Restorative Neurology and Neuroscience - Volume 2, issue 4-6

Authors: Kallehauge, H.

Article Type: Other

DOI: 10.3233/RNN-1991-245601

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. iii-iv, 1991

Authors: Sørensen, Torben | Zimmer, Jens

Article Type: Other

DOI: 10.3233/RNN-1991-245602

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. v-v, 1991

Authors: Anderson, Douglas K.

Article Type: Research Article

Abstract: We have tested the capacity of several compounds with in vitro and/or in vivo antioxidant or antilipolytic activity to ameliorate locomotor function in cats subjected to static loading (i.e. compression) injury of the spinal cord. These include the synthetic glucocorticoid, methylprednisolone sodium succinate (MP), and the new 21-aminosteroid antioxidant, U74006F. Treatment of spinal cord-injured cats with high doses of MP promoted or spared locomotor function and preserved spinal cord tissue. Extending these findings in cats to humans, it was recently demonstrated that high doses of MP administered within 8 h of injury significantly improved neurologic recovery in human spinal cord-injured …patients. The compound U74006F is one of a series of 21-aminosteroids that, unlike MP, lack glucocorticoid, mineralocorticoid or other hormonal activity yet are potent inhibitors of lipid perioxidation. Over a 100-fold range of doses, U74006F promoted recovery of locomotor function in spinal cord-injured cats. The lowest effective dose for U74006F was 100 times lower than the maximally effective dose for MP. The efficacy of U74006F is unchanged if treatment is initiated within 4 h of injury. However, if treatment is delayed for 8 h, the therapeutic potency of U74006F is substantially reduced. These findings suggest that antioxidant therapy can successfully limit the effects of both experimental and clinical spinal cord injury especially if the treatment is initiated shortly after injury. Show more

Keywords: Spinal cord injury, Methylprednisolone, U74006F, Lipid peroxidation

DOI: 10.3233/RNN-1991-245603

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 169-174, 1991

Authors: Nieto-Sampedro, M. | Bailón, C. | Rivas, F. | Moreno, M.T.

Article Type: Research Article

Abstract: The induction of functional paraplegia in female rats by contusive spinal cord injury was not prevented by compound MK-801. However, the treatment reduced cavitation around the lesion epicenter to 14 mm3 compared to 17 mm3 in untreated controls t-test, P < 0.28) and conserved more neurons in defined regions outside the lesion epicenter (drug-treated animals vs untreated controls: 299 vs 73 neurons/mm2 ; t-test, P < 0.009). Thus, although MK-801 was only partially effective in preventing neuronal death secondary to contusion injury it appeared to have a definite neuroprotective effect. In view of the variety of side effects …of MK-801 and the controversy on the mechanism of neuroprotection, we examined the action of the drug on non-injured animals. The effects of the drug were strongly sex-dependent. One hour after subcutaneous injection (0.5 mg/kg), female rats were hypothermic (36.8 °C treated vs 38.3 °C control) whereas male rats were hyperthermic (39.6 °C treated vs 38.4 °C control). In females, MK-801 caused cessation of cycling and appearance of numerous polymorphonuclear (PMN) phagocytes in vaginal frotis. Also, beginning 24 h after MK-801 injection, the proportion of PMN increased 400% in female blood, whereas males maintained control values. Arthritis-like joint inflammation was prominent in the toes of female rats, but males were unaffected. After continued treatment with the drug for 15 days, PMN count in female rats decreased and the animals resumed cycling. However, during this period female rats lost 20% of their weight, whereas males gained 26%. One hour after MK-801 injection large increases in blood pressure occurred in both sexes, returning to normal values 2 h later. Hypothermia does not appear to be a factor in the neuroprotective effect of MK-801, but the drug has a number of potentially dangerous side effects, particularly in female rats. Because polymorphonuclear cells are known sources of oxygen free radicals, neuroprotection by MK-801 treatment ought to be much more efficient in males than in females and the drug should be used in combination with a free-radical scavenger. Show more

Keywords: Spinal contusion, Neuroprotection, NMDA receptor, MK-801, Sex difference, Polymorphonuclear phagocyte, Free radical

DOI: 10.3233/RNN-1991-245604

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 175-179, 1991

Authors: Gehrmann, Jochen | Monaco, Salvatore | Kreutzberg, Georg W.

