Distribution Of Nerve Growth Factor Research Articles

Quantitative Biofabrication Platform for Collagen-Based Peripheral Nerve Grafts with Structural and Chemical Guidance.

Owing to its crucial role in the human body, collagen has immense potential as a material for the biofabrication of tissues and organs. However, highly refined fabrication using collagen remains difficult, primarily because of its notably soft properties. A quantitative biofabrication platform to construct collagen-based peripheral nerve grafts, incorporating bionic structural and chemical guidance cues, is introduced. A viscoelastic model for collagen, which facilitates simulating material relaxation and fabricating collagen-based neural grafts, achieving a maximum channel density similar to that of the native nerve structure of longitudinal microchannel arrays, is established. For axonal regeneration over considerable distances, a gradient printing control model and quantitative method are developed to realize the high-precision gradient distribution of nerve growth factor required to obtain nerve grafts through one-step bioprinting. Experiments verify that the bioprinted graft effectively guides linear axonal growth in vitro and in vivo. This study should advance biofabrication methods for a variety of human tissue-engineering applications requiring tailored cues.

Permeability and distribution of nerve growth factor in the brain of neonatal rats by periphery venous injection in hypoxic-ischemic state.

ObjectiveTo investigate the permeability of β-NGF through blood–brain-barrier (BBB) in neonatal and adult rats, and the spatial distribution of β-NGF in different brain regions in hypoxic-ischemic (HI) and normal neonatal rats.MethodsTo investigate the overall permeability of β-NGF through BBB, β-NGF labeled with I125 was injected into adult rats, neonatal rats and HI neonatal rats via tail vein. The radioactivity of brain tissue and blood was examined and analyzed 30 min after injection. Also, brain regions including the basal forebrain, frontal cortex, hippocampus, hypothalamus, cerebellum, bulbus olfactorius and hypophysis, of all the rats were dissected and radioactivity was examined to investigate the spatial specificity of NGF permeation through BBB.ResultsStatistically significant results were observed in I125-β-NGF contents in brain tissues of adult rats group, neonatal rats group and HI neonatal rats group (P < 0.05). Compared to the HI neonatal rats’ brain with the highest I125-β-NGF contents, normal neonatal rats ranks the second while the adult rats were the lowest. While for the spatial specificity examination part, I125-β-NGF in both HI group and control group were widely distributed in basal forebrain, frontal cortex, hippocampus, cerebellum and bulbus olfactorius. But the radioactivity in frontal cortex, hippocampus and cerebellum of HI groups are statistically higher than control groups (P < 0.05).Conclusionβ-NGF can more easily penetrate the BBB of newborn rats than adult rats via peripheral venous administration and this effect can be enhanced by HI insult. Also, this HI-induced permeation of β-NGF through BBB is more obvious in frontal cortex, hippocampus and cerebellum.

Expression of NGF, BDNF and their receptors in subcutaneous adipose tissue of lactating cows

Currently, there are no reports of neurotrophins in adipose tissue of cows. The distribution of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and their high-affinity tyrosine kinase receptors TrkA and TrkB, was investigated by immunohistochemical method in the subcutaneous adipose tissue of cow at mid-lactation. Results revealed the localization of NGF and BDNF along the plasma membrane and cytoplasm of adipocytes. Neurotrophin receptors TrkA and TrkB showed moderate and strong positive staining in adipocytes, respectively. The expression of NGF, BDNF, TRKB — but not of TRKA — was also confirmed at transcriptional level by RT-PCR analyses.Considering the involvement of BDNF on fat metabolism and of NGF on activation of the sympathetic response in human and rodents, these neurotrophins could be related to lipogenesis and lipolysis occurring during lactation in cows. The local production of these neurotrophins supports their potential paracrine function for the regulation of adipocyte activity and deserve further investigations.

Expression of NGF, BDNF and their high-affinity receptors in ovine mammary glands during development and lactation.

