Restorative Neurology and Neuroscience - Volume 26, issue 6

Authors: Vazin, Tandis | Chen, Jia | Spivak, Charles E. | Amable, Rose | Gabitzsch, Emily | Lee, Chun-Ting | Lupica, Carl R. | Freed, William J.

Article Type: Research Article

Abstract: Background and Purpose: Human embryonic stem cells (hESC) are considered a renewable source of dopamine producing neurons, and are of particular interest for their potential clinical use in Parkinson's disease. In this study, we characterized human dopaminergic neurons generated by stromal-derived inducing activity (SDIA) from BG01V2, a strain of human embryonic stem cell line, BG01, characterized by a chromosome 17 trisomy. Similar chromosomal changes have been repeatedly observed in hESC cultures in …different laboratories, indicating the importance of chromosome 17 for growth and adaptation of hESC to culture. Methods: We investigated in vitro proliferation of differentiating cells using a BrDU incorporation assay, and monitored the cell population in long term cultures. Despite the cytogenetic abnormality, TH+ neurons were postmitotic at all stages of differentiation. After 30 days of differentiation, cell division ceased in 91% of the overall population of cells in the culture, indicating intact cell cycle regulation. Results: Expression of midbrain specific marker genes (Otx2, Pax5, Msx-1) showed differentiation of hESC-derived neural progenitor cells into midbrain specific dopamine neurons. These neurons expressed the dopamine transporter (DAT), and displayed functional DAT activity and electrical excitability. Conclusions: TH+ cells derived from the BG01V2 hESC line using SDIA are postmitotic and have functional characteristics of normal dopaminergic neurons. Show more

Keywords: SDIA, embryonic stem cells, human, dopaminergic neuron, PA6 cells, BG01V2, trisomy 17

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 447-458, 2008

Authors: Ciriza, J. | Moreno-Igoa, M. | Calvo, A.C. | Yague, G. | Palacio, J. | Miana-Mena, F.J. | Muñoz, M.J. | Zaragoza, P. | Brûlet, P. | Pinzolas, R. y Osta

Article Type: Research Article

Abstract: Purpose: Amyotrophic Lateral Sclerosis (ALS) is a paralyzing disorder that kills individuals within three to five years of onset without any possibility for effective treatment. One proposed therapy has been the use of neurotrophic factors to inhibit the apoptosis of motorneurones. At the present, one way to deliver neurotrophic factors after intramuscular injection to the motor neurones is through the use of adenoviral vectors. An alternative strategy is the use of the atoxic C fragment of …tetanus toxin (TTC) as a neurotrophic factor carrier for motorneurones. Methods: We have produced the recombinant protein fusion Glial Derived Neurotrophic Factor and C fragment of tetanus toxin (GDNF-TTC) and we have tested its antiapoptotic activity in degeneration culture cells and in the symptomatic SOD^{G93A} transgenic animal model for ALS. Results: We demonstrated that GDNF-TTC induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and~maintains its antiapoptotic neuronal activity in Neuro2A cells. Moreover, we have found that genetic fusion is able to increase survival by 9 days and improves life quality in symptomatic ALS animal models. Conclusion: These results suggest that recombinant GDNF-TTC fusion protein intramuscular injections provide a potential therapy for ALS treatment. Show more

Keywords: SOD1^{G93A} animal model, apoptosis, survival, neurotrophic factor, neurodegenerative diseases, Amyotrophic lateral Sclerosis, fragment C of tetanus toxin

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 459-465, 2008

Authors: Shuchang, He | Qiao, Niu | Piye, Niu | Mingwei, He | Xiaoshu, Sun | Feng, Shao | Sheng, Wang | Opler, Mark

Article Type: Research Article

Abstract: Purpose: High brain levels of aluminum (Al) can be neurotoxic and cause learning and memory deficits. Gastrodia elata (GE) is a Chinese herb widely used for improving mental function in traditional Chinese medicine. We measured changes in Al-induced neurotransmitter alteration and performance on a learning and memory task to elucidate the mechanism of Al toxicity and to assess whether these alterations could be attenuated by GE. Methods: Thirty-six adult, male rats were randomly divided …into six groups. Four Al-exposed groups were given aluminum chloride at 5 mg/kg/day or 10 mg/kg/day (i.p.) for two months, with two of these groups (one for each dose of Al) receiving GE (0.4 g/kg, via oral intubation, with the GE powder mixed in the drinking water) while the other two groups received vehicle. A GE control group was given injections of saline plus GE and a saline control group was given injections of saline and with 3 injection days and one day off. A step-down test was used to measure learning and memory ability. Al concentrations in the neocortex were assayed with a graphite furnace atomic absorption spectrophotometer. Amino acid neurotransmitter levels in the neocortex were determined by high performance liquid chromatogram-fluorescence. Results: Al-exposed rats showed impaired learning and memory ability as indicated by shorter step down latency and more retention errors. Cortical concentrations (mean ± SEM) of Al were: 56.22 ± 34.10 ng/g (wet weight) in the Saline control group; 172.87 ± 111.06 in the 5 mg/kg/dayAl group; 289.15 ± 102.55 in the 10 mg Al group; 74.98 ± 19.00 in the GE control group; 232.55 ± 35.74 in 5 mg Al+GE group; and 291.35 98.38 in 10 mg Al+GE group respectively. Al exposure produced a significant increase in cortical GABA levels. Gastrodia elata reduced learning and memory deficits without affecting brain Al levels. Conclusions: Rats exposed to AlCl_{3} suffer from deficits in learning and memory, accompanied by increases in GABA levels in the neocortex. Gastrodia elata is effective in improving memory functions and normalizing GABA levels. Show more

