Restorative Neurology and Neuroscience - Volume 13, issue 3-4

Authors: Kawabuchi, M. | Chongjian, Z. | Islam, A.T.M.S. | Hirata, K. | Nada, O.

Article Type: Research Article

Abstract: The extent of the muscle endplate reinnervation that followed crush injury of the sciatic nerve was compared between young adult (4 and 5 months old) and aged (24 months old) animals. The time course of regeneration in the muscular nerve bundle, its ramification, and the nerve terminal was immunohistochemically estimated using an antibody against the neuron specific enolase (NSE), a neuronal marker. During early phases of regeneration (7, 21 and 28 days post-crush) in the young …adult animal, there were tortuosity, vacuolation and/or unfasciculation in the nerve bundle and its ramification, along with immature nerve terminals and multiple innervation. Following a subsequent advancement in reinnervation to the denervated motor endplates, the adult type of single motor innervation was common on the day 56. The old muscles basically followed the course of reversible axotomy alike the young adult ones. The age difference accounted for as fol-lows: a reduced rate of reinnervation as indicated by a greater frequency of abnormal nerve bundles and immature nerve terminals at 28 days and 56 days post-crush, as well as unusual pathways or striking tortuosity represented by the NSE-labeled processes between day 7 and 56; late in the reinnervation period, abnormal regeneration characterized by damage of the nerve bundle, and poorly developed terminal architec-tures. These results suggest that despite the capability of the nerve from the old animals to extend its process, re-establishment of normal single motor innervation is reduced due to some age-related deficits, which may be related to the impaired Schwann cell-axon interactions. Show more

Keywords: Denervation, Rat, Regeneration, Immunohistochemistry, Neuron specific enolase, Aging, peripheral nervous system (PNS), nerve crush

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 117-127, 1998

Authors: Atchabahian, Arthur | Doolabh, Vaishali B. | Mackinnon, Susan E. | Yu, Samuel | Hunter, Daniel A. | Flye, M. Wayne

Article Type: Research Article

Abstract: It is hypothesized that unlike solid organ transplants immunosuppression of peripheral nerve allografts is needed only for the finite time period required for regeneration of proximal host nerve axons through the allograft and subsequent re-establishment of host end-organ connections. The aim of this study was to explore the consequences of temporary and continuous systemic Cyclosporine A (CsA) immunosuppression upon peripheral nerve allograft survival. Buffalo rats received Lewis nerve allografts under CsA immunosuppression (5 mg/kg/day) either continuously for 20 weeks, or for only 10 weeks followed by abrupt withdrawal. At 20 weeks, the nerve segments from both groups were regrafted into …naïve Buffalo or Lewis recipients without further immunosuppression. These grafts were compared with isografts, unimmuno-suppressed allografts and allografts immunosuppressed for 10 weeks in situ. By eight weeks following regrafting, the secondary Lewis recipients had rejected the temporarily immunosuppressed allografts and accepted the continuously immunosuppressed allograft, while the secondary Buffalo recipients accepted both the temporarily and continuously immunosuppressed allografts as assessed by histology and morphometry. Functional recovery was earlier in secondary recipient strain animals that received temporarily immunosuppressed allografts in comparison to those that received continuously immunosuppressed allografts. Analysis of secondary recipients of temporarily immunosuppressed allografts demonstrated greater in vitro MLR and LDA reactivity than did those receiving continuously immunosuppressed allografts. These findings support the hypothesis that donor alloantigens are lost or replaced by the recipient after immunosuppression withdrawal. Moreover, the change to recipient antigenicity in the nerve allograft is retarded and incomplete under continuous CsA immunosuppression, resulting in acceptance by both secondary donor and recipient strains upon regraftment. Show more

Keywords: peripheral nerve, nerve allograft, Cyclosporin A immunosuppression, temporary immunosuppression, Schwann cell, Schwann cell replacement

