bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of repetitive transcranial magnetic stimulation on freezing of gait in patients with Parkinsonism
Authors: Lee Seung Yeol , Kim Min-Su , Chang Won Hyuk , Cho Jin-Whan , Youn Jin-Young , Kim Yun-Hee
Published: December 2019

Purpose: The aim of this study was to investigate the site-specific effects of repetitive transcranial magnetic stimulation (rTMS) on freezing of gait (FOG) in patients with parkinsonism. Methods: Twenty patients with parkinsonism and FOG were included. A single session of 10 Hz rTMS was applied over three different cortical regions of the dominant hemisphere: the primary motor cortex of the lower leg (M1-LL), the supplementary motor area (SMA), and the dorsolateral prefrontal cortex (DLPFC). We also performed sham stimulation as a control. The Timed Up and Go (TUG) test, Turn Steps and Turn Time in 180° turning, Unified Parkinson's Disease Rating Scale (UPDRS) part III, FOG Questionnaire (FOG-Q), and motor evoked potential (MEP) studies were performed before and after each intervention. Results: There were significant improvements in TUG test times after rTMS over the M1-LL and the DLPFC. Improvement was significantly greater after the M1-LL stimulation than sham condition. The M1-LL and DLPFC stimulation also resulted in significant improvements in both the number of Turn Steps and Turn Time. UPDRS-III scores were significantly decreased after the M1-LL and DLPFC stimulation. Conclusions: Use of 10 Hz rTMS on the M1-LL and DLPFC is therapeutically effective for FOG in patients with parkinsonism.
Human induced pluripotent stem cells improve recovery in stroke-injured aged rats
Authors: Tatarishvili Jemal , Oki Koichi , Monni Emanuela , Koch Philipp , Memanishvili Tamar , Buga Ana-Maria , Verma Vivek , Popa-Wagner Aurel , Brüstle Oliver , Lindvall Olle , Kokaia Zaal
Published: December 2019

Purpose: Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into the stroke-injured adult rodent brain. How the aged brain responds to grafted iPSCs is unknown. We determined survival and differentiation of grafted human fibroblast-derived iPSCs and their ability to improve recovery in aged rats after stroke. Methods: Twenty-four months old rats were subjected to 30 min distal middle cerebral artery occlusion causing neocortical damage. After 48 h, animals were transplanted intracortically with human iPSC-derived long-term neuroepithelial-like stem (hiPSC-lt-NES) cells. Controls were subjected to stroke and were vehicle-injected. Results: Cell-grafted animals performed better than vehicle-injected recipients in cylinder test at 4 and 7 weeks. At 8 weeks, cell proliferation was low (0.7 %) and number of hiPSC-lt-NES cells corresponded to 49.2% of that of implanted cells. Transplanted cells expressed markers of neuroblasts and mature and GABAergic neurons. Cell-grafted rats exhibited less activated microglia/macrophages in injured cortex and neuronal loss was mitigated. Conclusions: Our study provides the first evidence that grafted human iPSCs survive, differentiate to neurons and ameliorate functional deficits in stroke-injured aged brain.
Inhibitory repetitive transcranial magnetic stimulation of the contralesional premotor and primary motor cortices facilitate poststroke motor recovery
Authors: Wang Chien-Chih , Wang Chih-Pin , Tsai Po-Yi , Hsieh Chin-Yi , Chan Rai-Chi , Yeh Shih-Ching
Published: December 2019

Purpose: The premotor cortex plays a major role in motor planning and control, exhibiting hierarchical importance comparable to that of the primary motor cortex (M1). In this study, we compared the effects of cPMd modulation, which was achieved using inhibitory repetitive transcranial magnetic stimulation (rTMS), with those of contralesional M1 (cM1) modulation, to elucidate the roles of both regions on longitudinal motor recovery following a stroke. Methods: Forty-four patients who had sustained hemiplegia for 3 to 12 months were randomly allocated to a cPMd group, cM1 group, or sham group and received 10 sessions of 1-Hz rTMS. The Medical Research Council (MRC) Scale, Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), and a cortical excitability test were administered pre- and post- rTMS intervention. Results: cPMd modulation yielded significant improvements in MRC, FMA, and WMFT scores compared with sham stimulation and a significant effect on cortical excitability suppression equivalent to that of cM1 modulation, but engendered effects on motor improvement inferior to those of cM1 modulation. Conclusions: In patients with chronic stroke, the cPMd can fulfill a role similar to that of the cM1 in interhemispheric imbalance, which can be ameliorated by applying inhibitory rTMS to achieve substantial motor restoration.
Post-operative environmental enrichment improves spatial and motor deficits but may not ameliorate anxiety- or depression-like symptoms in rats following traumatic brain injury
Authors: Moritz Kasey E. , Geeck Katalin , Underly Robert G. , Searles Madeleine , Smith Jeffrey S.
Published: December 2019