The distribution of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and their high-affinity tyrosine kinase receptors TrkA and TrkB was investigated by immunohistochemical method in the mammary gland of ewes from prepubertal stage to involution. NGF and BDNF protein expressions were strong during development of glands at prepubertal stage and during pregnancy and decreased during lactation and involution. The expressions localized in both stromal and parenchymal cells of developing gland were mainly arranged in the apical side of secretory cells during lactation. These observations were also confirmed at transcriptional level by RT-PCR analyses. The highest expression of all genes significantly occurred at prepubertal stage. NGF was then down-regulated from pregnancy to involution, and no statistical differences were observed among these stages. The receptor TrkA was also under-expressed from pregnancy to involution, and its expression significantly differed between pregnancy and 30 days of lactation and also between 30 and 60 days of lactation. BDNF was significantly down-regulated at 60 days of lactation in comparison with prepubertal stage and again between pregnancy and 30 days of lactation. The relative abundance of its receptor, TrkB, showed also a significant down-regulation at 60 days of lactation in comparison with pregnancy and involution. Among the myriad of other molecular signals involved in the mammary gland cycle, the local production of neuropeptides and their receptors could be of interest in understanding their potential role in mammary biology.

Distribution of nerve growth factor, pro‐nerve growth factor, and their receptors in human salivary glands

Nerve growth factor (NGF) is a pluripotent mediator that is present in a range of human tissues. Nerve growth factor was originally considered important only in neuronal homeostasis and pathophysiology, but later it was also implicated in the pathophysiology of inflammation, epithelial differentiation, and wound healing. In this study, the distribution of nerve growth factor beta (NGF-β) and pro-NGF, and their receptors - tyrosine kinase A (TrkA) and p75(NTR) - was examined in human parotid, submandibular, sublingual, and labial salivary glands by immunohistochemistry. Intercalated, striated, and collecting-ducts in all gland types showed strong staining for pro-NGF but only weak cytoplasmic or sparse nuclear staining for NGF-β. Tyrosine kinase A was strongly expressed in the ducts of all gland types, whereas p75(NTR) expression was mainly confined to collecting ducts. In acini, no or only weak cytoplasmic staining was found for all markers, and some nuclei stained positive for NGF-β, pro-NGF, and TrkA. Western blotting of saliva showed secretion of several forms of pro-NGF, while no mature NGF-β was detected. Salivary pro-NGF may play a role in oral wound healing.

Neurotrophic Factor Changes in the Rat Thick Skin following Chronic Constriction Injury of the Sciatic Nerve

BackgroundCutaneous peripheral neuropathies have been associated with changes of the sensory fiber innervation in the dermis and epidermis. These changes are mediated in part by the increase in local expression of trophic factors. Increase in target tissue nerve growth factor has been implicated in the promotion of peptidergic afferent and sympathetic efferent sprouting following nerve injury. The primary source of nerve growth factor is cells found in the target tissue, namely the skin. Recent evidence regarding the release and extracellular maturation of nerve growth factor indicate that it is produced in its precursor form and matured in the extracellular space. It is our hypothesis that the precursor form of nerve growth factor should be detectable in those cell types producing it. To date, limitations in available immunohistochemical tools have restricted efforts in obtaining an accurate distribution of nerve growth factor in the skin of naïve animals and those with neuropathic pain lesions. It is the objective of this study to delineate the distribution of the precursor form of nerve growth factor to those cell types expressing it, as well as to describe its distribution with respect to those nerve fibers responsive to it.ResultsWe observed a decrease in peptidergic fiber innervation at 1 week after the application of a chronic constriction injury (CCI) to the sciatic nerve, followed by a recovery, correlating with TrkA protein levels. ProNGF expression in CCI animals was significantly higher than in sham-operated controls from 1-4 weeks post-CCI. ProNGF immunoreactivity was increased in mast cells at 1 week post-CCI and, at later time points, in keratinocytes. P75 expression within the dermis and epidermis was significantly higher in CCI-operated animals than in controls and these changes were localized to neuronal and non-neuronal cell populations using specific markers for each.ConclusionsWe describe proNGF expression by non-neuronal cells over time after nerve injury as well as the association of NGF-responsive fibers to proNGF-expressing target tissues. ProNGF expression increases following nerve injury in those cell types previously suggested to express it.

