Cerebral Palsy

Alcohol-induced alterations of cerebellar function cause motor coordination impairments that are responsible for millions of injuries and deaths worldwide. Cognitive deficits associated with alcoholism are also a consequence of cerebellar dysfunction. The mechanisms responsible for these effects of ethanol are poorly understood. Recent studies have identified neurons in the input layer of the cerebellar cortex as important ethanol targets. In this layer, granule cells (GrCs) receive the majority of sensory inputs to the cerebellum through the mossy fibers. Information flow at these neurons is gated by a specialized pacemaker interneuron known as the Golgi cell, which provides divergent GABAergic input to thousands of GrCs. In vivo electrophysiological experiments have previously shown that acute ethanol exposure abolishes GrC responsiveness to sensory inputs carried by mossy fibers. Slice electrophysiological studies suggest that ethanol causes this effect by potentiating GABAergic transmission at Golgi cell-to-GrC synapses through an increase in Golgi cell excitability. Using patch-clamp electrophysiological techniques in cerebellar slices and computer modeling, we show here that ethanol excites Golgi cells by inhibiting the Na(+)/K(+) ATPase. Voltage-clamp recordings of Na(+)/K(+) ATPase currents indicated that ethanol partially inhibits this pump and this effect could be mimicked by low concentrations of ouabain. Partial inhibition of Na(+)/K(+) ATPase function in a computer model of the Golgi cell reproduced these experimental findings. These results establish a novel mechanism of action of ethanol on neuronal excitability, which likely has a role in ethanol-induced cerebellar dysfunction and may also contribute to neuronal functional alterations in other brain regions.Neuropsychopharmacology advance online publication, 2 June 2010; doi:10.1038/npp.2010.76.

Vascular toxicity is important for understanding the neurotoxicity of methylmercury, because microvessels strongly influence the construction of microenvironment around neurons. Previously, we found that low density-human brain microvascular pericytes are markedly susceptible to methylmercury cytotoxicity due to high expression levels of the L-type amino acid transporter 1 (LAT-1) that transports methylmercury into the cells. Although LAT-1 can be, in general, highly expressed in sparse cells that require amino acids for growth, we found that human brain microvascular endothelial cells, regardless of cell density, were resistant to methylmercury cytotoxicity. To investigate the mechanisms underlying this resistance, we exposed the endothelial cells at low and high cell densities to methylmercury and determined the extent of nonspecific cell damage, intracellular accumulation of methylmercury, expression of LAT-1 and LAT-2 mRNAs, and intracellular expression of reduced glutathione and metallothionein. These experiments indicate that sparse endothelial cells intracellularly accumulate more methylmercury via the highly expressed LAT-1, but are resistant to methylmercury cytotoxicity by higher expression of the protective sulfhydryl peptides, namely, reduced glutathione and metallothionein. It is suggested that both nonspecific and functional damage is caused in pericytes, whereas functional abnormalities rather than nonspecific damage may occur to a greater extent in the endothelial cells in the brain microvessels exposed to methylmercury. The previous and present data also suggest that methylmercury exhibits toxicity in endothelial cells in a manner different from that in pericytes in the brain microvessels.

Glutamate-induced excitotoxicity has been implicated in the etiology of stroke, epilepsy, and neurodegenerative diseases. NMDA receptors (NMDARs) play a pivotal role in excitotoxic injury; however, clinical trials testing NMDAR antagonists as neuroprotectants have been discouraging. The development of novel neuroprotectant molecules is being vigorously pursued. Here, we report that downstream regulatory element antagonist modulator (DREAM) significantly inhibits surface expression of NMDARs and NMDAR-mediated current. Overexpression of DREAM showed neuroprotection against excitotoxic neuronal injury, whereas knockdown of DREAM enhanced NMDA-induced toxicity. DREAM could directly bind to the C0 domain of the NR1 subunit. Although DREAM contains multiple binding sites for the NR1 subunit, residues 21-40 of the N terminus are the main binding site for the NR1 subunit. Thus, 21-40 residues might relieve the autoinhibition conferred by residues 1-50 and derepress the DREAM core domain by a competitive mechanism. Intriguingly, the cell-permeable TAT-21-40 peptide, constructed according to the critical binding site of DREAM to the NR1 subunit, inhibits NMDAR-mediated currents in primary cultured hippocampal neurons and has a neuroprotective effect on in vitro neuronal excitotoxic injury and in vivo ischemic brain damage. Moreover, both pretreatment and posttreatment of TAT-21-40 is effective against excitotoxicity. In summary, this work reveals a novel, negative regulator of NMDARs and provides an attractive candidate for the treatment of excitotoxicity-related disease.