Purpose: Anxiety-like (ANX) and depression-like (DEP) symptoms are common consequences of traumatic brain injury (TBI). Environmental enrichment (EE) attenuates many deficits, though its impact on ANX and DEP symptoms has yet to be described. Methods: Adult male Long-Evans rats were subject to a medial frontal cortex (mFC) cortical impact injury or sham preparation, then placed into EE or standard housing (SE). ANX symptoms were analyzed using the open field test (OFT) and elevated plus maze (EPM). The forced swim task (FST) and sucrose consumption task (SCT) were used to quantify DEP symptoms. In order to measure changes in spatial learning and motor performance, the Barnes maze (BM) and rotor rod (RR) were utilized. Results: Damage to the mFC resulted in functional losses in motor and cognitive behavior and an increase in ANX and DEP symptoms. Placement of injured rats into the EE improves motor functioning after TBI and resulted in an decreased latency to locate the escape box in the BM. Though the application of an EE attenuated deficits in BM and RR performance, the ANX and DEP behavioral symptoms persisted. Conclusions: Additional therapeutic approaches paired with EE may be necessary to address all functional changes post-TBI. Additionally, no single behavioral assessment appears to clearly identify symptoms of ANX or DEP in rats following TBI, however utilizing multiple tests can be potentially confounding.
Effects of pigment epithelium-derived factor on traumatic brain injury
Authors: Terzi Menderes Yusuf , Casalis Pablo , Lang Veronika , Zille Marietta , Bründl Elisabeth , Störr Eva-Maria , Brawanski Alexander , Vajkoczy Peter , Thomale Ulrich , Piña Ana Luisa
Published: December 2019

Purpose: Pigment epithelium-derived factor (PEDF) is a multifunctional protein with antiangiogenic, anti-inflammatory, neurotrophic and neurogenic properties. The effect of PEDF on traumatic brain injury (TBI) has not been explored. In this study, we aimed to show the in vivo effects of PEDF on lesion volume, cell death and cell proliferation after TBI. Methods: Rats were subjected to controlled cortical impact injury (CCII). PEDF mRNA brain levels were measured by RT-PCR. The lesion volume, cell proliferation, cell death and microglia activation were assessed in the brains of lesioned animals with intraventricular alzet infusion of PEDF or aCSF, and intraperitoneal injections of BrdU. Results: We detected a significant increase of PEDF mRNA levels after TBI. PEDF intraventricular infusion showed no significant effect on the contusion volume, whereas the number of dead cells, activated microglia, BrdU-positive cells around the lesion were significantly decreased. In contrast, PEDF application increased cell proliferation in the ipsilateral subventricular zone. No effect was found on cell proliferation in the dentate gyrus. Conclusion: The present work indicates that PEDF acts as a multifunctional agent after TBI influencing cell death, inflammation and cell proliferation.
Selegiline promotes NOTCH-JAGGED signaling in astrocytes of the peri-infarct region and improves the functional integrity of the neurovascular unit in a rat model of focal ischemia
Authors: Nardai Sándor , Dobolyi Arpád , Pál Gabriella , Skopál Judit , Pintér Nándor , Lakatos Kinga , Merkely Béla , Nagy Zoltán
Published: December 2019

Purpose: Our experiments aimed at exploring potential neurorestorative mechanisms of selegiline, a compound routinely used in the treatment of Parkinson's disease and previously shown to improve the functional recovery of stroke patients. Methods: Selegiline was administered continuously via osmotic mini-pumps between 48 and 216 hours following middle cerebral artery occlusion (MCAO) in rats. Twenty-four hours before sacrifice, the animals underwent magnetic resonance imaging (MRI). After decapitation, the peri-infarct region was dissected to perform a TAQMAN array gene expression study, and brains were fixed for immunolabeling. Results: In addition to the previously known induction of anti-apoptosis genes, selegiline significantly increased the mRNA level of Notch 1 receptor and its ligand Jagged 1. Immunohistochemistry demonstrated elevated Notch 1 and Jagged 1 immunoreactivities in the peri-infarct region. Double labeling with glial markers revealed that both Notch 1 and Jagged 1 were expressed in astrocytes but not in microglia. MRI examination indicated significantly reduced edema in selegiline-treated rats compared to control MCAO rats, and increased capillary network density was found in the peri-infarct region of the selegiline-treated animals. Conclusion: Our results suggest that selegiline treatment enhances Notch-Jagged signaling in astrocytes, reduces peri-lesional edema and potentially helps preserve the capillary network following focal ischemia.
Chronic spinal cord lesions respond positively to tranplants of mesenchymal stem cells
Authors: de Almeida Fernanda Martins , Marques Suelen Adriani , Ramalho Bruna dos Santos , Massoto Tamires Braga , Martinez Ana Maria Blanco
Published: December 2019

Purpose: Despite substantial advances in surgical care and rehabilitation, the consequences of spinal cord injury (SCI) continue to present major challenges. Here we investigate whether transplantation of mesenchymal stem cells (MSCs) in mice during the chronic stage of SCI has benefits in terms of morphological and functional outcomes. Methods: Mice were subjected to laminectomy at the T9 level, followed by a 1 minute spinal cord compression with a vascular clip. Four weeks later, 8 × 105 MSCs obtained from GFP mice were injected into the injury site. After eight weeks the analyses were performed. Results: The spinal cords of MSC-treated animals exhibited better white-matter preservation, greater numbers of fibers, higher levels of trophic factor expression, and better ultrastructural tissue organization. Furthermore, transplanted MSCs were not immunoreactive for neural markers, indicating that these cells mediate functional recovery through a paracrine effect, rather than by transforming into and replacing damaged glia in the spinal cord. MSC-treated mice also showed better functional improvement than control animals. Conclusion: We conclude that MSC-based cell therapy, even when applied during the chronic phase of SCI, leads to changes in a number of structural and functional parameters, all of which indicate improved recovery.
Recovery of preoptic–anterior hypothalamic functions after transplantation
Authors: Verma S. , Kumar V. Mohan , Gopinath G. , Sharma R. , Tandon P.N.
Published: December 2019

