Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl−, which is achieved by the opposing regulation of Na+–K+–Cl− cotransporter 1 (NKCC1) and K+–Cl−–cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl− concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-016-1292-z) contains supplementary material, which is available to authorized users.

A BS TRACT: Background: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD). Methods: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content). Results: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls. Conclusions: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with

No abstract

Previous multimodal magnetic resonance imaging (MRI) studies of parkinsonian syndromes have focused primarily on motor-related basal ganglia structures. The present study investigated MRI changes in non-motor-related limbic structures in 35 Parkinson's disease (PD), 16 multiple system atrophy parkinsonian subtype (MSA-P), 17 progressive supranuclear palsy (PSP), and 37 control subjects. Mean diffusivity (MD), fractional anisotropy (FA), transverse relaxation rate (R2*), quantitative susceptibility mapping, and volume measurements were obtained from the amygdala, hippocampus, and nucleus accumbens (NAc) to examine differences between groups, and to test for associations with clinical scores. Compared to controls, PD subjects had lower NAc volume; MSA-P subjects had higher NAc R2*; PSP subjects had higher amygdala and hippocampus MD, and lower hippocampus FA (ps ≤ 0.008). Among parkinsonian subjects, amygdala and hippocampus MD associated positively with Unified Parkinson's Disease Rating Scale (UPDRS)