RESUMEN
Melanocortins, non-corticotropic fragments of adrenocorticotropic hormone, accelerate growth of the developing neuromuscular system and regrowth of damaged neurons, both in the adult and neonatal rat. Morphological, electrophysiological and behavioral characteristics are all improved by melanocortins, which, however, vary in potency, with alpha-MSH being the most effective. Tissue substrate, dosage, critical time periods and pattern of neuropeptide administration are all important variables. Melanocortins protect central neurons affecting motor behavior during development or following neuronal damage in the adult brain. Possible mechanisms of melanocortin action are discussed.
Asunto(s)
Hormona Adrenocorticotrópica/fisiología , Actividad Motora/efectos de los fármacos , Músculos/inervación , Fármacos Neuromusculares/farmacología , Hormona Adrenocorticotrópica/química , Hormona Adrenocorticotrópica/farmacología , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Células Cultivadas , Electrofisiología , Humanos , Datos de Secuencia Molecular , Desarrollo de Músculos , Músculos/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuromusculares/administración & dosificación , Fármacos Neuromusculares/uso terapéutico , Unión Neuromuscular/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Receptores de Corticotropina/efectos de los fármacos , Receptores de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
Short peptide sequences of ACTH 1-39 (the ACTH 4-9 analog Org 2766, ACTH 4-10 and its analog BIM 22015, and ACTH 1-13 [alpha-MSH]), which do not stimulate the adrenal cortex, have profound effects on the developing and regenerating neuromuscular system, in neonatal and in adult rats. Both development and regeneration are accelerated, as indicated by improved morphological, electrophysiological, behavioral and biochemical parameters. Regeneration in the central nervous system is problematic but the ACTH peptides may provide protection for CNS neurons, enhance denervation sensitivity or permit compensatory processes which facilitate functional recovery. Neuronal cells in culture respond to ACTH peptides by greater neurite outgrowth, and in some cell types, by increased B-50 expression. In all cases, susceptibility to ACTH peptide treatment varies with cell type, age, the specific peptide administered, its dosage and pattern of administration. External stress and the gender of the animal are additional factors that interact with the neurotrophic actions of the melanocortins.
Asunto(s)
Hormona Adrenocorticotrópica/fisiología , Regeneración Nerviosa/fisiología , Sistema Nervioso/crecimiento & desarrollo , Fragmentos de Péptidos/fisiología , Animales , Humanos , Enfermedades del Sistema Nervioso/fisiopatologíaRESUMEN
Structural differences between noncorticotropic ACTH peptides result in marked differences in their effects on regenerating nerve and muscle in rats. The ACTH/MSH(4-10) analog BIM 22015 was administered IP in dosages from 0.1 to 40 micrograms/kg/48 h for 5, 7, or 11 days after peroneal nerve crush, and characteristics of extensor digitorum longus (EDL) muscle were studied and compared with ACTH/MSH(4-10). Eleven days postcrush 40 micrograms/kg BIM 22015 increases rate of development of tetanic tension and amplitude of contraction of indirectly stimulated EDL. In a 21-day study, reinnervated BIM 22015-treated muscles retain tetanic strength, whereas ACTH/MSH(4-10)-treated muscles are significantly weakened. Both peptides show neurotrophic characteristics in their stimulation of endplate nerve terminal branching. However, in contrast to ACTH/MSH(4-10), BIM 22015 also prevents denervation atrophy of the EDL. This dual neurotrophic and myotrophic role for BIM 22015 accords it a clinical potential for degenerative myopathies of either pure or mixed origin, such as muscular dystrophy, infantile spinal atrophy, and hypotonia.
