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Biomedical subjects

Otto W Witte

Publications and source records attributed to Otto W Witte.

At least 19 recordsLinked to original sources
PubMed2006

Levetiracetam as a treatment option in non-convulsive status epilepticus.

Non-convulsive status epilepticus (NCSE) is characterized by continuous or recurrent, generalized or focal epileptiform activity on the electroencephalogram and diverse clinical symptoms with alterations of mental state and vigilance. NCSE is not rare but certainly under diagnosed. There is some debate about how aggressive NCSE should be treated, as high dose anticonvulsants maybe partially responsible for the morbidity and mortality of patients with NCSE. We hypothesized that levetiracetam (LEV) as a well tolerated, highly effective new anticonvulsant, may be a safe treatment option. We retrospectively analyzed all (8) patients with NCSE who received levetiracetam from our database, compared with 11 patients with NCSE treated with conventional intravenous status medication as controls. These eight patients showed a marked clinical improvement with final cessation of ictal EEG-activity and clinical symptoms of NCSE after initiation of LEV within 3 days (mean 1.5 days). The response to conventional treatment was similarly effective but there were severe side effects whereas no relevant side effects in the LEV-treated group were noticed. A long-term follow up (6-36 months from discharge) revealed six patients with a persisting reduction in seizure frequency on medication with LEV. One patient changed the anticonvulsive medication because of inefficacy and one died from other causes than epilepsy 2 months after discharge from hospital. We found no significant differences in hospitalisation time, time in intensive care unit and outcome between the LEV group and the control group. This retrospectively acquired data suggests that LEV may be a well tolerated, effective treatment option in NCSE. This highlights the need for a prospective controlled study to further elucidate the utility of LEV in the treatment of NCSE, particularly as an intravenous formulation is now available.

Aged↗
PubMed2006

The combined use of non-radioactive in situ hybridization and real-time RT-PCR to assess gene expression in cryosections.

Gene expression changes in pathophysiological states can be spatiotemporally monitored by in situ hybridization and reliably quantified by real-time RT-PCR. Here we developed a new method whereby adjacent slides of frozen sections can be used for gene expression analysis by in situ hybridization and real-time RT-PCR. We applied this method to assess the mRNA expression of connexin 43 (Cx43), the major astrocytic connexin, after kainate-induced seizures in rat hippocampus. Gap junction-building connexins play a role in the pathogenesis of several diseases of the brain, including epilepsy. The number of Cx43 mRNA-positive cells in the hippocampus of kainate-treated and control rats was automatically quantified by computerized image analysis of brain sections hybridized with DIG-labeled RNA probes. In parallel, real-time RT-PCR was used to examine the relative Cx43 mRNA levels in hippocampal tissue from adjacent brain sections. Applying these two very sensitive methods we showed that kainate induced seizures do not affect hippocampal connexin 43 mRNA expression.

Animals↗
PubMed2006

Glucose transporter proteins GLUT1 and GLUT3 like immunoreactivities in the fetal sheep brain are not reduced by maternal betamethasone treatment.

Synthetic glucocorticoids administered to accelerate fetal lung maturation in threatened preterm delivery change electrocortical brain activity in the human and sheep fetus and alter structural neuronal proteins in fetal baboon and sheep. We hypothesized that these changes are due to a decreased amount of glucose transporter proteins (GLUT). Glucose uptake into cerebral neurons is selectively facilitated by glucose transporter protein GLUT1 in the blood brain barrier and GLUT3 in neuronal membranes. GLUT1 and GLUT3 immunoreactivity was examined in fetal sheep brain sections of the frontal neocortex, caudate putamen and hippocampus at 0.73 gestation after fetal exposure to betamethasone by direct fetal intravenous infusion or maternal intramuscular injections at the clinically relevant dosage. Betamethasone did not alter GLUT1 and GLUT3 immunoreactivity in any of the brain regions investigated, independently of the dose and route of administration. These data indicate that alteration of GLUT expression is unlikely to explain the cerebral functional effects of antenatal glucocorticoids.

