Restorative Neurology and Neuroscience - Volume 28, issue 3

Authors: Minnich, Jennie E. | Mann, Sarah L. | Stock, Megan | Stolzenbach, Kathryn A. | Mortell, Bridget M. | Soderstrom, Katherine E. | Bohn, Martha C. | Kozlowski, Dorothy A.

Article Type: Research Article

Abstract: Purpose: The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) gene delivery was examined in a rodent model of traumatic brain injury (TBI), the controlled cortical impact (CCI). Methods: An adenoviral vector harboring human GDNF (AdGDNF) or green fluorescent protein (AdGFP) was injected unilaterally into the forelimb sensorimotor cortex (FL-SMC) of the rat one week prior to a unilateral CCI. Tests of forelimb function and asymmetry were administered for 2 weeks post-injury. At …2 weeks post-injury, animals were sacrificed and contusion size, neuronal survival, neurodegeneration, and virally-mediated GDNF and GFP protein expression were measured. Results: Rats injected with AdGDNF had significantly smaller contusions, more surviving neurons, and less neurodegeneration than AdGFP injected and uninjected injured animals. GDNF gene delivery also resulted in significantly faster recovery of forelimb coordination and a smaller initial preference for the uninjured forelimb during exploration of the walls of a platform. However, overall recovery of symmetrical forelimb use was not achieved. Conclusions: The discrepancy between neural protection and behavioral recovery suggests that while GDNF gene delivery provided a high degree of protection of damaged cortical neurons in this model of TBI, it may not have fully protected their terminals and synaptic functioning, resulting in only mild protection against behavioral deficits. Show more

Keywords: Traumatic brain injury, growth factors, behavioral assessments, forelimb sensorimotor cortex, controlled cortical impact

DOI: 10.3233/RNN-2010-0528

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 293-309, 2010

Authors: Ekmark-Lewén, Sara | Lewén, Anders | Israelsson, Charlotte | Li, Gui Lin | Farooque, Mohammad | Olsson, Yngve | Ebendal, Ted | Hillered, Lars

Article Type: Research Article

Abstract: Purpose: Astroglial responses after traumatic brain injury are difficult to detect with routine morphological methods. The aims for this study were to compare the temporal and spatial expression pattern of vimentin- and glial fibrillary acidic protein (GFAP) in a weight drop model of mild cerebral contusion injury in the rat. We also wanted to study the vimentin response with immunohistochemistry and vimentin mRNA RT-PCR analysis in severe cortical contusion injury produced by the controlled cortical impact …in the mouse. Methods: Vimentin and GFAP immunohistochemistry (1day, 3 days and 7 days) combined with vimentin mRNA RT-PCR analysis (1 h, 4 h, 22 h, 3 days and 7 days) were used after experimental traumatic brain injury in the rat and mouse. Results: Increases in post-traumatic vimentin mRNA levels in the cortex and in the hippocampus appeared together with vimentin immunoreactivity in astrocytes in the perimeter of the cortical lesion, in the subcortical white matter and in the hippocampus starting at one day after severe trauma. GFAP immunostaining revealed hypertrophic astrocytes peaking at day 3 in the perifocal cortical region. There was no significant increase in GFAP immunoreactivity in the white matter in the rat. However, in the mouse there was a slight increase in the number of GFAP positive cells in this region, 3 days after trauma. Overall the pattern of vimentin immunoreactivity was very similar in the rat and mouse. Conclusions: Vimentin immunoreactivity was more sensitive than the GFAP staining method to demonstrate the distribution and time course of astrocyte reactions after a contusion injury, especially in the white matter distant from the cortical lesion. Show more

Keywords: Traumatic brain injury, rat, mouse, astrocytes, gliosis

DOI: 10.3233/RNN-2010-0529

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 311-321, 2010

Authors: Hamed, Sherifa A.

Article Type: Research Article

Abstract: Cumulative evidences from experimental and clinical studies indicate that in some patients, not only prolonged but also repetitive brief seizures, may trigger series of damage promoting mechanisms which evolve over a period of time (up to years). They result in progressive degeneration and loss of function of several neuronal cell populations, thus rending the brain abnormal and resistant to antiepileptic medications (AEDs). This probably explains that in some patients, a) there is a delay from the …onset of brain insult to the seizure onset, and b) suppression of seizures by AEDs is alone insufficient without clear prediction of disease progression. In this review, the analysis of information follows the assumption that epilepsy is a slowly progressive and a neurobiologically pleotropic disorder. Interaction between genes, neurotransmitters, ion channels, acid-base balance, mitochondria, calcium, glutamate and oxidative/antioxidants mechanisms, will determine the fate of the epilepsy process. The concept of neuroprotection aims not only to suppress seizures (anticonvulsant effect), but also to strengthen the auto-protective and repair mechanisms (antiepileptogenic and disease-modification effects) which prevent the development of spontaneous seizures, cognitive and behavioral problems later in life. This review is focusing on molecular evaluation of several models of epilepsy for the potential to follow disease modification and neuroprotection. Although AEDs of today possess multiple mechanisms of action, but mostly they are treating one part of the disease which is the seizures and do not offer high prospects of modification of the disease. This review is also discussing the prospects of novel drugs, molecular manipulations and cell therapy which address disease modification as approachs that will dominate the field of drug development and research on epilepsy in the future. Show more

