epidermal-growth-factor and Nervous-System-Diseases

Protein molecules known as Growth Factors (GFs) appear to play an important regulatory role in a number of CNS functions. In particular Nerve Growth Factor (NGF), the best characterized among about 30 GF molecules, is endowed with specific activities on cholinergic and peptidergic CNS neurons. Indexes of neurobehavioral maturation are accelerated in the mouse by neonatal NGF exposure, while a similar treatment with EGF exerts both growth-promoting and growth-inhibiting effects on somatic and behavioral development. Scopolamine hyperactivity is enhanced around weaning by NGF pretreatment. Data are discussed along with (a) NGF prevention of cholinergic system damage and (b) the molecular mechanism of endogenously-triggered CNS repair processes.

Topics: Animals; Behavior, Animal; Epidermal Growth Factor; Growth Substances; Mice; Nerve Growth Factors; Nervous System; Nervous System Diseases; Peptides; Rats

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.

Topics: Area Under Curve; Biomarkers; Case-Control Studies; Chemokine CCL11; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokine CXCL10; Chemokine CXCL9; Decision Trees; Dipeptidyl Peptidase 4; Early Diagnosis; Epidermal Growth Factor; Fibroblast Growth Factor 2; Hepatocyte Growth Factor; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-7; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Multivariate Analysis; Nervous System Diseases; Prognosis; Risk Assessment

ALS2/alsin is a member of guanine nucleotide exchange factors for the small GTPase Rab5 (Rab5GEFs), which act as modulators in endocytic pathway. Loss-of-function mutations in human ALS2 account for a number of juvenile recessive motor neuron diseases (MNDs). However, the normal physiological role of ALS2 in vivo and the molecular mechanisms underlying motor dysfunction are still unknown. To address these issues, we have generated mice homozygous for disruption of the Als2 gene. The Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiological analyses identified an age-dependent, slowly progressive loss of cerebellar Purkinje cells and disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, indicating a subclinical dysfunction of motor system in Als2-null mice. Further, quantitative epidermal growth factor (EGF)-uptake analysis identified significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of endosome/vesicle trafficking in the cells. Collectively, while loss of ALS2 does not produce a severe disease phenotype in mice, these Als2-null animals should provide a useful model with which to understand the interplay between endosomal dynamics and the long-term viability of large neurons such as Purkinje cells and spinal motor neurons.

Topics: Age Factors; Analysis of Variance; Animals; Biological Transport; Blotting, Southern; Blotting, Western; Carrier Proteins; DNA Primers; Electrophysiology; Endosomes; Epidermal Growth Factor; Guanine Nucleotide Exchange Factors; Immunohistochemistry; Mice; Mice, Knockout; Motor Neurons; Nervous System Diseases; Purkinje Cells

In this study, we investigated cerebrospinal fluid of patients with various neurological symptoms for the presence of transforming growth factor alpha (TGF-alpha). 41 samples of cerebrospinal fluid were collected by lumbar puncture performed routinely due to the clinical suspicion of neurological disease from 22 females (age 15-80 years, median 42 years) and from 19 males (age 18-82 years, median 48 years). A highly sensitive and specific radioimmunoassay was used to determine the concentration of TGF-alpha in the samples. The detection limit of the assay was about 200 pg TGF-alpha. There was no cross-reactivity to human EGF. We showed CSF indeed does contain TGFalpha. As TGF-alpha was detected in all 41 samples investigated, this growth factor appears to be a constant component of CSF. The mean concentration was 5.5 ng TGF-alpha (S.D. +/- 2.7 pg/ml, range 1.1 to 13.9 pg/ml). There was no significant correlation between TGF-alpha concentration in CSF and age (r = -0.006) and there was no significant difference between females (mean 5.8+/-3.10 pg/ml) and males (mean 5.2+/-1.96 pg/ml). No diagnosis was over represented in patients with TGF-alpha concentrations above or below 1 S.D. off the mean. However, highest concentrations of TGF-alpha were found in the group of patients with peripheral neurological sensory dysfunctions and polyneuropathy. We conclude that TGF-alpha is not only a constant component of human cerebrospinal fluid in adults but could also be significantly involved in the pathophysiology of various neurological diseases. The earlier hypothesis that TGF-alpha could mainly have a role in brain development needs hence to be re-evaluated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Nervous System Diseases; Radioimmunoassay; Transforming Growth Factor alpha

We report three patients with persistent epithelial defects in the context of neurotrophic keratopathy that healed while on treatment with topically applied, mouse-derived epidermal growth factor (m-EGF). The clinical course of these patients was striking and suggests that EGF may have a potential role in the treatment of persistent epithelial defects in subjects suffering from neurotrophic keratitis.

Topics: Administration, Topical; Adolescent; Adult; Cornea; Epidermal Growth Factor; Epithelium; Fluorophotometry; Humans; Keratitis; Male; Nervous System Diseases; Pilot Projects