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 129-139, 1998

Authors: Aznar, Susana | Rasmussen, Thøger | Zimmer, Jens

Article Type: Research Article

Abstract: Hippocampal CA3 pyramidal cells grafted as cell suspensions to excitotoxic hippocampal lesions in adult rats can exchange several types of short and long range nerve connections with the host brain. We now examined whether such grafts also had functional effects in terms of ameliorating lesion-induced learning and memory deficits. Adult, male rats with bilateral, one week old, ibotenic acid-lesions of the hippocampal CA3 region, were grafted with suspensions of fetal (E18-19) CA3 cells. Seven weeks later the animals were tested for spatial navigation in the Morris Watermaze, together with groups of lesion-only and sham-operated, control rats. The tests were performed …over 5 days, with 4 trials per day. At the end of the trials, the size of the lesions and the size and structural incorporation of the transplants in the host brains were evaluated morphometrically for correlations with the behavioural data. We found significant differences in swim pathlength and latency to find the platform in the Morris Watermaze between the lesion-only group and the grafted group versus the sham operated group, but no significant difference between the lesion-only and the grafted group. There was a significant positive correlation between the size of the CA3 lesions and the paucity of performance of the rat in the Watermaze, just as spontaneous recovery accordingly had not occurred over the 8 weeks postlesion. We conclude that the behavioural improvement exerted by the CA3 cell suspension grafts, at a time point when graft-host connections have had time to establish, is at most incomplete by these transplants, pointing to the difficulties there may be in obtaining full functional integration. Show more

Keywords: neural transplants, ibotenic acid, CA3, behavior, Morris Watermaze, spatial memory, learning

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 141-151, 1998

Authors: Schmitt, Ulrich | Sabel, Bernhard A. | Cross, Robert | Samson, Fred E. | Pazdernik, Thomas L.

Article Type: Research Article

Abstract: Traumatic injury of the adult optic nerve causes a progressive degeneration of retinal ganglion cells. Despite this ongoing degeneration, a partial recovery of visual behavioral function and of local cerebral glucose use (LCGU) has been observed. To evaluate whether this partial recovery of LCGU is due to a recovery of visual conductance (extrinsic) or intrinsic neuronal activity, visual stimulation alone and combined with physostigmine,an acetylcholinesterase inhibitor, were used to activate the retinofugal pathway. …LCGU was determined in 30 male adult rats with or without physostigmine treatment 2 or 9 days after crush or 8 days after cut of the right optic nerve. Analysis of LCGU in contralateral first-order projection areas revealed no differences 8 days after cut and 9 days after optic nerve crush. Furthermore, LCGU in the contralateral areas could not be stimulated by the treatment with physostigmine. We therefore conclude that the increase in LCGU from 2 to 9 days after crush is not due to a recovery in the conductance of visual input. We hypothesize a relief of an injury-dependent active suppression (diaschisis) of LCGU. This reversal of diaschisis may, in part, account for the return of visual functions after mild optic nerve injury. Show more

Keywords: diaschisis, lateral geniculate nucleus, metabolic activity, neuroplasticity, recovery of function, superior colliculus, vision

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 153-161, 1998

Authors: Midha, Rajiv | Munro, Cathrine A. | Ang, Lee C.

Article Type: Research Article

Abstract: Previous work indicated that appropriate end-organ reinnervation fails to influence axonal degeneration in nerve allografts following immunosuppression withdrawal. In the present study, we examined if differences existed in axonal degeneration when axons regenerated across nerve allografts are allowed or completely denied end-organ reinnervation. Two ACI rat nerve allografts (3 cm long) were sutured into gaps created in both peroneal nerves in Lewis rats. In the right leg, the distal end of the graft was connected to the distal host nerve stump to allow end-organ reinnervation. In the left leg, the distal end was turned back and double ligated (unconnected) to …prevent end-organ reinnervation. Rats received Cyclosporin A daily for 12 weeks to allow for regeneration and were sacrificed at 16 (n = 5) or 18 (n = 5) weeks following engraftment to assess axonal degeneration following immunosuppression withdrawal. Five Lewis rats receiving autografts served as control and were sacrificed at 12 weeks. Morphometric analysis was performed. In the control group (autografts) the cross-sectional area of and the number of myelinated fibres in the unconnected grafts was double that of the connected grafts, suggesting a sprouting effect. There was a tenfold reduction in the mean number of fibres at weeks 16 and 18 in the allografts compared to controls, without any significant differences in the connected versus unconnected sides. End-organ reinnervation decreases sprouting of axons within the graft but does not protect axons from degeneration following immunosuppression withdrawal. Show more

Keywords: Cyclosporin A, demyelination, nerve transplatation, peripheral nerve, sprouting, Wallerian degeneration

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 163-172, 1998

Authors: Galani, R. | Coutureau, E. | Kelche, C.

