RESUMEN
Hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited disorder of motor neurons, has three phenotypes: accelerated, intermediate, and chronic. In the accelerated and intermediate phenotypes, axonal sizes in ventral roots were smaller than in controls. Reductions in axonal size occurred primarily in large axons, and the frequency of small-caliber axons was increased. In HCSMA, nerve fiber shape, i.e., circularity, was reduced, and the relative thickness of the myelin sheath as a function of axonal caliber was decreased. The density of fibers in motor nerves was increased, making it unlikely that a selective loss of large-caliber axons explained the increased frequency of small-caliber axons. These observations suggest that, in HCSMA, changes in axonal size in motor nerves are associated with both growth arrest and axonal atrophy.
Asunto(s)
Axones/patología , Neuronas Motoras/patología , Atrofia Muscular Espinal/patología , Factores de Edad , Animales , Atrofia/patología , Perros , Atrofia Muscular Espinal/genética , Vaina de Mielina/patología , FenotipoRESUMEN
This study examined Schwann cell behavior during paranodal demyelination induced by beta,beta'-iminodipropionitrile (IDPN). The stimuli for Schwann cell proliferation, extensively studied in vitro, are less well understood in vivo. Most in vivo systems previously used to examine Schwann cell proliferation in disease are dominated by loss of internodal myelin sheaths. As used in this study, IDPN administration produces neurofilamentous axonal swellings and paranodal demyelination, without segmental demyelination or fiber degeneration. We asked whether Schwann cells would proliferate following the restricted paranodal demyelination that accompanies the axonal swellings, and if so what the sources and distributions of new Schwann cells might be. IDPN was given as a single large dose (2 ml/kg) to 21-d-old rats. Neurofilamentous axonal swellings formed in the proximal regions of motor axons, reaching their greatest enlargement in the root exit zone 8 d after IDPN administration. These swellings subsequently migrated distally down the nerves at rates approaching 1 mm/d. The axonal enlargement was consistently associated with displacement of the myelin sheath attachment sites into internodal regions, and consequent paranodal demyelination. This stage was associated with perikaryal changes, including nucleolar enlargement, "girdling" of the perikaryon, and formation of attenuated stalks separating the perinuclear region from the external cytoplasmic collar. Schwann cells proliferated abundantly during this stage. Daughter Schwann cells migrated within the endoneurial space (outside the nerve fiber basal laminae) to overlie the demyelinated paranodes of swollen nerve fibers. In these regions, local proliferation of Schwann cells continued, resulting in large paranodal clusters of Schwann cells. As the axonal calibers subsequently returned to normal, the outermost myelin lamellae of the original internodes returned to their paranodal attachment sites and the supernumerary Schwann cells disappeared. Formation of short internodes, segmental demyelination, and nerve fiber loss were rare phenomena. These results indicate that paranodal demyelination is a sufficient stimulus to excite abundant Schwann cell proliferation; neither internodal demyelination nor myelin breakdown is a necessary stimulus for mitosis. The 3H-thymidine incorporation studies indicated that the sources of new Schwann cells included markedly increased division of the Schwann cells of unmyelinated fibers and, as they formed, supernumerary Schwann cells. In addition, there were rare examples of 3H-thymidine incorporation by Schwann cells associated with myelinated nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Células de Schwann/citología , Animales , Axones/ultraestructura , División Celular , Movimiento Celular , Masculino , Vaina de Mielina/fisiología , Fibras Nerviosas/citología , Nitrilos/farmacología , Ratas , Ratas Endogámicas , Células de Schwann/fisiología , Células de Schwann/ultraestructura , Factores de TiempoRESUMEN
Paranodal demyelination produces a reduction of conduction velocity and conduction block. The relative proportions of these changes appear to vary among different demyelinating disorders. In this study we have examined the effects on conduction of paranodal demyelination produced by giant axonal swellings. The axonal swellings were induced in rats by administration of beta, beta'-iminodipropionitrile (IDPN). In this experimental model synchronous axonal swellings occur in the proximal region of virtually every alpha-motorneuron without evidence of segmental demyelination or fiber loss. Conduction across the motor neuron was evaluated by two methods: a monosynaptic reflex pathway and intracellular recording from single motor neurons. Increases in the delay across the central region of the monosynaptic reflex pathway began between 2 and 4 days after toxin administration. Intracellular studies confirmed that the slowing occurred across the proximal regions of the motor axons; more distal regions of the motor axons were unaffected. The substantial reduction in conduction velocity over the swollen segment occurs with only moderate evidence of conduction block, as assayed by a reduction in the H-reflex/M-response amplitude ratio. Parallel morphological studies showed that in the enlarged fibers the myelin terminal loops maintained contact with the axon but were displaced from the paranodal region into the internode. The appearance of this "passive" paranodal demyelination correlated closely with the increase in conduction delay. We suggest that the contact maintained by the displaced myelin terminal loops with the axolemma allows saltatory conduction to continue, and explains the paucity of conduction block in this model despite the prominent conduction slowing.
