epidermal-growth-factor and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system characterized by loss of spinal motor neurons, for which no effective treatment exists. Epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP-6) have been considered as good candidates for the treatment of this disease, due to their well documented effects in eliciting pleiotrophic and cell survival mechanisms. The aim of the present work was to evaluate the separate and combined effects of both peptides in an experimental animal model of ALS, the proximal axonopathy induced by 1,2 diacetylbenzene (1,2 DAB) in mice. The evaluations were conducted by means of behavioral tests (trapeze, tail suspension, gait pattern, and open field) and by recording the complex muscle action potential (CMAP) in three different hind limb segments: proximal S1, medial S2, and distal S3. Intraperitoneal daily administration of 1,2 DAB produced significant reduction in body weight, muscle strength, extensor reflex, spontaneous activity, and changes in gait pattern parameters. In parallel 1,2 DAB produced significant prolongation of onset latency and decrease in amplitude of CMAP and in the integrated complex action potential index. Daily administration of the separate compounds did not accelerate the recovery of the affected parameters, except for the gait pattern. The combined treatment produced significant improvement in behavioral parameters, as well as in electrophysiological recovery, particularly in the proximal segment of CMAP. The latter results confirm the proximal character of 1,2 DAB neuropathy, and suggest that combined therapy with EGF and GHRP-6 might be a good therapeutic strategy for the treatment of ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Cell Survival; Disease Models, Animal; Drug Therapy, Combination; Epidermal Growth Factor; Female; Growth Hormone-Releasing Hormone; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oligopeptides

We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.

Topics: Amyotrophic Lateral Sclerosis; Animals; Bromodeoxyuridine; Cell Count; Cell Proliferation; Disease Models, Animal; Epidermal Growth Factor; Fibroblast Growth Factor 2; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Injections, Spinal; Mice; Mice, Transgenic; Motor Neurons; Nerve Tissue Proteins; Rotarod Performance Test; Spinal Cord; Statistics, Nonparametric; Stem Cells; Superoxide Dismutase

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Epidermal Growth Factor; Female; Humans; Male; Middle Aged

Epidermal growth factor (EGF), a mitogenic peptide, is widely distributed within the brain and endocrine cells of the gastro-intestinal tract. Using EGF radioreceptor assay, the EGF level was measured in lumbar cerebrospinal fluid from five patients with amyotrophic lateral sclerosis (ALS) and seven patients with intervertebral disc disease as a control group. The patients with ALS showed reduced EGF levels to 662.4 +/- 207 pg/ml as compared with controls 1013 +/- 182.8 pg/ml (P less than 0.02). These results indicate a possible EGF involvement in the pathogenesis of ALS.

Topics: Aged; Amyotrophic Lateral Sclerosis; Epidermal Growth Factor; Humans; Intervertebral Disc; Middle Aged; Spinal Diseases