Kainic acid lesion of the medial preoptic area resulted in the impairment of the thermoregulation and disruption of the reproductive cycle in female rats. The preoptic–anterior hypothalamic area from fetal donor was transplanted into the lesioned area ofthe host. After transplantation, these animals showed signs of estrus cyclicity and a recovery in basal temperature towards normal. They also showed a reduced shift of body temperature on exposure to a hot environment. Thus the female rats, which received transplantation, showed some degree of recovery of functions which were disrupted by kainic acid lesions.
Expression and distribution of microtubule proteins in neurites of dorsal root ganglion neurons in culture
Authors: Burgoyne Robert D. , Robson Susanne J.
Published: December 2019

The expression and distribution of β-tubulin gene products and post-translationally modified forms of α-tubulin in dorsal root ganglion neurons in culture were examined. The neurons in culture rapidly regenerated neurites and expressed multiple β-tubulin genes (Mβ2, Mβ3/4, Mβ5, Mβ6). The gene products were present in the neurites and growth cones. Unmodified tyrosinated α-tubulin was present in the neurites and growth cones but modified α-tubulins (detyrosinated and acetylated) were largely absent from growth cones. The distribution of the α-tubulin forms is consistent with assembly of tubulin occurring behind the growth cone after transport of non-polymeric subunits. Distal assembly of microtubules would provide a pool of unmodified α-tubulin subunits for the assembly of labile microtubules in the growth cone. Subsequent modification behind the advancing growth cone would stabilise the newly formed neurite.
Insulin-like growth factor I (IGF-I) and regeneration of the sciatic nerve of the rat
Authors: Kanje Martin , Skottner Anna , Sjöberg Jacob
Published: December 2019

We have found that insulin-like growth factor I (IGF-I) stimulates regeneration of the rat sciatic nerve. This paper reviews and adds some new data to our investigations on the effects of local administration of IGF-I to the sciatic nerve after infliction of a crush or freeze injury.
The expression of growth factor receptors during nerve regeneration
Authors: Raivich Gennadij , Hellweg Rainer , Graeber Manuel B. , Kreutzberg Georg W.
Published: December 2019

Growth factors and their receptors play a central role in the regulation of normal and injury-induced regenerative cell growth. In this article we review the data on the expression of growth factor receptors for β-nerve growth factor, platelet-derived growth factor and serum transferrin during regeneration following peripheral nerve injury. Particular emphasis is put on the pathophysiological mechanisms leading to the expression of these growth factor receptors, their interaction with their respective ligands and their specific role in this regenerative process.
B-50/GAP-43 in neuronal development and repair
Authors: Gispen W. H. , Boonstra J. , De Graan P. N. E. , Jennekens F. G. I. , Oestreicher A. B. , Schotman P. , Schrama L. H. , Verhaagen J. , Margolis F.L.
Published: December 2019

The protein kinase C substrate B-50 is identical to the growth-associated protein GAP-43. Although as yet no causal relationship has been established between B-50/GAP-43 and neurite outgrowth, evidence accumulates that the function of the protein relates to neuronal plasticity. Stimulation of PC12 cells by NGF results in translocation of the protein from cytosolic stores to the membrane of newly formed neurite-like extensions. The protein is associated with the inner leaflet of the growth cone membrane isolated from neonatal rat brain and was used as a marker to study the development of the rat pyramidical tract and olfactory system. In the adult rat, crush lesion of the sciatic nerve results in a rapid expression of B-50/GAP-43 mRNA followed by synthesis of B-50/GAP-43 protein in dorsal root ganglia and transport of the protein into the newly formed sprouts. Presumably, the neurotrophic effect of melanocortins on peripheral nerve repair is not brought about by enhancement of B-50/GAP-43 synthesis per se. Bulbectomy (central) or Triton X-100 lesioning (peripheral) of the olfactory epithelium results in a differential expression of B-50/GAP-43 and the olfactory marker protein characterizing two stages in the regeneration of this epithelium. Evidence that the degree of phosphorylation may co-determine the role of B-50/GAP-43 in neurite outgrowth is discussed.
Regeneration in vitro of the adult frog sciatic sensory axons
Authors: Edström Anders , Edbladh Magnus , Ekström Per , Remgård Pär
Published: December 2019

The adult frog sciatic nerve offers several advantages as an in vitro model to study nerve regeneration. The nerve with the attached dorsal root ganglia can easily be isolated and incubated in a culture medium for several days. If the nerve is subjected to a crush immediately after dissection there is a delay of 3.4 days after which the sensory axons start to regenerate into the distal nerve stump at a constant rate of about 1.1 mm · day−1 in serum-containing and 1.0 mm · day−1 in serum-free medium. Serum-free cultures may be used in future studies to examine the effect of various neurotrophic factors. The existence of an accurate method for examining the outgrowth distance, based on axonal transport of labelled proteins, contributes to the attractiveness of the model. A compartmental culture system permits separate exposure of the ganglia and the nerve to different agents. Taking advantage of this, pharmacological studies suggest that Schwann cells produce signals, dependent on newly transcribed RNA, which transform the preparation into a growth state. The present model system offers favourable conditions to learn more about the early events and also the subsequent steps of the regeneration process.
Preferential motor reinnervation: a sequential double-labeling study
Authors: Brushart Thomas M. E.
Published: December 2019

