Restorative Neurology and Neuroscience - Volume 31, issue 2

Authors: Yang, Sungchil | Bao, Shaowen

Article Type: Research Article

Abstract: Tinnitus, the phantom percept of sound, is a potentially debilitating disorder affecting up to ten percent of the general population. After decades of effort, we still lack an effective treatment for tinnitus, partly because of its diverse underlying etiology. Recent studies have yielded hypotheses for central mechanisms underlying hearing loss-induced tinnitus, the most common form of tinnitus. Here we review recent evidence that homeostatic down-regulation of phasic and tonic inhibition is a mechanism underlying hearing loss-induced tinnitus. We propose to treat tinnitus through novel strategies of sensory training and targeted pharmacological intervention to reverse the homeostatic changes induced by hearing …loss. Show more

Keywords: Phantom percept, map reorganization, rehabilitation, acoustic trauma

DOI: 10.3233/RNN-120248

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 99-108, 2013

Authors: Liu, Xiaojun | Yue, Rongcai | Zhang, Jigang | Shan, Lei | Wang, Rui | Zhang, Weidong

Article Type: Research Article

Abstract: Purpose: Bacopa monnieri (L.) WETTST. is extensively used in traditional Indian medicine as a nerve tonic. The neuropharmacological properties of bacopaside I, an important component from B. monnieri, have not been studied so far. The present study investigated the effects and possible mechanisms of bacopaside I in a rat model of transient focal ischemia induced by middle cerebral artery occlusion (MCAO). Methods: Adult male Sprague-Dawley rats were divided into five groups: sham-operated group, ischemia group, and three bacopaside I-treated groups (3, 10 and 30 mg/kg) respectively. Bacopaside I or vehicle (0.5% CMC-Na) was administered orally once a day for 6 …days. On the third day, the rats were subjected to 2 h right MCAO via the intraluminal filament technique and 70 h reperfusion. Assessment of behavioral deficits both at 22 and 70 h, and measurement of cerebral infarct volume, edema, cerebral energy metabolism, relative enzyme activities, malondialdehyde (MDA) content, nitric oxide (NO) level, and antioxidant enzyme activities at 70 h, performed after MCAO reperfusion. Results: Bacopaside I (10 and 30 mg/kg) treatment produced significant reduction in neurological deficits at 22 and 70 h, and significantly reduced cerebral infarct volume and edema at 70 h, when compared with the ischemia group. Animal, that were orally treated with bacopaside I (3, 10 and 30 mg/kg) showed increased the brain ATP content, energy charge (EC), total adenine nucleotides (TAN), nitric oxide (NO) level, Na+ K+ ATPase and Ca2+ Mg2+ ATPase activity. Bacopaside I (3, 10 and 30 mg/kg) treatment also improved antioxidant enzyme activities including brain superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), in varying degrees, compared with the ischemia group. In addition, three doses of bacopaside I (3, 10 and 30 mg/kg) markedly inhibited the increase in MDA content of the brain. Conclusions: These findings indicated that bacopaside I possess a neuroprotective effect against injury caused by cerebral ischemia. The protective mechanism might be related to improving cerebral energy metabolism and increasing antioxidant levels. Show more

Keywords: Bacopaside I, stroke, ischemic injury, reactive oxygen radicals, energy metabolism

DOI: 10.3233/RNN-120228

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 109-123, 2013

Authors: Mitchell, Teresa V. | Letourneau, Susan M. | Maslin, Melissa C.T.

Article Type: Research Article

Abstract: Purpose: This study examined the effects of deafness and sign language use on the distribution of attention across the top and bottom halves of faces. Methods: In a composite face task, congenitally deaf signers and typically hearing controls made same/different judgments of the top or bottom halves of faces presented with the halves aligned or spatially misaligned, while event-related potentials (ERPs) were recorded. Results: Both groups were more accurate when judging misaligned than aligned faces, which indicates holistic face processing. Misalignment affected all ERP components examined, with effects on the N170 resembling those of face inversion. Hearing adults were similarly …accurate when judging the top and bottom halves of the faces, but deaf signers were more accurate when attending to the bottom than the top. Attending to the top elicited faster P1 and N170 latencies for both groups; within the deaf group, this effect was greatest for individuals who produced the highest accuracies when attending to the top. Conclusions: These findings dovetail with previous research by providing behavioral and neural evidence of increased attention to the bottom half of the face in deaf signers, and by documenting that these effects generalize to a speeded task, in the absence of gaze shifts, with neutral facial expressions. Show more

Keywords: Face perception, deafness, event-related potentials, N170

DOI: 10.3233/RNN-120233

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 125-139, 2013

Authors: Shahlaie, Kiarash | Gurkoff, Gene G. | Lyeth, Bruce G. | Muizelaar, J. Paul | Berman, Robert F.