The functions of the lower urinary tract (LUT) are dependent upon neural circuits located in the brain, spinal cord and peripheral ganglia, organized as on-off switching circuits to regulate storage and periodic elimination of urine. Damage or disease in any of the nervous pathways controlling the lower urinary tract can cause impairment of normal bladder function. Nociceptive information from different organs are delivered to the dorsal horn of the spinal cord where a network of descending pathways projecting from cerebral structures either suppress or potentiate the passage of the nociceptive messages to the brain. Some of the central structures involved in the micturition reflexes and pain modulation are common, e.g. nucleus raphe magnum, nucleus locus coeruleus alpha, periacqueductal grey, etc. Functionally, however, their effects may be similar or contrasting. The central micturition reflexes and descending control pathways of pain also utilize common transmitters and transmitter systems with similar or different effects on micturition and pain, suggesting a certain degree of overlapping between these systems. All these findings have provided a rich palette of novel mechanisms potentially available for the improved control of LUT and pain. The proliferation of potential analgesic drug targets for the therapeutic manipulation of descending control of pain is testimony of a more (in comparison with LUT) intensive research programme in this field. Nevertheless, with the exception of parenteral administration of micro-opioids and spinal application of alpha(2)-AR agonists, no other approach has been extensively validated in the clinic. Great effort should be invested in the characterization of central mechanisms controlling the micturition reflexes, although the possibility to find novel drugs for micturition disorders with central effect appears to be problematic.

BACKGROUND: The aim of our study was to evaluate the results and effectiveness of early decompressive craniectomy in the treatment of severe traumatic brain injury. METHODS: We conducted a prospective study to investigate the clinical and radiological results of early unilateral decompressive craniectomy in 33 patients with severe traumatic brain injury. The mean area of the craniectomy, potential expansion volume of the decompressed brain, and distance between the lower border of the craniectomy and the temporal cranial base were calculated from computed tomography scans. Clinical results were analyzed with modified Rankin Scale (mRS). RESULTS: Time to surgery after trauma was 3.1+/-1.9 hours. There was a direct proportionality correlation between the area of the craniectomy and the calculated volume (p<0.0001). There was also a significant correlation between the state of the mesencephalic cisterns after craniectomy and the distance of the craniectomy to the base of the cranium (p<0.01). Assessment of overall one-year clinical outcome demonstrated favorable outcome (mRS 0-3) in 48.5% of patients. CONCLUSION: The high overall morbidity and mortality rates demonstrated in our group despite the performance of early decompressive procedures reflect the severity of the underlying injuries.

The long-term neuroimaging correlates of clinical recovery have not been described in anti-N-methyl-D: -aspartate receptor (NMDAR) encephalitis. The aim of the study is to evaluate the long-term outcome of brain atrophy in anti-NMDAR encephalitis. Patients were two women (ages 17 and 33 years) with severe anti-NMDAR encephalitis resulting in decreased level of consciousness, autonomic instability, hypoventilation, and dyskinesias requiring continuous infusion of anesthetic agents for 6-7 months. Brain MRI and cerebral blood flow SPECT obtained at the time of maximal neurological disability were compared with similar studies obtained 5-7 years later. Both patients were hospitalized for 9-14 months and developed frontotemporal atrophy and hypoperfusion 7-12 months after symptom presentation. In both patients, cognitive functions gradually improved over the next 4-5 years. Comparative neuroimaging studies obtained 5-7 years after symptom presentation showed dramatic improvement of the atrophy and frontotemporal hypoperfusion. The severe and protracted deficits and the frontotemporal atrophy that occur in some patients with anti-NMDAR encephalitis are potentially reversible. This suggests that a functional rather than a structural neuronal damage underlies the pathogenesis of this disorder.

Toscana virus (TOSV) is an arthropod-borne virus which is transmitted to humans by Phlebotomus spp sandflies. Infection is the cause of brain injuries, such as aseptic meningitis and meningoencephalitis, in Italy mainly during the summer. More recently some unusual clinical manifestations due to TOSV with severe sequelae, such as ischemic complications and hydrocephalus, have been reported. TOSV represents an important emerging pathogen and its presence is being investigated in several European countries on the Mediterranean basin, including Italy, France, Spain, Portugal and Cyprus. Phylogenetic analysis has distinguished two genotypes of TOSV, A and B; the first is circulating mainly in Italy and the second in Spain, indicating a different geographic distribution possibly related to the vector. This distribution, evolving with the climate, globalization and habitat modification, has implications for the epidemiology of TOSV.