Animals↗
PubMed2006

Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging.

gamma-Aminobutyric acid type A (GABA(A)) receptors are the most important inhibitory receptors in the central nervous system, playing a pivotal role in the regulation of brain excitability. The pentameric receptor is commonly composed of different alpha, beta, and gamma subunits which mediate the function and pharmacology of the receptor and show regional- and temporal-specific expression patterns. Under varying physiological and pathophysiological conditions, this diversity allows a multitude of adaptive changes in subunit composition leading to distinct biological and pharmacological properties of the receptor. Here, we investigated the expression of five major GABA(A) receptors subunits (alpha1, alpha2, alpha3, alpha5, gamma2) in early postnatal, adult, and aged rat brains. Immunohistochemistry was performed at postnatal day 10, 30, 60, 90, 180, 360, and 540. Morphological and semi-quantitative evaluations of regional optical densities revealed specific regional and temporal expression patterns for all subunits. The study clearly demonstrated that changes in GABA(A) receptor distribution not only occur in the early postnatal cortex and hippocampal formation but also during later periods in the adolescent and aging brain. These findings contribute to a better understanding of age-related changes in brain excitability and further elucidate the distinct pharmacological effects of different GABAergic drugs in young and elderly patients.

Age Factors↗
PubMed2006

Impairment of functional inhibition in the contralateral cortex following perinatally acquired malformations in rats.

Neonatal freeze lesions in newborn rats induce focal malformations of the cerebral cortex mimicking human polymicrogyria which is a common cause of epilepsy and neuropsychological deficits in children and adults. Experimental and clinical studies demonstrated hyperexcitability in the malformation itself and peridysplastic cortex associated with a widespread imbalance of excitatory and inhibitory function and extensive alterations in cortical connectivity. We investigated the integrity of functional cortical inhibition using a paired pulse paradigm in brain slice preparations of adult freeze-lesioned rats. In contrast to previous electrophysiological studies focusing on the dysplastic cortex and the ipsilateral hemisphere, we here mapped both hemispheres. Extracellular field potentials were evoked by application of double pulses at the border of layer VI/white matter and recorded in layer II/III. Evaluation of the ratio of the field potential amplitudes at different recording positions allowed an assessment of regional functional inhibition. Using this approach, we observed a significant reduction of functional inhibition in the somatosensory cortex of the contralateral hemisphere, whereas only slight alterations were detected in the ipsilateral lesion surround. Our results provide evidence that focal cortical malformations not only impair cortical excitability in the ipsilateral hemisphere but also induce a disinhibition of the contralateral cortex.

Animals↗
PubMed2006

Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine.

It is well established that axons of the adult mammalian CNS are capable of regrowing only a limited amount after injury. Astrocytes are believed to play a crucial role in the failure to regenerate, producing multiple inhibitory proteoglycans, such as chondroitin sulphate proteoglycans (CSPGs). After spinal cord injury (SCI), astrocytes become hypertrophic and proliferative and form a dense network of astroglial processes at the site of lesion constituting a physical and biochemical barrier. Down-regulations of astroglial proliferation and inhibitory CSPG production might facilitate axonal regeneration. Recent reports indicated that aberrant activation of cell cycle machinery contributed to overproliferation and apoptosis of cells in various insults. In the present study, we sought to determine whether a cell cycle inhibitior, olomoucine, would decrease neuronal cell death, limit astroglial proliferation and production of inhibitory CSPGs, and eventually enhance the functional compensation after SCI in rats. Our results showed that up-regulations of cell cycle components were closely associated with neuronal cell death and astroglial proliferation as well as the production of CSPGs after SCI. Meanwhile, administration of olomoucine, a selective cell cycle kinase (CDK) inhibitor, has remarkably reduced the up-regulated cell cycle proteins and then decreased neuronal cell death, astroglial proliferation, and accumulation of CSPGs. More importantly, the treatment with olomoucine has also increased expression of growth-associated proteins-43, reduced cavity formation, and improved functional deficits. We consider that suppressing astroglial cell cycle in acute SCIs is beneficial to axonal growth. In the future, therapeutic strategies can be designed to achieve efficient axonal regeneration and functional compensation after traumatic CNS injury.

Analysis of Variance↗
PubMed2006

Microarray-based long-term detection of genes differentially expressed after cortical spreading depression.