Previous experiments have shown that motor axons regenerating in mixed nerve will preferentially reinnervate a distal motor branch. The present experiments examine the mechanism through which this sensory-motor specificity is generated. An enclosed 0.5 mm gap was created in the proximal femoral nerves of juvenile rats. Two, three or eight weeks later the specificity of motor axon regeneration was evaluated by simultaneous application of horseradish peroxidase (HRP) to one distal femoral branch (sensory or motor) and Fluoro-Gold to the other. Motoneurons were then counted as projecting (i) correctly to the motor branch, (ii) incorrectly to the sensory branch, and (iii) simultaneously to both branches (double-labeled). Motor axon regeneration was random at 2 weeks, with equal numbers of motoneurons projecting to sensory and motor branches. However, the number of correct projections increased dramatically between 2 and 3 weeks. Twenty-six percent of neurons labeled at 2 weeks contained both tracers, indicating axon collateral projections to both sensory and motor branches. This number decreased significantly at each time period. Axon collaterals were thus ‘pruned’ from the sensory branch, increasing the number of correct projections at the expense of double-labeled neurons. These findings suggest random reinnervation of the distal stump, with specificity generated through trophic interaction between axons and the pathway and/or end organ.
Regeneration after spinal nerve root injury
Authors: Carlstedt T. , Risling M. , Lindå H. , Cullheim S. , Ulfhake B. , Sjögren A. M.
Published: December 2019

Spinal nerve root avulsion has been considered as a central nervous type of injury and therefore not repaired surgically in man. The possibility for axonal regeneration after root avulsion or root lesion has been investigated in laboratory animals by means of up to date neurophysiological, morphological and tracing techniques. It is shown that, after ventral root avulsion and implantation into the spinal cord, alpha and probably also gamma motoneurons are able to regenerate within the spinal cord for a considerable distance before entering the implanted root and reinnervate previously denervated skeletal muscles. The regenerated neurons were found to respond to afferent activity with excitatory or inhibitory responses, and the regenerated axons could conduct action potentials that elicited muscle twitch responses. After dorsal root injury in the adult animal, regeneration into the spinal cord does not occur. However, regeneration of primary sensory neurons into appropriate locations of the spinal cord can be demonstrated in immature animals.
Post-translational modification of proteins by arginine and lysine following crush injury and during regeneration of rat sciatic nerves
Authors: Luo Danhua , Chakraborty Goutam , Ingoglia Nicholas A.
Published: December 2019

Following crush injury to rat sciatic nerves, a crude fraction of the 150,000 g supernatant can post-translationally incorporate [3H]Arg and [3H]Lys into endogenous proteins in amounts approximately 10 times uninjured control nerves. These increases occur in the proximal nerve stump within 2 h of injury and 2 weeks later in a distal segment of nerve containing the tips of the regenerating axons. In the present experiments, the endogenous nerve proteins modified by Arg or Lys in these nerve segments have been identified using two-dimensional polyacrylamide gel electrophoresis. The fraction used to assay for protein modification, the void volume of a Sephacryl S-300 column, was found to contain only a few proteins visible by Coomassie blue staining, one of which is likely to be albumin (68 kDa, pI 6.4). While this protein was modified by both Arg and Lys, the majority of label was found in areas not showing Coomassie blue staining. This indicates that of the many potential targets of post-translational arginylation and lysylation, most are proteins of relatively low abundance. A variety of proteins were modified by Arg or Lys alone while others were modified by both Arg and Lys. A high molecular weight protein (175 kDa, pI 9.0) was modified only by Lys and only at 2 h post crush. Of a variety of modified proteins of approximately 17 kDa one (pI 6.3) was modified by both Arg and Lys and at both time points, while another (pI 9.0) was modified at both time points, but only by Lys. The results show that Arg and Lys can be added post-translationally to a large number of low abundance, soluble sciatic nerve proteins, and that some of those proteins are modified only by Arg or Lys while others are modified by both Arg and Lys. Also, the modification of certain proteins appears to be associated specifically with the immediate response of a nerve to injury (e.g. 88 kDa, pI 7.1) while others are associated with the regenerative period (e.g. 56 kDa, pI 7.4).
Morphology of embryonic hippocampus transplants and generation of long-distance extrinsic graft fiber connections to the lateral septum and the entorhinal cortex in the mature rat brain
Authors: Sprick U.
Published: December 2019

Pyramidal neurons inside transplants of embryonic nervous tissue are capable of generating axonal extrinsic hippocampal fiber connections over considerable distances to appropriate target areas in the mature brain. The establishment of long-distance graft efferents to the lateral septum and to the entorhinal cortex was shown by retrograde transport of the tracers HRP and bisbenzimide which were injected into these areas after bilateral neurotoxic lesions of the hippocampus. Additional AChE-staining demonstrated the presence of an afferent cholinergic graft input mainly from the medial septum via the fornix. Morphological analysis of the transplants grafted as cell suspensions showed typical details of the original hippocampus cytoarchitecture with bands of pyramidal and granule cells.
Cerebrovascular permeability in intracerebral implants of foetal basal forebrain cell suspensions
Authors: Sharkey John , McBean Douglas E. , Ritchie Isobel M. , Kelly Paul A.T.
Published: December 2019

