Growth factors: potential therapeutic applications in neurology.
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Basal Ganglia Diseases↗
Biomedical subjects
T J Kilpatrick
Publications and source records attributed to T J Kilpatrick.
The differentiation and survival of murine neurons in vitro is promoted by soluble factors produced by an astrocytic cell line.
The influence of accessory cells on the generation of neurons and neuronal survival has been studied in vitro using an immortalised, cloned cell line, Ast-1, which has many of the functional and phenotypic characteristics of cells of the astrocytic lineage. It was found that monolayers of Ast-1 cells were equivalent to monolayers of primary astrocytes in their ability to promote the generation of neurofilament positive neurons from neuroepithelial cells obtained from embryonic day 10 (E10) mice; and both were superior to NIH 3T3 cells. Ast-1 cell monolayers were also found to provide a suitable substrate for the prolonged survival (at least 3 days in vitro) of neurofilament positive neurons obtained from E17 mice, whereas neurons plated onto NIH 3T3 cells were all dead after 2 days. Medium conditioned by Ast-1 cells displayed similar biological activities to that of the monolayers: it increased the number of neurons generated from the E10 neuroepithelial cells, whether they were plated directly onto glass coverslips or onto monolayers of NIH 3T3 cells; and it increased the survival of E17 neurons plated directly onto glass coverslips. In addition, the Ast-1 conditioned medium was shown to promote the survival of the neuroepithelial cells. These results confirm that one of the mechanisms by which astrocytes or their precursors may regulate neuronal development is by secreting soluble growth factors, as has been previously documented in the case of fibroblast growth factor (FGF) (Hatten et al., 1988; Drago et al., 1991a). However, it appears in this system that FGF is not responsible for the demonstrated biological activities, and the Ast-1 action appears to be mediated by putatively novel factor(s).
Animals↗
Protracted form of encephalitis with good outcome.
OBJECTIVE: To present four patients seen over a five-year period who developed severe protracted encephalitic illnesses but whose outcomes were favourable. CLINICAL FEATURES: Of the four patients, aged 18, 22, 34 and 19, three presented with acute psychosis, and all had a prolonged clinical course requiring intensive care management. One patient had residual generalised seizures and the other three recovered fully. No infective or toxic agent could be identified but viral encephalitis was considered most likely. OUTCOME: Despite the protracted courses, the outcomes were favourable. This is in contrast to the generally poor outcomes in encephalitis caused by established infective agents such as herpes simplex type 1. CONCLUSIONS: When the aetiology and hence the natural history of the encephalitis is unknown, long-term intensive support is appropriate.
Adolescent↗
Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation.
The importance of intrinsic commitments and epigenetic influence to the development of mature neural cell phenotypes was assessed using embryonic day 10 murine neuroepithelial cells, isolated from telencephalon and mesencephalon. Two types of clones were generated with fibroblast growth factor: type-A clones consisted of large, amorphous cells, and type-B clones contained epithelial-like cells. In many type-B clones, very large numbers of precursor cells were produced. Twenty-four percent of type-B clones contained small numbers of neurons, and 59% of clones containing neurons also contained astrocytes, indicating that this clonal type was derived from a bipotential precursor cell. Neuronal differentiation was enhanced by culturing precursor cells with conditioned medium derived from an immortalized astroglial-like cell line. These results indicate that neuroepithelial precursors have discrete epigenetic requirements for their proliferation and differentiation.
Animals↗
Hematologic abnormalities occur in both cortical and lacunar infarction.