Article Type: Research Article

Abstract: Transection of the rat sciatic nerve induces retrograde changes in the dorsal root ganglia (DRG) neurons and in the motoneurons in the ventral grey matter of the lumbar L4 –L6 spinal cord segments. In the ipsilateral dorsal grey matter and in the ipsilateral nucleus gracilis, transganglionic changes occur in the terminal fields of the centrally projecting axons of injured DRG neurons. As revealed by immunocytochemistry, the neuronal reactions were associated with a rapid proliferation and activation of microglial cells in the lumbar spinal cord as well as in the nucleus gracilis. Reactive microglial cells were detected as early as …24 h after sciatic axotomy. The microglial reaction had a maximum around day 7 postlesion and disappeared around 6 weeks after axotomy. In addition to light microscopy, activated, perineuronal microglia were identified by immuno-electron microscopy in the ventral grey matter. In the DRG, satellite cells constitutively expressed major histocompatibility complex (MHC) class II antigens. Sciatic axotomy led to a proliferation of satellite cells and an increased expression of MHC class II molecules in particular. This satellite cell reaction started 24 h after axotomy and continued to increase gradually until about 6 weeks after the lesion. Resident macrophages, detected in the DRG interstitial tissue by their expression of monocyte/macrophage markers, also reacted to sciatic axotomy. Our data suggest that (1) sciatic axotomy leads to a rapid microglial reaction in both the ventral and dorsal grey matter of the lumbar spinal cord and in the ipsilateral nucleus gracilis; (2) the immunophenotype of activated microglia following sciatic axotomy is comparable with that observed after axotomy of cranial nerves, e.g. the facial nerve; (3) satellite cells in DRG constitutively express MHC class II molecules; and (4) sciatic axotomy leads to a rapid activation of satellite cells and interstitial macrophages in the axotomized DRG. Show more

Keywords: Retrograde reaction, Peripheral nerve injury, Macrophage, Vimentin, Transganglionic reaction, Dorsal root ganglia, Satellite cells, Major histocompatibility complex antigens

DOI: 10.3233/RNN-1991-245605

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 181-198, 1991

Authors: Wiese, Uwe H. | Emson, Piers C.

Article Type: Research Article

Abstract: The methods of non-radioisotopic in situ hybridization and immunocytochemistry were used to visualize sites of GAP-43 expression after a mid-thoracic spinal cord transection in adult rats. Neurons which expressed moderate to high levels of GAP-43 mRNA and showed strong GAP-43-like immunoreactivity were located immediately above the lesion site as well as at greater distances from the lesion site in the lower cervical and mid-lumbar spinal cord. The results of this study suggest a widespread occurrence of lesion-induced neuroplastic changes and may indicate that the increase in GAP-43 expression can be caused by axotomy, deafferentation and increased compensatory motor activity in …the spinal cord of paraplegic rats. Show more

Keywords: Spinal cord transection, Neuronal plasticity, Growth-associated protein (GAP-43), Axotomy, Deafferentation, Compensatory motor activity

DOI: 10.3233/RNN-1991-245606

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 199-204, 1991

Authors: Hoffmann, C.F.E. | Choufoer, H. | Marani, E. | Thomeer, R.T.W.M.

Article Type: Research Article

Abstract: The ventral cervical 7th root was avulsed from the adult cat spinal cord and the reaction of the torn axons in the underlying white matter was studied by light microscopy using histochemical staining for acetylcholinesterase and immunocytochemical staining for neurofilament and by electron microscopy, after different survival times. One day postoperatively some of the torn axonal ends were enlarged in the intraspinal trajectory of the root fibers in the white matter between the ventral horn and the pial surface as observed by acetylcholinesterase staining. The formation of terminal clubs had accordingly started at this postlesional survival time. From day 2, …terminal clubs positive to neurofilament antibody were found. The number of terminal clubs increased during the first 4 days after the avulsion, remained present at 30 days and then disappeared gradually during the next months. One such unmyelinated axonal terminal club was studied at the ultrastructural level. From its distal end an unmyelinated protrusion emanated which appeared myelinated on the most distal part. This protrusion may be the ultrastructural parallel of the ramifications from terminal axonal clubs described by Ramon Y Cajal after avulsion. Show more

Keywords: Ventral root, Avulsion, Terminal club, Regeneration, Degeneration, Ultrastructure

DOI: 10.3233/RNN-1991-245607

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 205-210, 1991

Authors: Lindsay, R.M. | Alderson, R.F. | Friedman, B. | Hyman, C. | Ip, N.Y. | Furth, M.E. | Maisonpierre, P.C. | Squinto, S.P. | Yancopoulos, G.D.

