Changes In Neurochemical Levels Research Articles

Decreased Taurine and Creatine in the Thalamus May Relate to Behavioral Impairments in Ethanol-Fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy.

Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease–induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.

News and views on in-vivo imaging of neurotransmission using PET and MRI.

Molecular neuroimaging with PET is an integrated tool in psychiatry research and drug-development for as long as this modality has been available, in particular for studying neurotransmission and endogenous neurotransmitter release. Pharmacologic, behavioral and other types of challenges are currently applied to induce changes in neurochemical levels that can be inferred through their effects on changes in receptor binding and related outcome measures. Based on the availability of tracers that are sensitive for measuring neurotransmitter release these experiments have focused on the brain's dopamine system, while recent developments have extended those studies to other targets such as the serotonin or choline system. With the introduction of hybrid, truly simultaneous PET/MRI systems, in-vivo imaging of the dynamics of neuroreceptor signal transmission in the brain using PET and functional MRI (fMRI) has become possible. fMRI has the ability to provide information about the effects of receptor function that are complementary to the PET measurement. Dynamic acquisition of both PET and fMRI signals enables not only an in-vivo real-time assessment of neurotransmitter or drug binding to receptors but also dynamic receptor adaptations and receptor-specific neurotransmission. While fMRI temporal resolution is comparatively fast in relation to PET, the timescale of observable biological processes is highly dependent on the kinetics of radiotracers and study design. Overall, the combination of the specificity of PET radiotracers to neuroreceptors, fMRI signal as a functional readout and integrated study design promises to expand our understanding of the location, propagation and connections of brain activity in health and disease.

Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour

Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.

Continuous Real-Time in vivo Measurement of Cerebral Nitric Oxide Supports Theoretical Predictions of an Irreversible Switching in Cerebral ROS after Sufficient Exposure to External Toxins

Mathematical models of the interactions between alphasynuclein (αS) and reactive oxygen species (ROS) predict a systematic and irreversible switching to damagingly high levels of ROS after sufficient exposure to risk factors associated with Parkinson's disease (PD). We tested this prediction by continuously monitoring real-time changes in neurochemical levels over periods of several days in animals exposed to a toxin known to cause Parkinsonian symptoms. Nitric oxide (NO) sensors were implanted in the brains of freely moving rats and the NO levels continuously recorded while the animals were exposed to paraquat (PQ) injections of various amounts and frequencies. Long-term, real-time measurement of NO in a cohort of animals showed systematic switching in levels when PQ injections of sufficient size and frequency were administered. The experimental observations of changes in NO imply a corresponding switching in endogenous ROS levels and support theoretical predictions of an irreversible change to damagingly high levels of endogenous ROS when PD risks are sufficiently large. Our current results only consider one form of PD risk, however, we are sufficiently confident in them to conclude that: (i) continuous long-term measurement of neurochemical dynamics provide a novel way to measure the temporal change and system dynamics which determine Parkinsonian damage, and (ii) the bistable feedback switching predicted by mathematical modelling seems to exist and that a deeper analysis of its characteristics would provide a way of understanding the pathogenic mechanisms that initiate Parkinsonian cell damage.

Effects of acute and chronic hyperglycemia on the neurochemical profiles in the rat brain with streptozotocin‐induced diabetes detected using in vivo1H MR spectroscopy at 9.4 T

Chronic hyperglycemia could lead to cerebral metabolic alterations and CNS injury. However, findings of metabolic alterations in poorly managed diabetes in humans and animal models are rather inconsistent. We have characterized the cerebral metabolic consequences of untreated hyperglycemia from the onset to the chronic stage in a streptozotocin-induced rat model of diabetes. In vivo ¹H magnetic resonance spectroscopy was used to measure over 20 neurochemicals longitudinally. Upon the onset of hyperglycemia (acute state), increases in brain glucose levels were accompanied by increases in osmolytes and ketone bodies, all of which remained consistently high through the chronic state of over 10 weeks of hyperglycemia. Only after over 4 weeks of hyperglycemia, the levels of other neurochemicals including N-acetylaspartate and glutathione were significantly reduced and these alterations persisted into the chronic stage. However, glucose transport was not altered in chronic hyperglycemia of over 10 weeks. When glucose levels were acutely restored to euglycemia, some neurochemical changes were irreversible, indicating the impact of prolonged uncontrolled hyperglycemia on the CNS. Furthermore, progressive changes in neurochemical levels from control to acute and chronic conditions demonstrated the utility of ¹H magnetic resonance spectroscopy as a non-invasive tool in monitoring the disease progression in diabetes.