BACKGROUND AND PURPOSE: Primary hematologic abnormalities are a rare but established cause of ischemic stroke. In addition, activation of hemostatic parameters is often present during the acute phase of stroke. However, it is uncertain whether these abnormalities occur in both cortical and lacunar infarction; this study aimed to further assess this issue. METHODS: Hematologic parameters (prothrombin, activated partial thromboplastin, thrombin clotting, and euglobulin lysis times; and fibrinogen, fibrinopeptide A, antithrombin III, protein C, protein S, and plasminogen levels) were measured in 19 patients within 48 hours of the onset of acute cerebral infarction. These patients included 10 with cortical infarcts and 9 with lacunar infarcts, as determined by standard clinical and radiological criteria. RESULTS: Five patients with lacunar infarction and 7 patients with cortical infarction demonstrated raised fibrinopeptide A levels, indicating enhanced thrombin activity. Fibrinolysis, assessed by the euglobulin lysis time, was impaired in 6 of 9 patients with lacunar infarction and in 2 of 10 patients with cortical infarction. Lupus anticoagulants were detected in 3 patients with lacunar infarction and in 1 patient with cortical infarction. Three patients in each group displayed decreased antithrombin III function, and 1 patient with a lacunar infarction had a low protein C level. CONCLUSIONS: Primary hematologic disorders and secondary hemostatic derangements may occur in patients with either cortical or lacunar infarction.
Adolescent↗
De novo generation of neuronal cells from the adult mouse brain.
Cells of neuronal morphology, expressing the 150- and 200-kDa neurofilament proteins, were generated in vitro from populations of neural cells dissociated from adult (greater than 60-day-old) mouse brain. Most of these neurons arose from dividing precursors, as demonstrated by the incorporation of [3H]thymidine during the culture period and autoradiography. Neuronal production was optimal under the conditions in which precursors were initially stimulated with basic fibroblast growth factor and then exposed to medium conditioned by an astrocytic cell line, Ast-1, in serum-free medium. Few, if any, neurons arose in control cultures or in cultures kept in serum and fibroblast growth factor. These results suggest that neuronal precursors exist in the adult mammalian brain, but they require discrete epigenetic signals for their proliferation and differentiation.
Age Factors↗
Leukemia inhibitory factor promotes the neuronal development of spinal cord precursors from the neural tube.
Recent evidence from our laboratory has shown that leukemia inhibitory factor (LIF) can act early in peripheral nervous system development. We have investigated a potential role of LIF in the developing spinal cord. In explants and dissociated cultures of spinal cord primordium, LIF stimulated a profuse neurite outgrowth. To determine if these effects were related to neuronal differentiation, cells were plated at low cell density and stained for neurofilament. LIF stimulated an increase in the number of newly differentiated neurons, without inducing proliferation of the precursors. Given that LIF has previously reported effects as a cholinergic switching factor for sympathetic neurons, we investigated whether LIF had similar effects in these spinal cord cultures. LIF increased the number of cholinergic neurons in proportion to its overall effect on the stimulation of all neurofilament positive neurons in the culture. These data show that LIF stimulates the generation of spinal cord neurons from their precursors and further implicates a role for LIF in nervous system development.
Animals↗
A case of neurofibromatosis 2 presenting with a mononeuritis multiplex.
A patient with neurofibromatosis 2 had an asymmetrical peripheral neuropathy. A nerve biopsy specimen revealed neurofibromatous changes, and the neuropathy may have been a direct consequence of neurofibromatosis. An apparent clinical response to immunosuppressive treatment and plasma exchange is also reported.
Adult↗
Neural transplantation for Parkinson's disease: a critical appraisal.
The medical treatment of severe Parkinson's disease is presently problematical and neural transplantation has been proposed as an additional therapy. While functional improvement in animal models of Parkinson's disease has been reported following neural grafting, the treatment of human Parkinsonian patients by adrenal medulla autografting into the neostriatum has produced little clinical improvement overall, and is associated with significant morbidity. Although recent grafting of human foetal dopaminergic neurons has shown more promise, many of the case reports lack rigorous assessment and long term follow-up. Further laboratory experimentation in animal models, particularly primates, to ascertain the mechanism of action of the grafts, the optimal sites for grafting, and the immunological responses to grafting, is essential. The future success of neural transplantation for Parkinson's disease may depend on the development of novel strategies such as the use of growth factors to aid cell survival, regulate neurotransmitter levels and promote connectivity. However, at present, the clinical application of neural transplantation for Parkinson's disease is premature.
Adrenal Medulla↗