Spreading depression (SD) is a slowly propagating wave of neuronal depolarization altering ion homeostasis, blood flow and energy metabolism without causing irreversible damage of the tissue. As SD has been implicated in several neurological diseases including migraine and stroke, understanding these disorders requires systematic knowledge of the processes modified by SD. Thus, we induced repetitive SD in the rat cerebral cortex by topical application of 3 m KCl for approximately 2 h and evaluated the kinetics of SD-induced changes in cortical gene expression for up to 30 days using Affymetrix RAE230A arrays. The temporal profile showed a rapid expression of immediate early genes, genes associated with inflammation, metabolism, stress and DNA repair, ion transport, and genes that play a role in growth/differentiation. Stress-response genes could still be detected after 24 h. At this time, induced genes were mainly related to the cell membrane and adhesion, or to the cytoskeleton. A subset of genes was still affected even 30 days after SD. Real-time polymerase chain reactions and immunohistochemistry confirmed the microarray results for several of the transcripts. Our findings demonstrate a temporal pattern of gene expression which might promote tissue remodeling and cortical plasticity, and might probably account for the mediation of neuronal tolerance towards subsequent ischemia.

Animals↗
PubMed2005

Proliferative response of distinct hippocampal progenitor cell populations after cortical infarcts in the adult brain.

Precursor cells in the adult dentate gyrus are a heterogeneous population. Astrocytic cell types with radial glia-like morphology and low proliferative activity have been distinguished from highly dividing subtypes expressing early neuronal properties. Recent evidence indicates that physiological stimuli predominantly increased proliferation of non-astrocytic cell types whereas radial glia-like precursors remained quiescent. We here analyzed the proliferative response of precursor cell subtypes under pathophysiological conditions in a model of photochemical cortical infarcts. Using transgenic pNestin-GFP mice and single intraperitoneal injections of 5-bromo-2-deoxyuridine 4 h after surgery, immunocytochemical analysis revealed a differential activation of the distinct subpopulations within 72 h after the infarct. The stimulation was most prominent in radial glia-like precursor cells but also non-astrocytic precursors with early neuronal phenotypes were activated. The present study indicates that the proliferative response of precursor cell subpopulations in the subgranular zone might differ under physiological and pathophysiological conditions.

Animals↗
PubMed2005

1alpha,25-dihydroxy-vitamin D3 in combination with 17beta-estradiol lowers the cortical expression of heat shock protein-27 following experimentally induced focal cortical ischemia in rats.

1alpha,25-(OH)(2)-vitamin-D(3) (1,25-D(3)) and 17beta-estradiol are both known to act neuroprotective in certain experimental in vitro and in vivo settings. We studied the effects of 1,25-D(3) or 17beta-estradiol or their combined application on heat shock protein-27 (HSP-27) distribution after focal cortical ischemia using the photothrombosis model. HSP-27 is a well-established marker of the cerebral oxidative stress response and a potent inhibitor of apoptosis. Lesioned rats were injected i.p. one hour after injury with either 1 microg 1,25-D(3)/kg or 7 microg 17beta-estradiol/kg or a combination of both steroids. Groups of non-lesioned steroid-treated rats and lesioned, solvent-treated rats served as controls. Treatment with both steroids did not affect the size of the lesion. In addition, 17beta-estradiol resulted in significant reduction of HSP-27 induction, whereas the combination of 1,25-D(3)+17beta-estradiol resulted in a highly significant reduction of HSP-27 within the infracted cerebral cortex, indicating that both steroids act synergistically in a protective manner.

Animals↗
PubMed2005

Motor improvements after focal cortical ischemia in adult rats are mediated by compensatory mechanisms.

Initial functional impairments after cerebral ischemia often improve considerably during the early period after the insult. Although pathological changes associated with post-lesion improvements have been widely investigated, it has not been resolved whether behavioral improvement represents true restoration of function (recovery) or development of new strategies (compensation). This study investigated whether early motor improvements after focal cerebral ischemia reflect recovery or compensation. Adult female Wistar rats were trained to retrieve food pellets in a skilled reaching task prior to receiving a unilateral cortical infarction induced by photothrombosis in forelimb motor cortex. Animals were continuously tested in the reaching task up to 3 weeks after lesion. The end point measures revealed that reaching success rates remained at pre-lesion levels, however, qualitative analysis of reaching movements indicated permanent changes in forelimb movement patterns. Similar observations were made in a skilled walking task and a test for forelimb asymmetry. These data indicate that lesion animals adopted alternative movement strategies in order to successfully perform the tasks. The changes in postoperative performance were compared to anatomical data in individual animals. The finding that reaching success was not related to lesion size supports the idea that the degree of adaptive behavior after cortical ischemia depends on plastic properties of the remaining intact tissue.