Keywords: Aluminum, learning and memory, amino acid neurotransmitter, gastrodia elata

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 467-473, 2008

Authors: Rossi, Silvia | Mataluni, Giorgia | De Bartolo, Paola | Prosperetti, Chiara | Foti, Francesca | De Chiara, Valentina | Musella, Alessandra | Mandolesi, Laura | Bernardi, Giorgio | Centonze, Diego | Petrosini, Laura

Article Type: Research Article

Abstract: Purpose: Recent anatomical studies showed the presence of cerebellar and basal ganglia connections. It is thus conceivable that the cerebellum may influence the striatal synaptic transmission in general, and synaptic plasticity in particular. Methods: In the present neurophysiological investigation in brain slices, we studied striatal long-term depression (LTD), a crucial form of synaptic plasticity involved in motor learning after cerebellar lesions in rats. Results: Striatal LTD was fully abolished in the left …striatum of rats with right hemicerebellectomy recorded 3 and 7 days following surgery, when the motor deficits were at their peak. Fifteen days after the hemicerebellectomy, rats had partially compensated their motor deficits and high-frequency stimulation of excitatory synapses in the left striatum was able to induce a stable LTD. Striatal plasticity was conversely normal ipsilaterally to cerebellar lesions, as well as in the right and left striatum of sham-operated animals. Conclusions: These data show that the cerebellum controls striatal synaptic plasticity, supporting the notion that the two structures operate in conjunction during motor learning. Show more

Keywords: EPSP, long-term depression, motor recovery, rat, synaptic plasticity

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 475-480, 2008

Authors: Thimm, M. | Fink, G.R. | Sturm, W.

Article Type: Research Article

Abstract: Purpose: To investigate the neural correlates associated with recovery from acute spatial neglect resulting from right hemispheric stroke. Methods: Four neglect patients were investigated both behaviourally and by fMRI at an acute (18 ± 5 days) and at a chronic stage (123 ± 18 days) post stroke. Results: At the second assessment all patients showed substantial behavioural improvements. These were associated with an increase of neural activity in the right middle frontal …gyrus, right inferior parietal cortex, right inferior temporal gyrus/fusiform gyrus, left superior temporal gyrus/angular gyrus and left anterior cingulate gyrus. Decreased neural activity at the second assessment was found in the right parahippocampal gyrus and left fusiform gyrus. Conclusions: The pattern of neural reorganisation comprises areas of a right hemisphere fronto-parietal attentional network and corresponding left hemisphere areas suggesting a compensatory recruitment of analogous contralesional areas. Interestingly, a more complex pattern of neural changes was observed in the fusiform gyri which have previously been implicated in lateralised directed spatial attention. There was an increase in the right hemisphere and a decrease in the left hemisphere. This pattern of recovery is reminiscent of a "push-pull" pattern previously described for the dorsal parietal cortex by Corbetta et al. (2005) in the recovery from spatial neglect. Show more

Keywords: Neglect, fMRI, visuospatial attention, functional reactivation, recovery of function, stroke, plasticity