Blood–brain barrier permeability was measured using [14C]-labelled a-aminoisobutyric acid (AIB) quantitative auto-radiography in rats which had previously received unilateral ibotenate-induced lesions of the nucleus basalis followed by intracortical implantation of foetal basal forebrain cell suspensions. The permeability characteristics of intracortical transplants were found to be dependent upon the site of implantation. Superficial transplants were invariably associated with AIB transfer constants (Ki) 3- to 4-fold higher than those in corresponding contralateral host cortex. In transplants sited deep in host neocortex, Ki values were not significantly different from those measured in surrounding host brain tissue.
Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat
Authors: Goldstein Larry B. , Coviello Andrea , Miller Gerald D. , Davis James N.
Published: December 2019

Beam-walking in the rat provides a method for investigating the effects of drugs on motor recovery following unilateral injury to the sensorimotor cortex. In the present experiment, the impact of norepinephrine depletion on beam-walking recovery was investigated. Groups of rats were first given either the neurotoxin DSP-4 or saline. Two weeks later, the animals were trained at the beam-walking task. Rats were then subjected to either a unilateral sensorimotor cortex lesion or sham operation. Recovery of beam-walking performance was measured over the next 12 days. Pretreatment with DSP-4 significantly slowed the rate of recovery but did not significantly affect sham-operated rats. Norepinephrine was significantly diminished in both lesioned and sham-operated rats that had been given DSP-4. These results are consistent with the hypothesis that recovery of beam-walking in the rat is mediated, at least in part, through noradrenergic neurons.
Accumulation of neurofilament proteins in the regenerating facial nerve
Authors: de Jong Andrew , Wang-Bennett Lolin T. , Liebl Daniel J. , Coker Newton J.
Published: December 2019

In order to compare the extent of axonal regeneration in two surgical nerve repair procedures, we measured the levels of the neurofilament (NF) proteins in the regenerating facial nerve of adult New Zealand rabbits. The animals were operated on bilaterally, with a chamber model placed on one side and a cable graft model inserted on the contralateral side. Normal nerve from unoperated animals or nerve removed during nerve repair surgery served as controls. Using immunoblot techniques and densitometric measurement, we examined specific changes in the individual NF [High (H), Medium (M), and Low (L) molecular weight (MW)] in the regenerating nerve at 3 and 7 weeks postoperation time. Linearity of the densitometric system was established by separation of serial dilutions of known NF on the gel, and blotting for immunostaining. The amount of all 3 NF's decreased during the regeneration process compared to normal nerve, but there were differences between the two procedures. The NFH in the distal segment of the chamber repaired nerve at 7 weeks was 60–70% of the preoperative state, which correlated with a previous morphological study of axona) caliber during regeneration. At 3 weeks, NF content was lower in the distal segment of the chamber than in the distal cable graft. By 7 weeks, NF content was similar in proximal and distal segments of both models. Thus, although initial regeneration is slower in the chamber model, the eventual outcome is similar in both chamber and graft.
Sabeluzole accelerates neurite outgrowth in different neuronal cell lines
Authors: Geerts Hugo , Nuydens R. , Nuyens R. , Cornelissen F.
Published: December 2019

The outgrowth of neurites in neuronal cell cultures reflects the intrinsic capacity for neurite regeneration and morphological rearrangements after axotomy and in plasticity. The role of fast axonal transport in these neurite outgrowth responses has not been investigated. We have recently shown that sabeluzole (R58735), a new neuro-active compound increases fast axonal transport in cultures of hippocampal neurons. In rat hippocampal neurons, N4 neuroblastoma cells and adult rat dorsal root ganglion cultures, incubation with sabeluzole at an optimal concentration of between 0.1 μM and 0.5 μM enhances neurite outgrowth between 10 and 30%. The relative number of cells with neurite length greater than twice the cell body, is also increased dose-dependently. Time-dependent studies further indicate that the rate of neurite elongation is markedly enhanced during the first 24–48 h. This neurite enhancing effect of sabeluzole is discussed in relation to the enhancement of fast axonal transport.
Factors influencing structure and function of intracerebral grafts in the mammalian brain: a review
Authors: Cassel J.C. , Kelche C. , Majchrzak M. , Will B.E.
Published: December 2019