Article Type: Research Article

Abstract: Purpose: Second insults following traumatic brain injury (TBI), such as ischemia and hypoxia, significantly worsen outcome in patients and in experimental models of TBI. Following TBI there is a pathological increase in intracellular calcium, triggering cellular mechanisms of dysfunction and death. N-type specific voltage gated calcium channel (VGCC) blockers reduce cell death in both in vitro mechanical strain injury (MSI) and in vivo models of TBI, but they have not been previously explored in a model of TBI followed by a second insult. Methods: In the following studies, cortical neurons and astrocytes experienced MSI followed by incubation in 20% CO2 …. Cultures were treated with the N-type VGCC blocker, ω-conopeptide SNX-185 (1 μM), 5-minutes post-injury and intracellular calcium accumulation was assessed at 3, 6 and 24 h. Neuronal viability was assessed 24 h after MSI. Results: Increasing incubator CO2 to 20% significantly increased calcium accumulation and cell death regardless of MSI severity. Treatment with 1 μM of SNX-185 significantly reduced the accumulation of calcium 3 hours following injury and increased the number of viable neurons 24 h post-injury and incubation in 20% CO2 . Conclusions: In vitro models provide a critical tool for identifying roles of cell specific mechanisms involved in neuronal dysfunction and death following injury. These data demonstrate the potential of N-type VGCC blockers in reducing the damaging effects of TBI and second insults. Show more

Keywords: In Vitro, traumatic brain injury, ischemia, hypoxia, neuronal cell death, rat

DOI: 10.3233/RNN-120243

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 141-153, 2013

Authors: Korecka, Joanna A. | Eggers, Ruben | Swaab, Dick F. | Bossers, Koen | Verhaagen, Joost

Article Type: Research Article

Abstract: Purpose: Parkinson's disease (PD) is a movement disorder mainly characterized by progressive neurodegeneration of dopaminergic (DAergic) neurons in the substantia nigra (SN). As yet, unknown molecular changes contribute to the development of PD leading to a great need for in vivo models that herald this disorder. Here we characterize an animal model presenting early PD pathology. Methods: Young, adult C57/BL6 mice were treated for five weeks twice a week with 15 mg/kg 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) in combination with 250 mg/kg probenecid. During the treatment mice were tested on their dopamine dependent movement skills. The integrity of their nigrostriatal system was examined …through immunohistochemical studies. Results: During the treatment, mice developed dopamine-dependent movement deficits induced by loss of tyrosine hydroxylase (TH) positive nigrostriatal axon terminals. Immunohistochemical study identified astrogliosis and microgliosis in the SN but no decrease of TH immunostaining, demonstrating lack of DAergic neuron degeneration. We also observed formation of α-synuclein inclusion bodies in the SN. Conclusions: The combined features of this MPTP model appear to represent an early neurotoxic cellular stress to the SN neurons bearing a striking resemblance to the early stages of PD neuropathology. This model might prove very useful to investigate early neurodegenerative events in the nigrostriatal DAergic system and to study the effects of potential treatment strategies counteracting the early PD cellular changes. Show more

Keywords: MPTP, substantia nigra, dopaminergic neuron, tyrosine hydroxilase, astrogliosis, microgliosis, grid test, dying back hypothesis

DOI: 10.3233/RNN-110222

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 155-167, 2013

Authors: Brown, Todd J. | Pittman, Amy L. | Monaco, Gina N. | Benscoter, Brent J. | Mantravadi, Avinash V. | Akst, Lee M. | Jones, Kathryn J. | Foecking, Eileen M.