Aging affects l-arginine and its metabolites in memory-associated brain structures at the tissue and synaptoneurosome levels

l-arginine, one of the most metabolically versatile amino acids, can be metabolized to form a number of bioactive molecules. The present study systematically investigated age-related changes in l-arginine and its metabolites in the hippocampus, parahippocampal region, and prefrontal cortex at the tissue (crude homogenates) and synaptoneurosome (a subcellular preparation enriched for synaptic material) levels. As aging leads to reduced water content in the brain, age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level were compared. There were significant differences in l-arginine, l-citrulline, l-ornithine, agmatine, putrescine, spermidine, spermine, and glutamate, but not GABA, in the CA1, CA2/3, and dentate gyrus sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, and postrhinal cortices in 24 (aged) and 4 (young) months old rats in a region-specific manner. The overall pattern of age-related changes in amino acids (l-arginine, l-citrulline, l-ornithine, glutamate, and GABA) was largely similar between homogenates and synaptoneurosomes, whereas the pattern for the amines (agmatine, putrescine, spermidine, and spermine) was quite different. Furthermore, the pattern of age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level was very similar for all 9 neurochemicals measured. These findings suggest that there are differential effects of aging on l-arginine metabolism at the tissue and synaptoneurosome levels and that the way of data normalization (tissue weight vs. protein level) has no or very minor effects on 9 neurochemicals measured.

The Effect of Swim Stress on Morphine Tolerance Development and the Possible Role of Nitric Oxide in this Process

It has been shown that stress and chronic pain could prevent the development of tolerance to morphine analgesia, which appears to be related to the activation of hypothalamus–pitutitary– adrenal (HPA) axis, activation of neuroendocrine systems and changes in neurochemical levels. Moreover, the involvement of nitric oxide (NO) in the development of tolerance to morphine analgesia has been implicated. In the present study, we have tried to investigate the effect of swim stress, as a painless kind of stress, on the development of tolerance to find out whether the inhibition of tolerance is mediated by the direct effect of pain on the pain conduction pathway, or by its stress aspect. Besides, we evaluated the probable interactions between swim stress, nitric oxide level and the development of morphine tolerance. Adult male Wistar rats, weighing 180220 g, were used in all these experiments. The experimental groups received chronic morphine (20 mg/kg, i.p), swim stress in 20oC water bath (4 min), or a combination of swim stress and chronic morphine (20 mg/kg, i.p), each for 4 days, while the first control group received saline (1 ml/kg, i.p) for 4 days. On the 5 th day, all the experimental and control groups received a single dose of morphine (10 mg/kg i.p). The second control group received saline for 5 days. The intact group received only one single dose of morphine (10 mg/kg, i.p). All the mentioned groups were subjected to tail-flick and formalin tests on the 5 th day. Other experimental groups were subjected to the assay for measuring nitrite as an indicator of NO, using the Griess method. Our results showed that co-administration of swim stress with chronic morphine prevented the development of morphine tolerance and the level of NO increased in the presence of swim stress (p<0001). The combination of morphine and swim stress significantly decreased NO production in comparison with the chronic morphine administered group (p<0.001). These data suggest that the activation of HPA axis and consequently the suppression of (NO) production induced by chronic morphine, lead to the inhibition of morphine tolerance.

Acute neurochemical changes in mouse brain following cerebral ischemia

Acute changes in neurochemical levels induced by ischemia were studied in the mouse brain. Contents of neurochemicals in the frontal, parietal and occipital cortices and hippocampus were determined immediately after 15 min of ischemia (0), and then at 15, 30, 90 and 180 min after recirculation following ischemia. These data were compared with those for sham-operated control mice. Choline (Ch) contents in ischemic animals increased by 530–630% from control levels immediately after ischemia, and returned to control levels by 90 min. Decreases in levels of norepinephrine (NE) and serotonin (5-HT) were observed during 30 min after recirculation. There were no significant changes in levels of acetylcholine (ACh) or dopamine (DA), throughout recirculation. On the other hand, DA and 5-HT metabolites (3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid) significantly increased. Thus, comprehensively investigating the various neurotransmitters will provide meaningful information regarding the disturbance of central nervous system induced by cerebrovascular disease.