Article Type: Research Article

Abstract: The recent molecular cloning of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) has established the existence of an NGF-related family of neurotrophic factors – the neurotrophins. Purification and recombinant production of BDNF and NT-3 has allowed the initiation or extension of in vitro studies of the neuronal specificity of each of these factors. We have found that NT-3, like NGF and BDNF, promotes survival and neurite outgrowth from certain populations of sensory neurons. There appear to be both distinct and overlapping specificities of the 3 neurotrophins towards peripheral neurons – sympathetic neurons and subpopulations of neural crest and neural placode-derived …sensory neurons. Using cultures of central nervous system neurons, we have recently established that BDNF: (i) promotes the survival and phenotypic differentiation of rat septal cholinergic neurons, a property consistent with the discovery of high levels of BDNF mRNA expression within the hippocampus; (ii) promotes the survival of rat nigral dopaminergic neurons and furthermore protects these neurons from two dopaminergic neurotoxins, 6-hydroxydopamine (6-OHDA) and MPTP. Thus the neurotrophic effects of these factors towards peripheral neurons and neuronal populations known to degenerate in two of the major human neurodegenerative diseases – Alzheimer's and Parkinson's disease – provokes the question of whether neurotrophic factors may have therapeutic potential in halting the progression and ameliorating the symptoms of devastating neurological disorders of the CNS or PNS, or improving regeneration of neurons of CNS or PNS after traumatic injury. Show more

DOI: 10.3233/RNN-1991-245608

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 211-220, 1991

Authors: Bovolenta, Paola | Wandosell, Francisco | Nieto-Sampedro, Manuel

Article Type: Research Article

Abstract: A classic problem in CNS fiber regeneration is that the glial scar, generated after a lesion, is not crossed by regenerating axons. We know that reactive astrocytes are important in the formation of this barrier and that the barrier is not mechanical. However, its precise nature remains unclear. To study interactions of normal and reactive astrocytes with central neurites, we have attempted to create an in vitro model of the glial scar. We found the following: (1) Cultured astrocytes, independently of their lineage, morphology, immunological type and treatment with differentiating agents, induced profuse neurite outgrowth from various kinds of embryonic …CNS neurons. The outgrowth was comparable to that elicited by laminin. (2) Membranes from isomorphic gliotic tissue (induced by deafferentation or excitotoxic injury and containing a large number of reactive astrocytes), inhibited central neurite outgrowth as powerfully as myelin. Reactive astrocyte membranes from areas of anisomorphic gliosis (following penetrating trauma) were permissive for neurite outgrowth, but growth was more limited than on cultured astrocyte membranes. (3) When given a choice, growing neurites actively avoided membranes from isomorphic gliosis (similar to myelin), while they seemed to follow anisomorphic membrane boundaries and crossed unhindered into membranes of cultured astrocytes. In conclusion, reactive glia seem to contain both inhibitory and neurite promoting molecules, the proportion of which depends on the way gliosis has been generated. For isomorphic reactive astrocytes the balance is inhibitory for central neurite outgrowth, while anisomorphic reactive astrocytes probably express inhibitory components at lower levels and the growth promoting factors predominate. Overall, our observations suggest that reactive astrocytes are still the major problem for axonal regeneration in the CNS. Show more

Keywords: Gliosis, Reactive astrocyte, Glial scar, Neurite outgrowth, Inhibition

DOI: 10.3233/RNN-1991-245609

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 221-228, 1991

Authors: Müller, Hans W. | Matthiessen, H. Peter | Schmalenbach, Corinne | Schroeder, Welf O.

Article Type: Research Article

Abstract: In an attempt to identify specific molecular and cellular requirements necessary to support long-term maintenance and differentiation of central neurons we have identified laminin-HSPG and free fibronectin as two major neurite promoting substrate adhesion factors released by immature cerebral astrocytes in serum-free culture. Astrocytes further secrete diffusible neurotrophic protein factor(s) which are permanently required for survival of cultured neurons from various brain regions. However, both the presence of substrate-bound neurite-promoting factors and diffusible neurotrophic activities were not sufficient to support long-term maintenance of central neurons in culture. Cell contact-mediated interactions which appear to be cell type-restricted (e.g. to neurons and …astrocytes, but not to fibroblasts) are further required for neuronal stabilization. The implantation of immature astroglial cells into the injured adult CNS should provide a supportive environmental condition for damaged neurons to enhance their recovery and stimulate regenerative responses. Show more

Keywords: Astrocyte, Central nervous system, Cell culture, Implantation, Neurite growth, Neurotrophic factor, Regeneration

DOI: 10.3233/RNN-1991-245610

Citation: Restorative Neurology and Neuroscience, vol. 2, no. 4-6, pp. 229-232, 1991