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 481-492, 2008

Authors: Hätinen, Sonja | Sairanen, Mikko | Sirviö, Jouni | Jolkkonen, Jukka

Article Type: Research Article

Abstract: Purpose: Rolipram, a specific phosphodiesterase 4 inhibitor (PDE4), is suggested to facilitate functional recovery following brain injury by activation of cAMP/CREB pathway. We examined the effect of rolipram on sensorimotor recovery in rats following transient occlusion of the middle cerebral artery (MCAO). Methods: Rats were subjected to transient MCAO for 2 h. Rolipram was administered at a dose of 0.1 or 1 mg/kg (i.p., twice a day, for 13 days) starting administration on postoperative …day 2. Sensorimotor outcome was assessed using limb-placing, beam-walking and cylinder tests at baseline and 7, 14, and 21 days after MCAO. Results: Rolipram decreased locomotor activity and rearing, produced atypical head twitches, and possible hyperalgesia immediately after treatments, which were all considered as acute side effects. The analysis of hindlimb function utilizing beam-walking tests showed that overall performance was impaired in MCAO vehicle rats (p < 0.01) and MCAO rats treated with rolipram, at a dose of 0.1 mg/kg (p < 0.01), compared to sham-operated rats. Interestingly, MCAO rats treated with rolipram at a dose of 1.0 mg/kg had significantly fewer slips when traversing an elevated beam than those treated with a dose of 0.1 mg/kg (p < 0.05) indicating improved sensorimotor function. More importantly, hindlimb function at the higher rolipram dose was not different from sham-operated rats after cessation of drug treatment at day 21. There was a significant group effect (p < 0.001) in the cylinder test, however, this was due to the decreased use of the impaired forelimb in MCAO rats compared to sham-operated rats at day 7, 14 and 21. In addition, MCAO rats treated with rolipram seemed to use their impaired forelimbs less compared to MCAO controls. Limb-placing performance was severely impaired but not different among MCAO rats. Conclusions: The present data suggest that rolipram provides some improvement in sensorimotor recovery in MCAO rats possibly by augmenting cAMP/CREB signalling, but this is masked by its side effects. Show more

Keywords: Behavioral recovery, focal cerebral ischemia, PDE4 inhibition, rolipram

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 493-499, 2008

Authors: Di Giorgio, Anthony M. | Hou, Yongjin | Zhao, Xueren | Zhang, Bin | Lyeth, Bruce G. | Russell, Michael J.

Article Type: Research Article

Abstract: Purpose: The objective of this study was to evaluate the neuroprotective potential of the antioxidant, curcumin compared to α-tocopherol in a rat model of traumatic brain injury (TBI). Methods: Male Sprague-Dawley rats were administered curcumin (3, 30, 300 mg/kg), α-tocopherol (100 mg/kg), DMSO vehicle, or saline, 30 min prior to and 30 and 90 min after moderate lateral fluid percussion TBI. Rats were euthanized at 24 hours after injury and coronal brain sections were …stained with Fluoro-Jade to identify degenerating neurons. Degenerating neurons in the CA2-3 sector of the dorsal hippocampus were quantified in 10 sections spaced 300 μm apart in each rat. Results: One way ANOVA revealed a significant difference (p = 0.01) between groups. The curcumin, α-tocopherol, and DMSO groups had significantly reduced numbers of degenerating neurons compared to the saline-treated group. No significant differences were observed between any of the drug treatment groups or the DMSO group. Conclusions: Since protection in the DMSO vehicle group was equal to that of the experimental groups, no conclusions about neuroprotection regarding α-tocopherol or curcumin can be made from this study. The results suggest that DMSO may be acting as an overriding neuroprotectant in this experiment. We conclude that DMSO is a viable neuroprotective agent against secondary cell death in TBI. Show more

Keywords: DMSO, curcumin, traumatic brain injury, antioxidant, neuroprotection

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 501-507, 2008

Authors: Groutsi, F. | Mason, M.R.J. | Anderson, P.N. | Martins, S. | Anesti, M. | Coffin, R.S. | Campbell, G.

Article Type: Research Article

Abstract: Purpose: The primary motor pathway, the corticospinal tract, is a major target for spinal cord regeneration studies. One way of improving the regeneration of corticospinal axons is to introduce regeneration-associated genes into cortical motor neurons using viral vector delivery. Methods: We used an engineered Herpes Simplex virus (HSV1) with the EF1α promoter encoding either LacZ or GFP to transduce cortical neurons through retrograde transport following the injection of vector into adult rat striatum …or spinal cord. After three-days to one-month post-injection, sections of brain and spinal cord were viewed with fluorescence microscopy or processed for LacZ histochemistry. Results: Many layer V motor cortical neurons were transduced following striatal injections. These were not corticospinal neurons as they were not fluorogold-labelled following tracer injection into spinal cord. Corticospinal neurons in both hemispheres were, however, transduced following direct vector injections into the dorsal column of spinal cord, yielding 250–400 transduced corticospinal neurons per animal. No non-pyramidal neurons or thalamic neurons were transduced by spinal injections. Conclusions: Therefore, this HSV1.EF1α vector is highly effective for the transduction of corticospinal neurons without direct injection into the brain and could be used to introduce regeneration-relevant genes into these neurons with the aim of regenerating the corticospinal tract. Show more

Keywords: In vivo transduction, corticospinal neurons, HSV1 vector, elongation factor 1α, rat

Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 509-520, 2008