After twenty years of intensive research, the possibility to induce recovery from various disorders in brain damaged mammals by means of intracerebral grafts of fetal CNS tissue is well documented and largely accepted by the scientific community. However, there are several reports on animal research suggesting that intracerebral grafts may fail to induce the expected recovery after brain injury or even that they may cause deficits which are actually more pronounced than those induced by the lesions alone. In addition, attempts to produce functional benefits with catecholamine-releasing tissue grafts in the brain of Parkinsonian patients have given limited and variable results; graft-induced deleterious effects have also been occasionally reported in a few clinical cases. One way to progress towards a better understanding of such disappointing, although informative, discrepancies between successful and less successful experimental studies and clinical trials would be to consider that there are several factors which may influence, in one direction or the other, the survival, development, integration and functional expression of intracerebral fetal CNS grafts. The present review considers the following factors: (i) some of the technical factors such as the constraints of transplantation surgery, the origin of donor tissue, the implantation site, the age of both the donor and the recipient, and tissue manipulations prior to grafting (i.e., cryopreservation, culture, genetic modification); (ii) exogenous and endogenous neurotrophic factors, the latter being distinguished by whether they may be host- or graft-derived; (iii) immunological factors (from the particular immunological status of the brain to some effects of immunosuppression in the case of xenografting)’, (iv) pharmacological factors, with a particular focus on experimental data suggesting that administration of drugs may or might contribute to elicit, enhance or block some functional effects of grafts. It is concluded that all these factors may become simultaneously operative and interacting, thereby presiding over the functional outcome of intracerebral grafting in both experimental research and clinical trials.
Grafted fetal suprachiasmatic nucleus cells survive much better in tissue pieces than in suspension
Authors: Boer Gerard J. , Griffioen Henriëtte A. , Saeed Peerooz
Published: December 2019

A comparison was made between the survival of fetal suprachiasmatic nucleus (SCN) grafted either in tissue pieces or as tissue suspension. Donor tissue was obtained from day 15, 16 or 17 Wistar fetuses, and stereotaxically placed in the dorsal thalamus of the brain of vasopressin(VP)-deficient Brattleboro adult rats. One month post-grafting, the suspension grafts largely failed to show the immunocytochemical presence of VP- and vasoactive intestinal polypeptide(VIP)-producing SCN cells, but solid piece grafts did. In the suspension grafts only a few tiny clusters of surviving VP SCN neurons were seen and hardly any VIP cells. This suggests that intrinsic contacts are necessary for SCN cells to survive and/or to express their genotype. Efferent VP fiber growth was observed to run from the tissue piece derived SCN grafts towards the periventricular area of the thalamus, a nearby SCN projection area. However, the number of VP efferents was very limited and not consistently present. Surprisingly, magnocellular VP neurons, also present in the fetal SCN grafts, showed an opposite survival pattern. Several of such cells were seen in day 15 suspension grafts, whereas hardly any were found in day 15 tissue piece grafts. These results indicate that the type of graft preparation might be important when survival of particular cells is desired.
Infantile right hemisphere injury: a case report with MRI and 13 year follow-up
Authors: Levin Harvey S. , Goldstein Felicia C. , Crofford Marsha J. , Eisenberg Howard M. , Guinto Jr. Faustino C.
Published: December 2019

Serial neuropsychological findings were obtained in a case of infantile right parietal injury who was studied over a 13 year follow-up period. Magnetic resonance imaging at age 13 years documented extensive injury to the right hemisphere, particularly the parietal region. Serial examinations at age 7 and 13 years showed intact visual attention, normal expression and processing of affect and variable visuospatial abilities. However, intellectual development was generally depressed. Implications of these findings for recovery from early brain injury are discussed.
Sensory deprivation prevents integration of neocortical grafts with the host brain
Authors: Bragin A.G. , Vinogradova O.S. , Stafekhina V.S.
Published: December 2019

The histological and electrophysiological properties of embryonic neocortical grafts transplanted into the barrel field of adult rats were compared between the side receiving normal vibrissae input vs. chronic deprivation of input produced by clipping of the recipients vibrissae. Each animal received ablation of the neocortex and transplantation of neocortical tissue bilaterally. Vibrissae were clipped unilaterally immediately after surgery and were trimmed for up to 4 months. Significant differences were found between volume of the grafts as well as the number of grafts showing contact with the wall of the lesion cavity, indicating that the tissue growth was directly influenced by sensory deprivation. Decrements in functional integration with the host brain measured electrophysiologically were also observed.
Functional consequences of transplantation of frontal neocortex vary with age of donor tissue and behavioral task
Authors: Fantie Bryan , Kolb Bryan
Published: December 2019

The spatial learning of rats with medial prefrontal lesions was compared to that of animals with cortical transplants of frontal tissue from donors of embryonic age 17, 19, 21, or 23 days. The age of the donor tissue significantly affected the extent that the transplanted tissue developed as the E17 and E19 grafts were markedly larger than those from E21 or E23 animals. Nonetheless, transplants were viable at all ages. Rats with E19 grafts, but not rats with grafts at other ages, showed significant reduction of the expected deficit on the Morris water task. In contrast, only rats with E21 grafts showed enhanced performance on a T-maze alternation task. The contrasting effects of the grafts of different aged tissue suggests that there may be some specific contributions of cortical grafts of different ages that leads to partial restoration of function.
Effect of highly concentrated gels of sodium hyaluronate on early phases of regeneration in the transected and tubulized rat sciatic nerve
Authors: Tona Alessandro , Perides George
Published: December 2019

Silicone regeneration chambers prefilled with sodium hyaluronate (HA) gels of different molecular weight (MW) and at different concentrations were used to tubulize the transected rat sciatic nerve. After two weeks, the tissue cables bridging the severed nerve ends within the silicone tubes were examined. Low MW HA gels had no significant effect while high MW HA gels reduced the diameter of the growing bridges.
Nerve regeneration is improved by insulin-like growth factor I (IGF-I) and basic flbroblast growth factor (bFGF)
Authors: Vergara Jorge , Medina Luis , Maulén José , Inestrosa Nibaldo C. , Alvarez Jaime
Published: December 2019