Animals↗
PubMed2005

Long-term effects of sequential cortical infarcts on scar size, brain volume and cognitive function.

Focal ischemia induces long-term pathophysiological consequences in widespread brain areas. Here we analyzed long-term effects of sequential cortical lesions on brain volume and cognitive function. Rats received either single photothrombotic lesions in the forelimb sensorimotor cortex (SL) or two lesions in sequence either immediately (DL0), 2 days (DL2), 7 days (DL7), or 10 days (DL10) after the first surgery in the homotopic contralateral area. Infarct and global brain volume were measured 7 days (SL and DL2 groups) and one month (all groups) after the last period of ischemia. In the weeks following a stroke, the single lesion shrank considerably. This shrinkage was accentuated by a further lesion received either earlier or later. Thirty-one days after obtaining the second lesion, the lesion scars on both sides had a mean volume of 5.8 +/- 2.3 mm3 in DL2 as compared to 8.5 +/- 3.5 mm3 in SL-animals. In addition, there was a super-additive loss of residual brain volume by 2.2-8.0% in each hemisphere in animals with sequential lesions. In the watermaze, this loss of brain volume corresponded to a slight but significant impairment in performance. The present study revealed a complex interaction of lesions in animals with sequential strokes associated with global reduction of brain volume and cognitive impairment indicating degenerative processes beyond the lesions itself.

Animals↗
PubMed2005

Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary-adrenal axis.

Synthetic glucocorticoids are administered to pregnant women in premature labour to accelerate fetal lung maturation at a time when fetal cerebrovascular and endocrine systems are maturing. Exposure to glucocorticoids at 0.8-0.9 of gestation increases peripheral and cerebrovascular resistance (CVR) in fetal sheep. We examined whether the increase of CVR and its adverse effect on cerebral blood flow (CBF) depend on the current level of maturation of the pituitary-adrenal axis and the cerebrovascular system. Using fluorescent microspheres, regional CBF was measured in 11 brain regions before and 24 h and 48 h after the start of 3.3 microg kg(-1) h(-1) betamethasone (n = 8) or vehicle (n = 7) infusions to fetal sheep at 0.73 of gestation. Hypercapnic challenges were performed before and 24 h after the onset of betamethasone exposure to examine betamethasone effects on cerebrovascular reactivity. Betamethasone exposure decreased CBF by approximately 40% in all brain regions after 24 h of infusion (P < 0.05). The decline in CBF was mediated by a CVR increase of 111 +/- 16% in the cerebral cortex and 129 +/- 29% in subcortical regions (P < 0.05). Hypercapnic cerebral vasodilatation and associated increase in CBF were blunted (P < 0.05). Fetal CBF recovered after 48 h of betamethasone administration. There were no differences in glucocorticoid induced CBF and CVR changes compared with our previous findings at 0.87 of gestation. We conclude that the cerebrovascular effects of antenatal glucocorticoids are independent of cerebrovascular maturation and preparturient increase in activity of the fetal pituitary-adrenal axis.

Animals↗
PubMed2005

Perception of phrase structure in music.

Neither music nor spoken language form uniform auditory streams, rather, they are structured into phrases. For the perception of such structures, the detection of phrase boundaries is crucial. We discovered electroencephalography (EEG) and magnetoencephalography (MEG) correlates for the perception of phrase boundaries in music. In EEG, this process was marked by a positive wave approximately between 500 and 600 ms after the offset of a phrase boundary with a centroparietal maximum. In MEG, we found major activity in an even broader time window (400-700 ms). Source localization revealed that likely candidates for the generation of the observed effects are structures in the limbic system, including anterior and posterior cingulate as well as posterior mediotemporal cortex. The timing and topography of the EEG effect bear some resemblance to a positive shift (closure positive shift, CPS) found for prosodic phrase boundaries during speech perception in an earlier study, suggesting that the underlying processes might be related. Because the brain structures, which possibly underlie the observed effects, are known to be involved in memory and attention processes, we suggest that the CPS may not reflect the detection of the phrase boundary as such, but those memory and attention related processes that are necessary to guide the attention focus from one phrase to the next, thereby closing the former and opening up the next phrase.