Article Type: Research Article

Abstract: Purpose: To investigate the effects of the androgen testosterone propionate (TP), on regeneration of the recurrent laryngeal nerve (RLN) after unilateral crush injury using assessment of vocal fold mobility (VFM) as a measure of behavioral recovery. Methods: 48 adult male rats underwent standardized crush injury of left RLN and received treatment in the form of 2 silastic capsules containing TP or controls receiving a blank capsule (untreated). Direct laryngoscopic assessment of vocal cord mobility was performed before, immediately following and 1, 2, 3, 4, 5 or 6 weeks post injury. Results: Treatment with TP enhanced the recovery of full VFM …following crush injury of the RLN compared to controls. There was statistically significant improvement in VFM seen at the 1 and 2 week time points (p < 0.05). By 4 weeks TP-treated rats displayed a 100% recovery of VFM function, compared to only 50% by the control group. Conclusions: TP enhances RLN functional recovery following a crush injury, which further supports its potential general applicability as a therapeutic agent in peripheral nerve injury. Show more

Keywords: Testosterone propionate, recurrent laryngeal nerve, vocal fold mobility, crush injury

DOI: 10.3233/RNN-120287

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 169-176, 2013

Authors: Assenza, G. | Zappasodi, F. | Pasqualetti, P. | Vernieri, F. | Tecchio, F.

Article Type: Research Article

Abstract: Background and purpose: Despite similar clinical onset, recovery from stroke can be largely variable. We searched for electrophysiological prognostic indices, believing that they can guide future neuromodulation treatments boosting clinical recovery. Methods: 19-channels resting electroencephalogram (EEG) was collected in 42 patients after 4–10 days (t0) from a unilateral ischemic stroke in the middle cerebral artery (MCA) territory and 20 controls. National Health Institute Stroke Scale (NIHSS) was collected at t0 and 6 months later (t1). Standard spectral band powers and interhemispheric coherences between homologous MCA regions were calculated in both hemispheres. Results: Total spectral, delta and theta band powers were …higher bilaterally in patients than in controls and directly correlated with NIHSSt0 in both hemispheres. A linear regression model including each EEG patient's variable differing from those of controls and correlating with effective recovery [ER = (NIHSSt0–NIHSSt1)/(NIHSSt0–NIHSS in healthy conditions)] showed contralesional delta power as the only valid predictor of ER. A further regression model including also NIHSSt0 confirmed that contralesional delta power can add prognostic information to acute clinical impairment. Contralesional delta activity increase was best explained, in addition to the increasing ipsilesional delta activity, by a reduction of interhemispheric functional coupling - which did not explain a significantly portion of effective recovery variability by itself. Conclusions: Contralesional EEG delta activity retains relevant negative prognostic information in acute stroke patients. Present results point to the interhemispheric interplay as a decisive target in setting up enriched rehabilitations. Show more

Keywords: Stroke, EEG, middle cerebral artery territory, interhemispheric coherence, recovery

DOI: 10.3233/RNN-120244

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 177-188, 2013

Authors: Mercerón-Martínez, Daymara | Almaguer-Melian, William | Serrano, Teresa | Lorigados, Lourdes | Pavón, Nancy | Bergado, Jorge A.

Article Type: Research Article

Abstract: Purpose: To investigate a possible role of neurotrophins in the memory improving effect of stimulating the basolateral amygdala. Methods: The BDNF and NGF levels were measured in the hippocampus of fimbria-fornix lesioned male rats after four days of training in the water maze and stimulation of the basolateral amygdala. Results: The behavioral results confirm that daily post-training stimulation of the amygdala improves the learning abilities of the lesioned animals. BDNF increased in lesioned and trained animals, but stimulating the basolateral amygdala induces a significantly greater increase. NGF showed a slight (but significant) increase in fimbria-fornix lesioned and trained animals, but …stimulating the amygdala does not produce a further increase. In separate groups of animals we measured the levels of both neurotrophins in acute experiments, after 2 and 24 hours of stimulating the amygdala. BDNF was significantly increased at both times, while NGF showed again only slight increases (significant at 24 h). Conclusions: These results suggest that the BDNF response to amygdala stimulation might be of functional importance in the observed learning improvement. The changes in NGF are most likely due to the accumulation of this protein after removal of the septal axons. Show more

Keywords: Neurotrophins, BDNF, NGF, hippocampus, amygdala, fimbria-fornix, spatial memory

DOI: 10.3233/RNN-120265

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 189-197, 2013

Authors: Brendel, Alexander | Felzen, Vanessa | Morawe, Tobias | Manthey, Dieter | Behl, Christian