In rat sciatic nerves, IGF-I or bFGF was applied distal to a crush to evaluate their effects upon the restoration of the neuromuscular function. In comparison with the recovery following a simple crush, treatment with growth factors resulted in (i) enhanced elongation of regenerating axons ( + 24%) up to day 3 post lesion (PL); (ii) more sprouts at early times; (iii) reduced participation of macrophages in the removal of the degenerating myelin in the first week PL; (iv) restoration of the neuromuscular transmission 2 days earlier; (v) a prolonged relaxation time and a reduced specific tetanic tension at week 3 PL but not at week 7 PL. Other indicators of recovery such as conduction velocity of nerve impulse, muscle weight, specific twitch tension, and time to peak were not affected by bFGF or IGF-I. Results suggest that IGF-I and bFGF affect locally Schwann cells and axons, and also the neuron as a whole, including its trophic function. We conclude that IGF-I and bFGF applied to the nerve, albeit moderately, improve the recovery of the neuromuscular function.
Persisting axonal degeneration in the hippocampus after transection of the fimbria-fornix
Authors: Miettinen R. , Lahtinen H. , Riekkinen P.J. , Freund T.F. , Hsu M. , Horváth Z. , Buzsáki G.
Published: December 2019

Degeneration within the hippocampus was examined at the light microscopic level using the Gallyas silver stain two, four or nine months after bilateral transection of the fimbria-fornix and commissural connections. At two or four months after the lesion the strata oriens and radiatum of the subicular end of the CA1 subfields were strongly argyrophilic as was the inner third of the molecular layer of the dentate gyrus. At nine months post-lesion argyrophilia diminished but clearly persisted in the same layers. Electron microscopic examination revealed a large number of electron-dense axon terminals in the argyrophilic areas, most of them making asymmetric synaptic contacts with dendritic spines. These findings suggest that at least a portion of the Schaffer collaterals of the CA3 pyramidal cells and associational collaterals of hilar neurons were in a process of acute degeneration at all time points after the initial surgical trauma. This persistent synaptic reorganization of intrahippocampal circuits may be related to abnormal electrical activity observed several months after fimbria-fornix transection.
Effects of applied electric fields on clinical cases of complete paraplegia in dogs
Authors: Borgens Richard B. , Toombs James P. , Blight Andrew R. , McGinnis Michael E. , Bauer Michael S. , Widmer William R. , Cook Jr. James R.
Published: December 2019

A clinical trial of applied, slowly oscillating, weak electric fields was performed in dogs with naturally occurring spinal cord injuries due to intervertebral disc herniation. Criteria for admission to the study were: complete paraplegia, defined by neurological examination and electrophysiological testing; intact segmental reflexes; radiologic and myelographic evidence of spinal cord compression due to disc herniation and a focal lesion, without appreciable rostrocaudal spread of necrosis; weight less than 16 kg; onset of paralysis less than 1 month before surgery. The injured cord was exposed by laminectomy, and decompressed by aspiration of disc material. Active (n = 13) or sham (n = 11) stimulators were implanted subcutaneously, with platinum/iridium electrodes sutured to muscle several millimeters above the cord surface, at either end of the laminectomy site. Active stimulators delivered 200 μA of direct current, switching polarity every 15 min, for 3, 6, or 15 weeks. Neurological and electrophysiological examinations were repeated approximately 6 weeks and 6 months after implantation. Few complications were noted. None were attributable to current application. The group of dogs with active stimulators showed greater improvement in function than the group with sham implants, with a trend towards greater recovery in all neurological measures, and evoked potentials. The combined neurological score derived from these separate tests was significantly different from controls at 6 weeks and 6 months (P < 0.05). Application of slowly oscillating electric fields thus appears to be beneficial in the treatment of paraplegia in dogs.
Comparison of the Semmes-Weinstein monofilaments with the Pressure-Specifying Sensory Device
Authors: Dellon Evan S. , Crone Sylvia , Mouery Robin , Dellon A. Lee
Published: December 2019

Measuring human sensibility remains a challenge, with the primary limitation being the instrumentation traditionally available. The Pressure-Specifying Sensory Device (PSD) permits quantitation of the human pressure perception threshold by means of transducers that couple two rounded prongs to a personal computer. If just one prong is perceived in constant contact with the skin, the cutaneous pressure threshold is directly obtained, scaling along a continuum from .05 to 100 g/mm2 (readout on computer monitor). This measurement is analogous to that obtained with the series of Semmes–Weinstein monofilaments (SWM) (readout in logarithmic marking on nylon rod). The present study evaluated twenty normal volunteers and ten nerve-impaired patients with both the PSD and the SWM. There was a poor correlation between the measurement offeree (r = 0.21) and pressure (r = 0.29) obtained with the PSD and the SWM. This study reaffirms the value of measuring pressure perception threshold during the sensibility evaluation, while calling attention to selection of instrumentation for obtaining this measurement.
Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice
Authors: Lalonde Robert , Joyal Christian C. , Guastavino Jean-Marie , Côté Chantal , Botez M.I
Published: December 2019

The effects of amantadine and ketamine were compared to a placebo in a coat-hanger test on lurcher mutant mice. This test measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cerebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition. This result indicates that NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease.
Acute unilateral sensorimotor cortex injury in the rat blocks d-amphetamine induced norepinephrine release in cerebellum
Authors: Goldstein L.B. , MacMillan V.
Published: December 2019