The distribution of nerve growth factor in rabbits' eyes after intraocular injection in two different means

Objective To observe the distribution and concentration of ~(125)I-nerve growth factor (NG-F) in rabbits' eyes after intravitreal injection and posterior juxtascleral injection.Methods Intravitreal injection(group A) and posterior juxtascleral injection (group B) were performed with the dosage of 30μg/100μl ~(125)I-NGF on left and right eyes in 45 white rabbits respectively.The γ-counts and the concentration of ~(125)I-NGF (%ID/g) of each ocular tissue was determined 15 and 30 minutes,and 1,3,6,12,24,and 48hours after injection.Results The ~(125)I-NGF diffusion in group A was faster in ocular content and ocular inner wall.The vitreous content of ~(125)I-NGF decreased gradually in group A,the curve changes in other eye tissues were normal.The concentration of ~(125)I-NGF reached the peak 3 hours after injection in aqueous humor,iris and ciliary body,retina,and choroids,but 6 hours after injection in sclera and 8 hours in cornea.The changes of concentration of ~(125)I-NGF in group B showed normal curve change.The peak time in group B were all 6 hours,in all the tissues except aqueous humor (3 hours).Except the high concentration in vitreous body caused by intravitreal injection,the concentration of ~(125)I-NGF in retina was the highest in group A.Conclusion Intravitreal injection of ~(125)I-NGF can gain higher concentration in each ocular tissue than posterior juxtaseleral injection,especially in retina.So intravitreal injection of NGF is a better ocular delivery method to treat the ocular fundus diseases. Key words: Nerve growth factor/administration & dosage; Microinjections/methods; Drug delivery systems/methods; Animal experimentation

Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study

Evidence suggests that neurotrophins may regulate certain immune functions and inflammation. In the present study, the localization and distribution of nerve growth factor (NGF) and its receptors were explored using immunohistochemical methods, with the aim of detecting the cause of the neurohyperplasia in early lesions of atopic dermatitis (AD). In AD involved skin, strong NGF-immunoreactive (IR) cells were observed in the epidermis. In some cases, a huge number of infiltrating cells with stronger NGF immunoreactivity was seen mainly in the dermal papillae. Some trkA immunoreactivity was observed in the outer membrane of cells in the basal and spinal layers of the epidermis. In the papillary dermis, a larger number of cells demonstrated strong trkA immunoreactivity. The p75 NGFr-IR nerve fibre profiles were increased (900 per mm(2); p<0.001) compared to normal [the involved skin also differed from the uninvolved skin (p<0.05)] in the dermal papillae. These nerve fibres were larger, coarser and branched, some of them terminated at p75 NGFr-IR basal cells, and also revealed a stronger fluorescence staining than the controls or the uninvolved skin. In normal healthy volunteers and AD uninvolved skin, the NGF immunoreactivity was weak in the basal layer of epidermis. Only a few trkA positive cells were seen in the basal layer of the epidermis and upper dermis. The IR epidermal basal cells revealed a striking patchy arrangement with strong p75 NGFr immunostaining in the peripheral part of the cells, and short and thick NGFr-IR nerve fibre profiles appeared as smooth endings scattered in the dermis including the cutaneous accessory organs. Using NGF and p75 NGFr double staining, both immunoreactivities showed a weak staining in the epidermis and dermis in normal and uninvolved skin. In the involved dermis of AD, the intensity of p75 NGFr-IR nerves was stronger in areas where there were also increased numbers of NGF-IR cells. These findings indicate that NGF and its receptors may contribute to the neurohyperplasia of AD.

Cellular Localization of NGF and its Receptors trkA and p75LNGFR in Male Reproductive Organs of the Japanese Monkey, Macaca fuscata fuscata

The actions of neurotropins are not restricted to the nervous system. Immunohistochemical methods were used in the present study to clarify distribution of nerve growth factor (NGF) and its receptors TrkA and p75LNGFR in excurrent ducts of the adult male Japanese monkey (Macaca fuscata fuscata). NGF was found in the seminal vesicle, epididymis, and testis, and has been thought to affect male reproductive functions. Leydig cells, Sertoli cells, and spermatogonia at various stages were positively stained for NGF, as well as for TrkA and p75LNGFR. Signals for these proteins were also found in epithelial cells and stromal tissues of the caudal epididymidis, as well as in the seminal vesicle. In the prostate, smooth muscle cells and basal cells were positively stained for NGF, TrkA, and p75 LNGFR. The results were comparatively discussed.