Adult↗
PubMed2005

Optical imaging of epileptiform activity in experimentally induced cortical malformations.

Electrophysiological studies of human cortical dysplasia and rodent models revealed widespread hyperexcitability in the malformation itself as well as in its vicinity. We here analyzed the initiation of paroxysmal epileptiform activity using optical imaging of neuronal activity in rats with cortical malformations induced by neonatal freeze lesions. Brain slice preparations were incubated with the voltage-sensitive dye RH795 and neuronal activity was monitored using a fast-imaging photodiode array combined with standard field potential recordings. Spontaneous paroxysmal epileptiform activity emerged in all slices from animals with cortical malformations and sham-operated controls 20-40 min after omission of extracellular Mg(2+). Following electrophysiological and optical recordings, slices were histochemically processed. Using this approach, the present study demonstrated that in animals with freeze-lesion-induced focal cortical malformations, paroxysmal epileptiform activity always emerged from the dysplastic cortex and then spread to adjacent areas through superficial layers. This distribution of initiation sites was significantly different to sham-operated controls in which epileptogenic foci were located in various cytoarchitectonic areas. The present study indicates that following global changes in excitability, the dysplastic cortex itself is the main initiation site of paroxysmal epileptiform activity in animals with focal cortical malformations.

Animals↗
PubMed2005

Reduced somatosensory hand representation in thalidomide-induced dysmelia as revealed by fMRI.

The concept of cerebral plasticity suggests that the hand representation in somatosensory cortex is abnormal in congenital malformation disorders. To investigate this issue we studied 11 subjects with different degrees of upper extremity dysmelia due to thalidomide embryopathy in comparison to 10 control subjects. In the affected subjects fingers are typically missing in radio-ulnar order beginning with the thumb. Haemodynamic responses to electrical stimulation of the radial-most and ulnar-most fingers were measured in each subject using functional magnetic resonance tomography. The size of the hand area in the primary somatosensory cortex was estimated by calculating the Euclidian distance between corresponding activation peaks on the lateral postcentral gyrus. The cortical somatosensory hand representation was found to be significantly smaller in dysmelic subjects as compared with the control subjects (P <0.001). The shrinkage of the hand area was not proportional to the number of missing fingers. Furthermore, the cortical representation of the ulnar fingers in the dysmelic subjects was shifted towards the cortical thumb representation of the control group. We suggest that the unproportional reduction of the hand area together with the observed shift may reflect use-dependent rather than malformation-induced reorganization of the somatosensory hand area.

Adult↗
PubMed2004

Regulation of GABA transporter mRNA and protein after photothrombotic infarct in rat brain.

Animal models of focal ischemic infarcts reveal an impaired GABAergic (gamma-aminobutyric acid) neurotransmission. GABA, the main inhibitory neurotransmitter, is primarily taken up by specific sodium-dependent transporters. As these transporters play a crucial role in maintaining levels of GABA concentration, they may be functionally involved in ischemic processes. We investigated whether the mRNA and protein expression of GAT-1, the dominant neuronal GABA transporter, is altered after cortical infarct induced by photothrombosis in Wistar rats. In situ hybridization was performed to analyze GAT-1 mRNA-positive cells in cortical brain regions and the hippocampus. The lesion dramatically raised the number of GABA transporter mRNA-expressing cells in all investigated cortical regions. Double-labeling studies with a general neuronal marker and a marker for astrocytes revealed that cells expressing GAT-1 mRNA after photothrombosis are neurons. The mRNA expression pattern of all hippocampal subfields remained unchanged. In contrast, cortical GAT-1 protein density was only slightly affected and surprisingly in the opposite way. In the primary and secondary somatosensory cortex, density values were significantly reduced. Immunoreactivity was not altered in all investigated hippocampal areas. We found a marked discordance between the increased number of cells expressing GAT-1 mRNA in the cortex and the reduced tissue GAT-1 protein content. Focal brain ischemia obviously triggers mechanisms that interfere with GAT-1 transcriptional regulation and protein synthesis or turnover.

Animals↗