Pharmacologic studies have implicated norepinephrine in amphetamine-facilitated motor recovery following sensorimotor cortex injury in rats. We studied the acute effects of unilateral sensorimotor cortex ablation on the release of norepinephrine in cerebellum with in vivo dialysis. In rats without a cortex lesion, the administration of a single dose of d-amphetamine (2.6 mg/kg base weight, i.p.) resulted in a substantial increase in dialyzable norepinephrine in cerebellum reaching its peak 30–40 min later (∼ 14 pg/μl, not corrected for recovery). The administration of the same dose of d-amphetamine to rats 60 min following a suction-ablation lesion of the right sensorimotor cortex did not result in norepinephrine release into the cerebellar dialysates. These data provide evidence for an acute remote effect of sensorimotor cortex injury on amphetamine-induced norepinephrine release in the cerebellum (diaschisis).
Upregulation of B-50/GAP-43 in Schwann cells at denervated motor endplates and in motoneurons after rat facial nerve crush
Authors: Ulenkate H.J.L.M. , Verhaagen J. , Plantinga L.C. , Mercken M. , Veldman H. , Jennekens F.G.I. , Gispen W.H. , Oestreicher A.B.
Published: December 2019

Crush or transection of peripheral nerves of the adult rat is accompanied by changes in protein expression, including the growth associated protein (GAP-43) B-50. Following peripheral nerve crush in rat enhanced B-50 immunoreactivity was observed in regenerating nerve fibres and in newly formed axon terminals. However, before reinnervation was apparent, an unexpected transient increase in B-50 immunoreactivity was observed at denervated motor endplates [J. Neurosci. 8 (1988) 1759]. This study was performed to clarify this observation. Four days following facial nerve crush B-50 immunoreactivity was detected by double immunofluorescence microscopy in Sl00-positive Schwann cells covering the denervated endplates. Using diluted polyclonal and monoclonal B-50 antibodies we found that B-50 immunoreactivity at the denervated motor endplates was strongly increased in comparison to innervated motor endplates in which B-50 immunoreactivity was hardly detectable. However, when a high concentration of B-50 antibodies was applied the normal innervated motor endplates were also B-50 immunoreactive. Muscle fibres did not display B-50 immunoreactivity. Northern blot analysis revealed elevated B-50 mRNA in denervated muscle and in degenerating nerve with respect to the controls. The B-50 mRNA levels in these non-neuronal tissues were very low compared to the intact and injured facial nucleus containing the neuronal cell bodies. Electron microscopy demonstrated that the B-50 protein was localized in the processes of Schwann cells covering axon terminals of intact and vacant motor endplates and in axon varicosities of sympathetic nerves. This study has confirmed that prior to reinnervation B-50 immunoreactivity is increased at denervated motor endplates and shows that B-50 is co-localized with S100 in Schwann cells. Therefore, upregulation of B-50 expression in Schwann cells may explain the early occurrence of B-50 immunoreactivity at the motor endplate.
Treadmill running combined with microdialysis can evaluate motor deficit and improvement following dopaminergic grafts in 6-OHDA lesioned rats
Authors: Hattori Satoshi , Li Qianming , Matsui Nobuo , Nishino Hitoo
Published: December 2019

To evaluate the physiological role of striatal dopamine (DA) during exercise and the mechanism of functional recovery mediated by grafted DAergic neurons, the locomotor ability (treadmill running) and DA turnover were investigated using treadmill running combined with in vivo microdialysis in the intact control rats, 6-hydroxydopamine (6-OHDA) lesioned rats (hemi-parkinsonian model rats) and DAergic cell grafted rats. The 3 groups of rats were trained to run on a straight treadmill at a speed of 1,800 cm/min for 20 min every day for 7 consecutive days. If the rats could not follow the speed they got electrostimulation (ES) from the grid behind the treadmill belt. The numbers of ES rats received during treadmill running were counted to quantify the locomotor ability. Control rats could keep up with the treadmill easily (0–1 ES/10 min), whereas lesioned rats could not follow the speed (80–100 ES/10 min). Most of the grafted rats received only a few ES, but a few received over 100 ES/10 min. Extracellular DA and its metabolites, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis and high-performance liquid chromatography (HPLC) during and after treadmill running. In control rats the basal levels of DA, DOPAC and HVA were 2.3 fmol/μl, 1,109.8 fmol/μl and 612.2 fmol/μl, respectively. They increased up to 130%, 140% and 160% by running. In 6-OHDA lesioned rats basal values of DA, DOPAC and HVA were less than 10% of controls. We did not perform microdialysis in these rats since they got too much ES during running. In grafted rats that showed good recovery in locomotor ability, DA returned to almost control level (1.9 fmol/μl), but those of DOPAC (127.8 fmol/μl) and HVA (100.2 fmol/μl) were still low. DA, DOPAC and HVA increased up to 130%, 130% and 150% by running in a similar pattern as in intact rats. These results suggest that grafted neurons can release and metabolize DA in the host striatum both tonically and phasically in relation with internal and external stimuli and also suggest that treadmill running ability is a good indicator of DA turnover in the striatum. Thus, the treadmill running test with microdialysis is useful for quantitative evaluation of motor function in grafted animals.