Postnatal changes in nerve growth factor and brain derived neurotrophic factor levels in the retina, visual cortex, and geniculate nucleus in rats with retinitis pigmentosa

Royal College of Surgeons (RCS) rats are a well established animal model of inherited retinitis pigmentosa (RP). Using RCS rats we examined the distribution of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the visual cortex, geniculate nucleus and retina at three different postnatal ages. It was found that the retina of rats with RP expresses low amounts of NGF and BDNF in young and adult life. Altered levels of these factors were found in the visual cortex and in the geniculate nucleus. Our findings indicate that NGF and BDNF are differentially affected in the visual system of developing and adult RCS rats, suggesting that neurotrophins may be implicated in the pathogenesis of inherited RP.

Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin – an exploration of the cause of neurohyperplasia

Neurotrophins and their receptors play an important role in cutaneous nerve development and reconstruction after injury. Recent developments indicate that this group of molecules not only exert a neurotrophic action, but are also involved in immune responses and inflammation. Prurigo nodularis is a skin disease characterized by neurohyperplasia and intense itch. In the present study, the localization and distribution of nerve growth factor (NGF) and its receptors were explored by immunohistochemical methods, with the aim of detecting the cause of the neurohyperplasia in the disease. In normal healthy volunteers and in uninvolved skin, NGF immunoreactivity was seldom seen in the basal layer of the epidermis or in the dermis. In prurigo nodularis skin, there was also very little NGF immunoreactivity in the epidermis. However, in the dermis, a huge number of cells showed an NGF-like immunoreactivity. In normal skin of healthy volunteers, only a weak staining for tyrosine kinase A (trkA) was seen in the epidermis, whereas in the dermis, there was no trkA staining seen at all. However, in the prurigo nodularis tissue, the hyperplastic nerves clearly showed trkA immunoreactivity, and it seemed that the staining was only present in the axons. By NGF and p75 NGF receptor double-labelling, both immunoreactivities showed weak staining in the epidermis and dermis of normal skin. However, in the dermis of prurigo nodularis, strong staining for both NGF and NGF receptor antibodies was seen. NGF receptor-immunoreactive nerves were more dense in areas where there were more NGF-immunoreactive cells. The results indicate that in prurigo nodularis skin, NGF is overexpressed, locally infiltrated inflammatory cells may be the source of this NGF, and NGF and its receptors may contribute to the neurohyperplasia of the disease.

Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain

The distribution of nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in substantia nigra pars compacta (SNc) of Parkinson's disease (PD) brains was investigated by immunofluorescence. Cases studied included four 69–77 year old neurologically normal male controls and four 72–79 year old male PD patients. Integrated optical densities (IODs) of immunofluorescence over individual neuromelanin-containing neurons and in areas of neuropil and the number of neurons on H & E stained adjacent sections were quantitated with the use of the BioQuant Image Analyzer. Data were statistically analyzed by ANOVA, including the unpaired two-tailed Student t-test and the Mann–Whitney test. The results showed 55.8% ( P<0.0001) dropout of SNc neurons in PD brains compared to age-matched controls. Despite considerable neuronal dropout, immunofluorescent NTFs in the PD brains showed differential reductions that were consistent within the group as compared to age-matched controls: reductions were GDNF, 19.4%/neuron ( P<0.0001), 20.2%/neuropil ( P<0.0001); CNTF, 11.1%/neuron ( P<0.0001), 9.4%/neuropil ( P<0.0001); BDNF, 8.6%/neuron ( P<0.0001), 2.5%/neuropil. NGF, NT-3 and NT-4 showed no significant differences within surviving neurons or neuropil. Since the depletion of GDNF both within surviving neurons and neuropil was twice as great as that of CNTF and BDNF and since the other NTFs showed no changes, GDNF, of the tested NTFs, is probably the most susceptible and the earliest to decrease in the surviving neurons of SNc. These observations suggest a role for decreased availability of GDNF in the process of SNc neurodegeneration in PD.