Article Type: Research Article

Abstract: Long-Evans male, adult rats received selective and bilateral lesions of either the hippocampus, subiculum or lateral entorhinal cortex, and were then housed for 30 days in either enriched or standard conditions. Rats were then tested in the eight-arm radial maze to assess spatial working memory and the strategies that were employed (i.e. pattern of arms visited). Lesions of the hippocampus induced both a working-memory impairment and a loss in the use of allocentric strategies to perform the task. Rats with lesions of the subiculum were also impaired but less than hippocampectomized rats and showed a similar pattern of arm visits …as control rats. In contrast with other lesioned rats, rats with lateral entorhinal cortex lesions performed the task like control rats. Postoperative enriched housing conditions (EHC) globally enhanced performance of rats, but did not affect the strategies selected by the rats to solve the task. The beneficial effect of EHC was particularly obvious in rats with lesions of the subiculum. In enriched rats with such lesions, performance was not significantly different from that of control rats housed in standard conditions. The present results indicate that 1) the structures within the hippocampal formation are not similarly involved in spatial learning and memory processes and in the management of navigational demands of the radial maze, and 2) enriched conditions may enhance the spared spatial abilities of some lesioned rats thus promoting functional recovery. Show more

Keywords: enriched environment, hippocampal formation, radial maze, spatial working memory, strategies

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 173-184, 1998

Authors: Joo, Jin-Yang | Uz, Tolga | Manev, Hari

Article Type: Research Article

Abstract: The endocrine system has been recognized as an important factor that may contribute to the outcome of stroke. We tested in rats the hypothesis that the pineal gland and/or its hormone melatonin may affect the outcome of a transient cerebral arteries occlusion (CerAO). Reversible 90 min focal ischemia was produced using a three-vessel occlusion method. Surgically or sham pinealectomized rats were exposed to CerAO 15 days after surgery. Melatonin (4 x 2.5 mg/kg: 30 min prior …to onset of CerAO, immediately after recirculation was established, and 1 and 2 hr later) or its vehicle were administered intraperitoneally. The outcome of CerAO was assessed by quantitative assay of DNA damage or by Nissl staining and measurement of the infarct volume. Pinealectomy increased both the extent of DNA damage and the infarct volume; administration of melatonin to pinealectomized rats reduced both these markers of brain injury. We propose that the pineal endocrine system may influence the outcome of stroke. The mechanism of action and the pathophysiological role of this system, e.g., in aging, should be further characterized. Show more

Keywords: pineal gland, pinealectomy, melatonin, DNA damage, stroke, rat

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 185-191, 1998

Authors: Duconseille, Elee | Woerly, Stéphane | Kelche, Christian | Will, Bruno | Cassel, Jean-Christophe

Article Type: Research Article

Abstract: To examine the regeneration capacity of dorsal septohippocampal neurons in the presence of an artificial growth-promoting substrate, biocompatible polymeric hydrogels were implanted between the septum and the hippocampus in a fimbria-fornix lesion cavity. Unmodified (control) or aminosugar-containing (glucosamines or N-acetyl-glucosamines) hydrogels were implanted immediately or ten days after the lesions. Six months later, brain sections were processed for cresyl-violet, acetylcholinesterase, and immunocytochemical (glial fibrillary acidic protein, protein S100, neurofilaments, laminin, fibronectin) staining. All hydrogels were well integrated in the brain, constituting a stable bridge between the septum and the hippocampus. Weak gliosis occasionally surrounded the hydrogel in rats from the …immediate-implantation group, whereas a more pronounced gliosis was observed in those from the delayed-implantation group. The hydrogels contained blood vessels and were invaded by host cells including astrocytes. Astrocytes formed a loose tissue network filling the porous structure of the hydrogels. Within the hydrogels, laminin-, fibronectin- or neurofilaments-immunopositive networks were also observed. Moreover, numerous acetylcholinesterase-positive fibers penetrated into the hydrogels from the septal, cortical and striatal areas. Fibre penetration was most important in the N-acetylglucosamines-containing hydrogels. Despite these features, the hippocampus failed to show any increase of acetylcholinesterase-staining as compared to that seen in lesion-only rats. These results confirm the regeneration capacity of severed septohippocampal neurons into polymeric substrates used as a bridge inserted in a fimbria-fornix lesion cavity. As such, biomaterials might be of clinical interest not only in the case of spinal cord sections, but also in cases of brain trauma. Show more