Article Type: Research Article

Abstract: Purpose: The neuroendocrinology of female sex hormones is of great interest for a variety of neuropsychiatric disorders. In fact, estrogens and estrogen receptors (ERs) exert neuromodulatory and neuroprotective functions. Here we investigated potential targets of the ER subtype alpha that may mediate neuroprotection and focused on direct modulators and downstream executors of apoptosis. Methods: We employed subclones of human neuroblastoma cells (SK-N-MC) stably transfected with one of the ER subtypes, ERalpha or ERbeta. Differences between the cell lines regarding the mRNA expression levels were examined by qPCR, changes on protein levels were examined by Western Blot and immunocytochemistry. Differences concerning …apoptosis induction were analysed by cell survival assays which included primary rat neurons. Results: In this report we show a potent protection against apoptosis-stimuli in ERalpha expressing cells compared to controls lacking ERalpha. In fact, almost a complete silencing of Caspase 3 expression in SK-ERalpha cells compared to SK-01 control transfected cells was observed. In addition, prosurvival bcl2, bag1 and bag3 expression was highly up-regulated in the presence of ERalpha. Conclusion: Taken together, we identified Caspase 3, BAG1 and BAG3 as key targets of ERalpha in neuronal cells that may play a role in ERalpha-mediated neuroprotection. Show more

Keywords: Estrogen, ERalpha, neuroprotection, Caspase 3, BAG1, BAG3

DOI: 10.3233/RNN-120272

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 199-211, 2013

Authors: García del Barco-Herrera, Diana | Martínez, Nelvys Subirós | Coro-Antich, Rosa María | Machado, Jorge Martín | Alba, José Suárez | Salgueiro, Sandra Rodríguez | Acosta, Jorge Berlanga

Article Type: Research Article

Abstract: Purpose: Stroke is the second cause of mortality worldwide, with a high incidence of disability in survivors. Promising candidate drugs have failed in stroke trials. Combined therapies are attractive strategies that simultaneously target different points of stroke pathophysiology. The aim of this work is to determine whether the combined effects of Epidermal Growth Factor (EGF) and Growth Hormone-Releasing Peptide-6 (GHRP6) can attenuate clinical signs and pathology in an experimental stroke model. Methods: Brain global ischemia was generated in Mongolian gerbils by 15 minutes of carotid occlusion. After reperfusion, EGF, GHRP6 or EGF+GHRP6 were intraperitoneally administered. Clinical manifestations were monitored daily. …Three days after reperfusion, animals were anesthetized and perfused with an ink solution. The anatomy of the Circle of Willis was characterized. Infarct volume and neuronal density were analyzed. Results: EGF+GHRP6 co-administration reduced clinical manifestations and infarct volume and preserved neuronal density. No correlation was observed between the grade of anastomosis of the Circle of Willis and clinical manifestations in the animals receiving EGF+GHRP6, as opposed to the vehicle-treated gerbils. Conclusions: Co-treatment with EGF and GHRP6 affects both the clinical and pathological outcomes in a global brain ischemia model, suggesting a suitable therapeutic approach for the acute management of stroke. Show more

Keywords: Stroke, combined therapy, EGF, GHRP6, global brain ischemia, neuroprotection, brain protection

DOI: 10.3233/RNN-120262

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 213-223, 2013

Authors: Schäfer, S.T. | Peters, J. | von Bohlen und Halbach, O.

Article Type: Research Article

Abstract: Purpose: The (pro)renin receptor ((P)RR) is receptor that has been shown to be involved in developmental processes. Adult neurogenesis shares many similarities with fetal and embryonic neuronal development, but is restricted to some brain areas, including the hippocampus. We therefore investigated the expression of the (P)RR within the adult hippocampal formation and investigated whether (P)PR is expressed by adult and newly generated neurons in the dentate gyrus. Methods: (P)PR protein expressing cells in the hippocampus were analyzed using immunohistochemistry. Double-labeling with markers for adult neurogenesis was used to investigate whether newly formed cells also express (P)PR. Results: (P)PR is expressed …by neuronal cells with the hippocampus. (P)RR protein is expressed during different stages of adult neurogenesis within the dentate gyrus (DG). (P)RR is not expressed by Sox2 positive neuronal stem cells, but by doublecortin positive cells located both in the subgranular zone and the granular layer of the DG. Conclusions: The results indicate that (P)PR is mainly expressed by adult neurons in the hippocampus as well as in late stages of adult neurogenesis within the hippocampus. However, to clarify the involvement of this receptor in adult hippocampal neurogenesis and neuronal cell differentiation in detail, functional analyses needed to be performed. Show more

Keywords: (pro)renin receptor, ATP6ap2, (P)RR, adult neurogenesis, hippocampus

DOI: 10.3233/RNN-120282

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 225-231, 2013