Cerebral Palsy

Neuron-restrictive silencer factor (NRSF) and its isoforms are differentially regulated in rodent models of self-sustaining status epilepticus (SSSE). NRSF isoforms regulate genes associated with SSSE, including the proconvulsant tachykinins, brain-derived neurotrophic factor and multiple ion channels. NRSF isoforms may direct distinct gene expression patterns during SSSE, and the ratio of each isoform may be a causative factor in traumatic damage to the central nervous system. Here, we analysed global gene expression changes by microarray in human SK-N-AS neuroblastoma cells following the over-expression of NRSF and a truncated isoform, HZ4. We used bioinformatics software to analyse the microarray dataset and correlated these data with epilepsy candidate gene pathways. Findings were validated by reverse transcriptase-polymerase chain reaction. We demonstrated that NRSF and HZ4 direct overlapping as well as distinct gene expression patterns, and that they differentially modulated gene expression patterns associated with epilepsy. Finally, we revealed that NRSF gene expression may be modulated by the anticonvulsant, phenytoin. We have interpreted our data to reflect altered gene expression directed by NRSF that might be relevant for SSSE.

Since there are no data about the protective role of selenium (Se) against cadmium (Cd)-induced oxidative damage in early life, we studied the effect of Se supplementation on antioxidative enzyme activity and lipid peroxidation (through thiobarbituric acid reactive substances; TBARS) in suckling Wistar rats exposed to Cd. Treated animals received either Se alone for 9 days (8 mumol, i.e., 0.6 mg Se as Na(2)SeO(3) kg(-1) b.w., daily, orally; Se group), Cd alone for 5 days (8 mumol, i.e., 0.9 mg Cd as CdCl(2) kg(-1) b.w., daily, orally; Cd group), or pre-treatment with Se for 4 days and then co-treatment with Cd for the following 5 days (Se + Cd group). Our results showed that selenium supplementation, with and without Cd, increased SOD activity in the brain and kidney, but not in the liver and GSH-Px activity across all tissues compared to control rats receiving distilled water. Relative to the Cd group, Se + Cd group had higher kidney and brain SOD and GSH-Px activity (but not the liver), while in the liver caused increased and in the brain decreased TBARS level. These results suggest that Se stimulates antioxidative enzymes in immature kidney and brain of Cd-exposed rats and could protect against oxidative damage.

The adenine nucleotides ADP and ATP are probably the most important endogenous inhibitors of the mitochondrial permeability transition (MPT). We studied the inhibitory effects of adenine nucleotides on brain MPT by measuring mitochondrial swelling and Ca(2+) and cytochrome c release. We observed that in the presence of either ADP or ATP, at 250 muM, brain mitochondria accumulated more than 1 mumol Ca(2+) x mg protein(-1). ADP or ATP also prevented Ca(2+)-induced mitochondrial swelling and cytochrome c release. Interestingly, ATP lost most of its inhibitory effects on MPT when the experiments were carried out in the presence of ATP-regenerating systems. These results indicate that MPT inhibition observed in the presence of added ATP could be mainly due to hydrolysis of ATP to ADP. From mitochondrial swelling measurements, half-maximal inhibitory values (K (i)) of 4.5 and 98 muM were obtained for ADP and ATP, respectively. In addition, a delayed mitochondrial swelling sensitive to higher ADP concentrations was observed. Mitochondrial anoxia/reoxygenation did not interfere with the inhibitory effect of ADP on Ca(2+)-induced MPT, but oxidative phosphorylation markedly decreased this effect. We conclude that ADP is a potent inhibitor of brain MPT whereas ATP is a weaker inhibitor of this phenomenon. Our results suggest that ADP can have an important protective role against MPT-mediated tissue damage under conditions of brain ischemia and hypoglycemia.

Lingual dystonia, a type of focal dystonia that may be primary or secondary, is related to brain damage, neuroleptic use, neurodegenerative, metabolic, and neurodevelopmental disorders, varicella infection, and so on. However, primary lingual dystonia induced by speaking is a rare type of focal dystonia that is usually idiopathic in origin and is characterized by increased tonus of the tongue, which causes protrusion only during speaking. This report describes a 55-year-old male patient with lingual dystonia during speech. One interesting clinical feature of this case was that the speech disturbance improved while the patient vocalized a praise-like hymn in a manner that resembled singing.

Nephropathic cystinosis is a rare genetic metabolic disorder that results in accumulation of the amino acid cystine in lysosomes due to lack of a cystine-specific transporter protein. Cystine accumulates in cells throughout the body and causes progressive damage to multiple organs, including the brain. Neuromotor deficits have been qualitatively described in individuals with cystinosis. This study quantitatively examined fine-motor coordination in individuals with cystinosis. Brain magnetic resonance imaging (MRI) scans were also performed to determine whether structural changes were associated with motor deficits. Participants were 52 children and adolescents with infantile nephropathic cystinosis and 49 controls, ages 2-17 years, divided into preacademic and school-age groups. Results indicated that both the preacademic and school-age cystinosis groups performed significantly more poorly than their matched control groups on the Motor Coordination Test. Further, the level of performance was not significantly different between the preacademic and school-age groups. There were no significant differences in motor coordination scores based on MRI findings. This is the first study to document a persistent, nonprogressive, fine-motor coordination deficit in children and adolescents with cystinosis. The fact that these difficulties are present in the preschool years lends further support to the theory that cystinosis adversely affects neurological functioning early in development. The absence of a relationship between brain structural changes and motor function suggests that an alternative cause for motor dysfunction must be at work in this disorder.