Expression of nerve growth factor in astrocytes of the hippocampal CA1 area following transient forebrain ischemia

We have examined by immunoassay and immunohistochemistry, the expression of nerve growth factor in the rat hippocampus, one to 28 days after transient forebrain ischemia. In the CA1 area, the overall level of nerve growth factor expression remained constant over the first three days of reperfusion while it increased by about 45% of control levels after longer postischemic periods. In contrast, a slight decrease in nerve growth factor levels, which was most prominent at three days postlesion, was observed in the other hippocampal regions. Immunohistochemical analysis of the distribution of nerve growth factor showed that its expression was up-regulated in astrocytes but not in microglia of the postischemic CA1 region and that the intensity and temporal profile of the changes in nerve growth factor immunostaining in these cells, was consistent with that observed in the immunoassay. Interestingly, the regulation of the nerve growth factor expression in reactive astrocytes of the postischemic CA1 area closely parallels that of kainate receptor subunits GluR5–7, raising the possibility of a cause–effect relationship. These results indicate that after ischemia nerve growth factor expression is up-regulated in reactive astrocytes suggesting that these cells may contribute to rescuing damaged neurons by means of increasing nerve growth factor production.

Distribution of nerve growth factor in cat brains following topical application of solution or Minipellet

The distribution of nerve growth factor (NGF) was studied after topical application ofNGF solution or NGF Minipellet into the caudate nucleus of cat brains. Each aliquot of NGF solution or a piece of NGF Minipellet contains 200 µ1g of mouse 2.5S β-NGF. The concentrations of NGF In vanous areas of the braIn were determined by enzyme-linked immunosolvent assay (ELISA). The tissue concentrations of NGF were very high at 6h after injection of NGF solution (124.0±2.46 to 2144.0± 16.03 ngg-1), but quickly decreased on day 1. The tissue concentrations of NGF were low at 6 h after Implantation of NGF Minipelletl but were considerably increased on day 1 (11.22 ± 3.36 to 72.04 ± 20.45 ngg-1), and slowly decreased during the following 6 to 14 days. The present study demonstrates the temporal and spatIal profiles ofNGF distribution in the brain of middle-sized animals after topical application. Injection of NGF solution resulted in abruptl but very transientl elevation of tissue NGF. Implantation of NGF Minipellet maintained the tissue NGF at biologically effective levels for 6 to 14 days. [Neural Res 1998, 20: 116–120)

The distribution of tenascin-R in the developing avian nervous system

Tenascin-R is an extracellular matrix glycoprotein found in the developing central nervous system. In vitro, tenascin-R promotes axon growth. In order to learn more about the function and regulation of tenascin-R in neural development, we have used monoclonal antibodies to localize tenascin-R immunoreactivity in the developing and adult chicken brain. The earliest stage stained with anti-tenascin-R was embryonic day 6.5, when the matrix surrounding the cell bodies of spinal cord motoneurons was stained. At embryonic day 18, specific brain regions were stained, including the basal nuclei, habenular nuclei, layer "i" of the optic tectum, and the motor nuclei of cranial nerves. Anti-tenascin-R staining persisted in these regions in the adult chicken brain. Thus, the distribution of tenascin-R immunoreactivity in the developing and mature avian brain is correlated with the distribution of nerve growth factor (NGF)-sensitive neurons, but it is not correlated with neurite outgrowth. Finally, NGF was shown to upregulate tenascin-R expression in PC12 cells, indicating that expression of neuron-derived tenascin-R may be regulated by exogenous NGF.

The distribution of tenascin‐R in the developing avian nervous system

Tenascin-R is an extracellular matrix glycoprotein found in the developing central nervous system. In vitro, tenascin-R promotes axon growth. In order to learn more about the function and regulation of tenascin-R in neural development, we have used monoclonal antibodies to localize tenascin-R immunoreactivity in the developing and adult chicken brain. The earliest stage stained with anti-tenascin-R was embryonic day 6.5, when the matrix surrounding the cell bodies of spinal cord motoneurons was stained. At embryonic day 18, specific brain regions were stained, including the basal nuclei, habenular nuclei, layer “I” of the optic tectum, and the motor nuclei of cranial nerves. Anti-tenascin-R staining persisted in these regions in the adult chicken brain. Thus, the distribution of tenascin-R immunoreactivity in the developing and mature avian brain is correlated with the distribution of nerve growth factor (NGF)-sensitive neurons, but it is not correlated with neurite outgrowth. Finally, NGF was shown to upregulate tenascin-R expression in PC12 cells, indicating that expression of neuron-derived tenascin-R may be regulated by exogenous NGF. J. Exp. Zool. 280:152–164, 1998. © 1998 Wiley-Liss, Inc.