For a retrospective observational investigation based on real clinical practice of relative efficacy of valpoic acid (VPA), carbamazepine (CBZ) and topiramate (TPM) we have selected 205 patient with age of seizure onset before 16 years with a undoubted diagnosis of medial temporal lobe epilepsy, who had received treatment according to ILAE recommendations, and observation time since the last treatment change was from 2 to 5 years. The groups of patient receiving CBZ, VPA small i, Cyrillic TPM did not differ significantly in presenting unfavorable prognostic factors and dose regimes that allowed to conduct direct comparison of efficacy of the investigated drugs. Efficacy of VPA in children with medial temporal lobe epilepsy was higher compared with CBZ (79% vs 61%; p</=0,05) and TPM (79% vs 53%; p</=0.001). CBZ caused seizure aggravation more frequently than VPA (10% vs 1%; p</=0,001). In case of presence of clinico-electroencephalografic signs of significant organic brain damage and in patient with seizure onset before age of 1 year CBZ was not effective while TPM showed efficacy of 20%, (p</=0,05) and VPA was the most effective drug in this case (50%; p</=0,001). In case of focal cortical dysphasia or the states after periventricular leucomalacia the efficacy of CBZ was lower than VPA (0% for CBZ vs 89% for VPA – p</=0,01 and 40% for CBZ vs 77% for VPA – p</=0,05, respectively) and TPM (0% for CBZ vs 100% for TPM – p</=0,01 and 40% for CBZ vs 100% for TPM – p</=0,01, respectively). In MRI-negative cases VPA was most effective (90% vs 53% for CBZ; p</=0,001 and 67% for TPM; p</=0,05). Efficacy CBZ reduces proportionally the number of previously used antiepileptic drugs (AEDs) (52% as a first AED vs 17% as a second AED; p</=0,01), this tendency is noted also for TPM but in less extend (80% vs 46%, respectively p</=0,05), but not for VPA (77% vs 75%; p>0,05, respectively). Adverse effects were more frequent during treatment with CBZ, than VPA (19% vs 5%; p</=0,001) and TPM (19% vs 9%; p</=0,05).

BACKGROUND/OBJECTIVES:: Ischemia-reperfusion (IR) is the restoration of blood flow to a tissue that was formerly deficient of blood flow. Tissue damage after IR is considered an IR injury (IRI). During IR, there is an increased level of cytosolic calcium ([Ca]i) due to the release of calcium from mitochondrial, sarcoendoplasmic reticulum, and nuclear organelles. Dantrolene sodium (dantrolene) is a 1-[[[5-(4-nitrophenol)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt with a nonspecific mechanism, inhibiting organelle release of Ca into the cytosol. This work reviews the outcomes of administering dantrolene in brain, heart, liver, and kidney animal models of IRI. METHODS:: An extensive PubMed, MEDLINE, and MEDLAR literature review during the last 30 years on the effect of dantrolene in IRI in animal models was analyzed to determine the clinical implications of this important study. Particular attention was given to dantrolene in heart, brain, liver, and kidney IRI. RESULTS:: Heart: Nine studies of heart IRI were reviewed and include an in vivo dog model (n = 1), in vivo rabbit model (n = 1), isolated dog myocardial fibers (n = 1), and isolated rat hearts (n = 6). Four studies showed decreased infarct size and increased cardiac function after IRI. One in vivo rabbit study found no difference in infarct size or cardiac function after IRI versus controls. Dantrolene may be protective or inductive of post-IRI arrhythmias depending on preestablished myocyte cycling times. Brain: Nine studies of brain IRI were reviewed and include an in vivo dog model (n = 1), in vivo gerbil model (n = 2), and in vivo rat models (n = 6). Dantrolene shows protective decreases in apoptotic markers in 6 studies, but it shows no effect on the necrotic core and mixed effects on reduction of infarct volume. One study found increased mortality in the dantrolene group. Liver: One study of in vivo rat liver IRI found that dantrolene decreased liver function tests, tissue necrosis factor alpha, tissue necrosis, and increased interleukin 10. Kidney: One study of in vivo rat kidney IRI showed that dantrolene had no effect. CONCLUSIONS:: Dantrolene shows protective effects in animal models of heart, brain, and potentially liver IRI, reinforcing the importance of calcium homeostasis during IRI. Variations of dose, timing of administration, route of administration, and outcomes between studies make definitive conclusions difficult. The nonspecific mechanism of action of dantrolene may also account for the variation among studies. Lack of studies in the liver and kidney makes any consensus in these organs premature, and thus, emphasis for this review was put on studies of the heart and brain.

A blood coagulation factor thrombin that leaks from ruptured vessels initiates brain tissue damage after intracerebral hemorrhage. We have recently shown that mitogen-activated protein kinases (MAPKs) activated by thrombin exacerbate hemorrhagic brain injury via supporting survival of neuropathic microglia. Here we investigated whether induction of heme oxygenase (HO)-1 is involved in these events. Zinc protoporphyrin IX (ZnPP IX), a HO-1 inhibitor, attenuated thrombin-induced injury of cortical cells in a concentration-dependent manner (0.3 – 3 muM), and tended to inhibit shrinkage of the striatal tissue at 0.3 muM. HO-1 expression was induced by thrombin in microglia and astrocytes in both the cortex and the striatum. The increase of HO-1 protein was suppressed by a p38 MAPK inhibitor SB203580, and early activation of p38 MAPK after thrombin treatment was observed in neurons and microglia in the striatum. Notably, concomitant application of a low concentration (0.3 muM) of ZnPP IX with thrombin induced apoptotic cell death in striatal microglia and significantly decreased the number of activated microglia in the striatal region. On the other hand, a carbon monoxide releaser reversed the protective effect of ZnPP IX on thrombin-induced injury of cortical cells. Overall, these results suggest that p38 MAPK-dependent induction of HO-1 supports survival of striatal microglia during thrombin insults. Thrombin-induced cortical injury also may be regulated by expression of HO-1 and resultant production of heme degradation products such as carbon monoxide. Copyright © 2010. Published by Elsevier B.V.