Purpose The use of therapeutic hypothermia (TH) and its application in out-of-hospital cardiac arrest patients are reviewed. Summary Each year in the United States, an estimated 250,000-300,000 out-of-hospital cardiac arrests occur. Despite advances in prehospital care, the survival rate from TH is only 6-12%. In addition, survivors often have devastating consequences ranging from mild memory impairment to permanent brain damage. It is presumed that early induction of hypothermia produces an optimal effect, though benefits can still be achieved with late induction. Several methods have been devised to induce hypothermia, yet the optimal methods of cooling have not currently been determined. Major adverse effects of cooling include hemodynamic changes, cardiovascular complications, hyperglycemia, coagulopathy, increased rates of infection, fluid and electrolyte disorders, and shivering. The majority of these adverse effects can be prevented or minimized in the intensive care setting. In 2002, the use of TH-cooling the core body temperature to 32-34 degrees C-was supported by two landmark human studies, whose results led to the endorsement of TH by the American Heart Association and its increased use. The studies demonstrated that hypothermia results in favorable neurologic outcomes in patients suffering from out-of-hospital cardiac arrest due to ventricular fibrillation (VF), without increasing complications. Conclusion TH is an effective strategy for improving neurologic outcomes of patients after out-of-hospital cardiac arrest due to VF. Further studies are needed to confirm the optimal time and methods for cooling to maximize the chance of complete neurologic recovery after cardiac arrest.

The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone we found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival. Copyright © 2010. Published by Elsevier Ireland Ltd.

ABSTRACT: BACKGROUND: Neuroinflammation occurs following brain injury, including soman (GD) induced status epilepticus (SE), and may contribute to loss of neural tissue and declined behavioral function. However, little is known about this important pathological process following GD exposure. Limited transcriptional information on a small number of brain-expressed inflammatory mediators has been shown following GD-induced SE and even less information on protein upregulation has been elucidated. The purpose of this study is to further characterize the regional and temporal progression of the neuroinflammatory process following acute GD-induced SE. METHODS: The protein levels of 10 cytokines was quantified using bead multiplex immunoassays in damaged brain regions (i.e., piriform cortex, hippocampus and thalamus) up to 72 hours following seizure onset. Those factors showing significant changes were then localized to neural cells using fluorescent IHC. RESULTS: A significant concentration increase was observed in all injured brain regions for four acute phase response (APR) induction cytokines: interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Increases in these APR cytokines corresponded both temporally and regionally to areas of known seizure damage and neuronal death. Neurotoxic cytokines IL-1alpha and IL-1beta were primarily expressed by activated microglia whereas the potentially neuroprotective cytokine IL-6 was expressed by neurons and hypertrophic astrocytes. CONCLUSIONS: Increases in neurotoxic cytokines likely play an active role in the progression of GD-induced SE neuropathology though the exact role that these and other cytokines play in this process require further study.

Abstract The developing human brain can compensate for pre- and perinatally acquired focal lesions more effectively than the adult brain. The mechanisms by which this effective reorganization is achieved vary considerably between different functional systems, reflecting differences in the normal maturation of these systems. In the motor system, descending cortico-spinal motor projections have already reached their spinal target zones at the beginning of the third trimester of pregnancy, with initially bilateral projections from each hemisphere. During normal development, the ipsilateral projections are gradually withdrawn, whereas the contralateral projections persist. When, during this period, a unilateral brain lesion disrupts the cortico-spinal projections of one hemisphere, the ipsilateral projections from the contralesional hemisphere will persist. This allows the contralesional hemisphere to take over motor control over the paretic extremities. Although this mechanism of reorganization is available throughout the pre- and perinatal period, the efficacy of this ipsilateral takeover of motor functions decreases with increasing age at the time of the insult. In the somatosensory system, ascending thalamo-cortical somatosensory projections have not yet reached their cortical target zones at the beginning of the third trimester of pregnancy. Therefore, these projections can still ‘react’ to brain lesions acquired during this period, and can form ‘axonal bypasses’ around periventricular white matter lesions to reach their original cortical target areas in the postcentral gyrus. Thus, somatosensory functions can be well preserved even in cases of large periventricular lesions. In contrast, when the postcentral gyrus itself is affected, no signs for reorganization have been observed. Accordingly, somatosensory functions are often poor in these patients. Language functions can be normal even in patients with extensive early left-hemispheric brain lesions. This is achieved by language organization in the right hemisphere, which takes place in brain regions homotopic to the classical left-hemispheric language areas in normal subjects. In patients with periventricular lesions, the degree of right-hemispheric takeover of language functions correlates with the severity of structural damage to facial (and, thus, articulatory) motor projections.

The CNS can exhibit features of inflammation in response to injury, infection or disease, whereby resident cells generate inflammatory mediators, including cytokines, prostaglandins, free radicals and complement, chemokines and adhesion molecules that recruit immune cells, and activate glia and microglia. Cerebral ischaemia triggers acute inflammation, which exacerbates primary brain damage. The regulation of inflammation after stroke is multifaceted and comprises vascular effects, distinct cellular responses, apoptosis and chemotaxis. There are many cell types that are affected including neurons, astrocytes, microglia and endothelial cells, all responding to the resultant neuroinflammation in different ways. Over the past 20 years, researchers examining brain tissue at various time intervals after stroke observed the presence of inflammatory cells, neutrophils and monocytes at the site of injury, as well as the activation of endogenous glia and microglia. This review examines the involvement of these cells in the progression of neural injury and proposes that the Toll-like receptors (TLRs) are likely to be an integral component in the communication between the CNS and the periphery. This receptor system is the archetypal pathogen sensing receptor system and its presence and signalling in the brain following neural injury suggests a more diverse role. We propose that the TLR system presents excellent pharmacological targets for the design of a new generation of therapeutic agents to modulate the inflammation that accompanies neural injury.