Keywords: Neuroprotection, epileptogenesis, excitotoxicity, neurotrophic factors, molecular manipulation, gene therapy

DOI: 10.3233/RNN-2010-0537

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 323-348, 2010

Authors: Landi, Doriana | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Brain plasticity can be considered the main result of brain communication with the 'external' and 'internal' environment. Learning new skills as well as endogenous brain function recovery following a lesion are based on neural plasticity, a dynamic phenomenon occurring in response to modification of conscious and pre- or sub-conscious experiences as they progressively stabilize at the synaptic and neural networks level. In spite of previously accepted theory, brain plasticity occurs throughout lifespan being …an inner property of the system. Different models of brain plasticity are examined in relation with different modifications of the CNS: healthy brain ageing, neurodegenerative disorders, ischemic stroke and multiple sclerosis. A clarification of advantageous as well as of aberrant brain plasticity mechanisms in pathological conditions may help to improve the development of rehabilitation methods to better address and facilitate such processes. Show more

Keywords: Restorative plasticity, fMRI, EEG, ageing, Alzheimer's disease, ischemic stroke, multiple sclerosis

DOI: 10.3233/RNN-2010-0538

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 349-366, 2010

Authors: Gharibani, Payam Mohammad | Tiraihi, Taki | Arabkheradmand, Jalil

Article Type: Research Article

Abstract: Bone marrow stromal cells (BMSCs) are multipotent and can be induced to differentiate into different lineages including osteogenic, chondrogenic, myogenic and neuronal phenotypes. BMSCs were reported to be a suitable option for regenerative medical research. In this study, BMSCs were induced into GABAergic phenotypes using β-mercaptoethanol (βME) and retinoic acid (RA) as preinducers followed by potassium chloride as inducer, and were evaluated by fibronectin and Oct-4. The percentages of cells immunoreactive for …nestin, neurofilaments (NF 68, NF 160, and NF 200), GABA and GABA synthesizing and packaging enzymes (GAD1, GAD2, VGAT) were used for evaluating GABAergic differentiation. RT-PCR was used for confirming the expression of these enzymes. The differentiated cells were loaded and unloaded with FM1-43 in order to assess the functionality of the cells. At the preinduction stage, the cells downregulated fibronectin and Oct-4, and expressed neuronal markers. At the induction stage, the preinduced cells transdifferentiated into GABAergic cells, as confirmed by immunohistochemistry and RT-PCR. The GABAergic cells were stained and destained with FM1-43. Therefore, the two-stage induction protocol resulted in transdifferentiation of BMSCs into GABAergic cells with synaptic release upon stimulation. Show more

Keywords: Rat, BMSCs, GABAergic cells, transdifferentiation, cell therapy

DOI: 10.3233/RNN-2010-0539

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 367-377, 2010

Authors: Schmidt, Sein | Holst, Eric | Irlbacher, Kerstin | Oltmanns, Frank | Merschhemke, Martin | Brandt, Stephan A.

Article Type: Research Article

Abstract: Purpose: The quality of presurgical evaluation in focal extratemporal epilepsy surgery is highly dependent on precise structural and functional identification of the epileptic focus. Navigated transcranial magnetic stimulation (nTMS) is a tool that combines the spatial information of high-resolution magnetic resonance imaging (MRI) with the functionality of non-invasive cortical stimulation. The non-invasive character of nTMS suggests that it could be a promising tool for presurgical evaluation of cortical excitability. Methods: …Presurgical nTMS evaluation was performed on an 8-year-old boy with left-sided intractable focal epilepsy, somatosensory auras and epilepsia partialis continua. In line with standardized procedures, motor evoked potentials were sought in both hemispheres over perirolandic cortex during simultaneous belly-tendon surface recordings of the first dorsal interosseus muscles. Results: One singular motor-evoked potential (MEP) could be elicited in the unaffected hemisphere. In contrast, in the affected hemisphere MEPs could be elicited over a large area of the cortex even after the stimulation strength was reduced by at least 44%. Latency stratification in the affected hemisphere differentiated a motor from a sensory region of interest. Stimulation over the sensory region induced a sensory aura. The sensory site was concordant with a previous transient diffusion restriction found in an MRI two years prior to nTMS. Conclusions: NTMS can locate pathological excitability with high spatial precision. Future studies should compare nTMS with direct cortex stimulation, as well as the combination of nTMS with electroencephalography (EEG) in a larger patient-collective. Show more

Keywords: Focal epilepsy, preoperative evaluation, navigated brain stimulation, cortical excitability, motor evoked potential, transcranial magnetic stimulation

DOI: 10.3233/RNN-2010-0540

Citation: Restorative Neurology and Neuroscience, vol. 28, no. 3, pp. 379-385, 2010