Immuno-electron Microscopy Characterization of Human Bone Marrow Stromal Cells with Anti-NGFR Antibodies

ABSTRACT Human bone marrow stromal cells have been examined with an immuno-electron microscopy technique in order to better define their structure and function in normal hematopoiesis. Bone marrow fragments from normal donors, after mild permeabilization and glutaraldehyde prefixation were labeled with the Me20.4 Mab, which recognizes the low-affinity nerve growth factor (NGFR) and was recently described as specifically identifying fibroblastic-like bone marrow stromal cells. Five nm gold immuno-conjugates served as markers. NGFR + cells were showing either a star-shape, with long and convoluted dendritic projections, and branching with each other to form a complex system of lacunae upon which hematopoietic cells were arranged. Other NGFR + cells had an elongated spindle-like morphology. NGFR + dendrites were seen in close contact with each other and with the different hematopoietic cells, although definite junctions were never noticed. NGFR+ dendrites were also observed surrounding mature plasma cells, in close apposition with adipocytes or surrounding bone marrow sinusoids. These findings may give some clues about the function of the bone marrow stromal cells, which are known to be involved in the homing and recirculation of hemopoietic cells; in addition, the presence and distribution of NGFR in the bone marrow stroma may support the recent evidence of a co-stimulatory effect of NGF in early hematopoiesis.

Age-related decrease of nerve growth factor-like immunoreactivity in the basal forebrain of senescence-accelerated mice.

The senescence-accelerated mouse P10 (SAMP10) is a murine model of accelerated senescence characterized by the deterioration of learning and memory with advancing age. In the present study, we examined the distribution of nerve growth factor (NGF) immunohistochemically in SAMP10 mice and its control strain, SAMR1. In both strains, NGF-like immunoreactivity (NGF-IR) was observed in neurons throughout the entire forebrain and in glial cells in a particular location. In aged SAMP10 mice, each layer of the cerebral cortex retained its NGF-IR, although the thickness of the cortical mantle was markedly decreased in comparison with younger animals. There was an age-related decline in NGF-IR in the substantia innominata of SAMP10 mice at the age of 10 months, when compared to 2-month-old SAMP10. These results indicate age-related decrease of NGF in the basal forebrain in SAMP10 mice.

Distribution of nerve growth factor following direct delivery to brain interstitium

Several studies suggest the potential of nerve growth factor (NGF) in the treatment of patients with Alzheimer's disease. To characterize NGF transport within the brain interstitium, we implanted controlled release polymers containing NGF and [ 125I]NGF into the brains of adult male rats and measured spatial distributions of NGF for up to one week. NGF concentration in the brain was quantified using ELISA, radiation counting, and autoradiography. At 2 days post-implantation, quantities of NGF in excess of 50 pg per section were detected within thick (1 mm) coronal slices of the hemisphere ipsilateral to the site of implantation up to 3 mm rostral and caudal to the edge of the polymer. Lower levels of radioactivity (> 5 pg but < 50 pg NGF per section) could be detected throughout the rest of the brain. Levels were highest in the tissue sections containing the polymer, reaching 9.5 ng per section. Autoradiography of thin (20 μm) coronal sections indicated that local NGF concentrations immediately adjacent to the polymer approached 40 μg/ml. Analysis of sequential sections on the autoradiograph confirmed that NGF was transported only 2–3 mm from the polymer in any direction. At one week post-implantation, the pattern of NGF distribution was similar to that seen at 2 days, and concentrations remained high near the site of the implant. Comparison of local NGF concentration profiles to simple models of diffusion with first-order elimination suggests that the NGF moved through the tissue by diffusion through the interstitial space with a half-life on the order of 0.5 h. The limited range of NGF transport in brain tissue indicates that: (i) protein drug agents such as NGF will probably need to be delivered almost directly to the site of action for efficacy; and (ii) toxicities associated with delivery of NGF and other protein agents to non-target cells, as often occurs with systemic delivery of drugs, may be reduced by local, interstitial delivery since therapy can be restricted to a small volume of the brain.

Growth factor receptors in amyotrophic lateral sclerosis.

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.