant delivery of Org.2766 from an osmotic mini-pump and from biodegradable polymere microspheres, and was as effective as repeated subcutaneous injections of alpha-MSH or Org.2766. Oral administration of Org.2766 was ineffective. Local application of Org.2766, achieved by wrapping a peptide-impregnated biodegradable gelatine foam matrix around the site of injury, facilitated recovery as well. The biodegradable microspheres and gelatine foam matrix may be of importance in eventual clinical use as effective vehicles for administration of melanocortins in the treatment of peripheral nerve damage.

Administration, Cutaneous↗
PubMed1984

Evidence that the neurotrophic actions of alpha-MSH may derive from its ability to mimick the actions of a peptide formed in degenerating nerve stumps.

The ability of alpha-MSH to facilitate the recovery of sensorimotor nerve function following crush lesion is restricted to a critical period following such a lesion. This period coincided with the initiation of sprouting and the disappearance of the 150 kD neurofilament protein from the degenerating distal stump of the nerve. Degenerating nerve contains a factor that is active in a bioassay system for MSH. This factor could not be detected in control nerves. The hypothesis is forwarded that a neurotrophic factor known to be present in degenerating nerve stumps is an alpha-MSH-like peptide formed by the breakdown of the 150 kD neurofilament protein.

Animals↗
PubMedDate not supplied

Beneficial effect of nimodipine on peripheral nerve function in aged rats.

In aged rats neuromuscular function and motor coordination is gradually impaired. Major motor deficits were seen in rats of more than 2 years of age; with increasing age, the incidence of abnormal footprints increased sharply. Oral nimodipine, a Ca2(+)-entry blocker of the dihydropyridine type, treatment suppressed and/or delayed the appearance of these abnormal footprints. In aged rats that already displayed a considerable amount of abnormal footprints in the free walking pattern, oral nimodipine treatment was similarly effective. Nimodipine not only delays the onset of age-related motor deficits, but also may counteract these deficits once already present. In aged rats the nerve conduction velocities were severely diminished. Nimodipine treatment resulted in an enhancement of the sciatic and caudal nerve conduction velocities. Histological analysis revealed a lower fiber density in aged rats compared to aged nimodipine-treated rats. Whether nimodipine acts directly on the peripheral nervous system is currently unclear. Nevertheless, the present study lends further support for the beneficial effects of nimodipine in age-related motor deficits in the rat.

Administration, Oral↗