Asunto(s)
Enfermedades Desmielinizantes/fisiopatología , Conducción Nerviosa , Nitrilos/farmacología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Animales , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Femenino , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Ratas Endogámicas , Reflejo MonosinápticoRESUMEN
Accumulations of neurofilaments are observed in a variety of neurological disorders, and their pathogenesis is a fundamental problem of neuropathology. 2,5-Hexanedione (HD) neurotoxicity provides an extensively studied model of axonal neurofibrillary changes in which the pathogenetic mechanisms have been conjectural. Chronic exposure to HD results in neurofilament-filled swellings in the distal regions of large axons of exposed humans and experimental animals. In this report we describe the changes produced by a potent analogue of HD, 3,4-dimethyl-2,5-hexanedione ( DMHD ), in slow axonal transport in the rat sciatic motor axons. Young rats received 0.6 mmol/kg of DMHD for 5 days before [35S]methionine was injected into the lumbar ventral horns. Slow axonal transport of the neurofilament proteins, tubulin, and selected slow component b (SCb) proteins in DMHD -treated animals was compared to the profiles found in age-matched control animals. DMHD administration reduced the rate of transport of the neurofilament proteins 75 to 90%, while tubulin and the SCb proteins were only modestly retarded. No alterations in electrophoretic mobilities of slowly transported proteins were found, nor were any proteins accelerated in transport. These findings were systematically compared to the changes produced by administration of beta,beta'- immino - dipropionitrile (IDPN) (2.0 gm/kg, i.p.), an agent known to impair neurofilament transport. Although slightly less severe, the changes produced by DMHD were nearly identical to those of IDPN. In correlative morphological studies, the neurofilamentous changes were also comparable. The results indicate that DMHD and IDPN share the capacity to interfere selectively with neurofilament transport and thereby share pathogenetic mechanisms. DMHD provides a new agent for exploration of the organization and transport of the neuronal cytoskeleton.
Asunto(s)
Transporte Axonal/efectos de los fármacos , Hexanonas/farmacología , Proteínas de Filamentos Intermediarios/fisiología , Cetonas/farmacología , Animales , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Nitrilos/farmacología , Ratas , Ratas EndogámicasRESUMEN
Beta, beta'-Iminodipropionitrile and 2,5-hexanedione are neurotoxins that produce neurofilamentous axonal swellings. The swellings produced experimentally with these agents are similar in structure but different in distribution. Neither the relationships between these agents nor the mechanisms of action are known. In this study local effects on nerve fibers were compared following injection of beta, beta'-iminodipropionitrile and 2,5-hexanedione beneath the perineurium of rat sciatic nerves. Soon after injection, 2,5-hexanedione reproduced the distinctive cytoskeletal disorganization previously described with beta, beta'-iminodipropionitrile: microtubules collected into a central channel, with neurofilaments segregated in a surrounding subaxolemmal ring. Later, the beta, beta'-iminodipropionitrile-injected nerves developed local neurofilaments accumulations, reproducing the neurofilamentous axonal swellings characteristic of systemic intoxication with these agents. The results indicate that both these agents have direct local effects on the axonal cytoskeleton and probably are similar in mechanism of action. Both these agents appear to segregate neurofilaments from the rest of the axonal cytoskeleton. This segregation may prevent the normal proximal-to-distal transport of neurofilaments, resulting in the formation of neurofilamentous axonal swellings.
Asunto(s)
Citoesqueleto/efectos de los fármacos , Hexanonas/toxicidad , Cetonas/toxicidad , Microtúbulos/efectos de los fármacos , Nitrilos/toxicidad , Animales , Axones/efectos de los fármacos , Perros , Microscopía Electrónica , Fibras Nerviosas Mielínicas/efectos de los fármacos , Neurofibrillas/efectos de los fármacos , Ratas , Nervio Ciático/efectos de los fármacos , Raíces Nerviosas Espinales/efectos de los fármacosRESUMEN
The subperineurial injection of beta,beta'-iminodipropionitrile (IDPN) into rat sciatic nerves resulted in focal disorganization of the axonal cytoskeleton characterized by segregation of neurofilaments and microtubules. Shortly after injection, microtubules clustered together to form a central channel, while neurofilaments became chaotically arrayed between the microtubule channel and axolemma. Electron microscopic autoradiography disclosed that rapidly transported organelles were preferentially associated with the microtubule-enriched central channels. These studies indicate that IDPN acts at the level of the axon to disrupt interactions between cytoskeletal elements and show that rapidly transported constituents are preferentially conveyed in association with microtubules. The model provides an opportunity to dissect the interactions of the cytoskeletal elements and other organelles.