Keywords: bridging matrice, fibronectin, fimbria-fornix, hydrogel, neurofilaments, regeneration, septohippocampal system

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 193-203, 1998

Authors: Schneider, J.S. | Peacock, V.

Article Type: Research Article

Abstract: The ability of a single intranigral infusion of glial cell line-derived neurotrophic factor (GDNF) to reverse deficits in skilled paw usage and sensorimotor orientation and to ameliorate apomorphine-induced rotational asymmetry in unilateral 6-hydroxydopamine-lesioned rats was examined. After lesioning, all rats developed sensory inattention on the side contralateral to the lesion, rotational asymmetry in response to apomorphine administration and significant deficits in succesfully performing a forelimb reaching task dependent upon the use of …somatosensory and proprioceptive feedback. A single intranigral injection of GDNF (300 µg) made 4 wks. after the 6-OHDA lesion, significantly decreased the number of drug-induced rotations at 1 and 2 wks. after GDNF administration. At the same time however, no improvements were noted in perfomance of the paw reaching task or in sensorimotor orienting. Post mortem analyses showed that the GDNF treatment did not cause any increase in striatal dopamine levels but did increase tyrosine hydroxylase-positive immunohistochemical staining in the substantia nigra on the side of the GDNF infusion. These results demonstrate the need for multiple behavioral measures of efficacy when evaluating treatments for parkinsonism in the unilateral 6-hydroxydopamine lesion model in the rat. Show more

Keywords: GDNF, dopamine, sensorimotor integration, behavior, rotation, paw usage, substantia nigra

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 205-212, 1998

Authors: Fukuyama, Ryuichi | Takeda, Hiroshi | Fushiki, Shinji | Yamamoto, Tetsuro

Article Type: Research Article

Abstract: We injected an immunoadjuvant, muramyl dipeptide (MDP), intrafascicularly into crushed rat sciatic nerve so as to test whether activation of macrophages promotes regeneration of peripheral nerve from crush injury and improves walking locomotion in rats. Immunohistochemical staining of Schwann cells and macrophages with anti-S100 and ED-1 monoclonal antibodies revealed that macrophages are more abundant and phagocytic in nerve injected with MDP than in control. Axonal elongation in damaged nerve and locomotion recovery in rats were evaluated with pinch test and measurement of sciatic nerve functional index (SFI), respectively. Pinch test showed a 15.5% increase in length (n = 6, p …< 0.05) of elongating axons for MDP-injected group 5 days after the crush injury comparing to the control group. The value of SFI obtained from the rats injected with MDP showed a 18.3 % increase (n = 4-6, p < 0.01) comparing to the control 3 weeks after the crush injury. Activation of macrophages in the nerve injected with MDP was monitored by detecting gene expression of marker molecules for macrophages such as apolipoprotein E (ApoE), interleukin-1ß (IL-1ß) and macrophage inflammatory protein-1a (MIP-1a) using reverse transcription-PCR (RT-PCR) technique 2 days and 1 week after the injection. Levels of transeripts of IL-1ß and MIP-1a were up-regulated in the nerves injected with MDP 1 week after MDP injection. These results suggest that an intrafascicular injection of MDP activates macrophages infiltrating into damaged nerve and that the macrophages support elongation of regenerating axon, resulting in functional recovery of sciatic nerve from injury in rats. Show more

Keywords: Wallerian degeneration, macrophages, murmamyl dipeptide, SFI, pinch test, RT-PCR

Citation: Restorative Neurology and Neuroscience, vol. 13, no. 3-4, pp. 213-219, 1998