Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

The blood-central nervous system barriers actively control immune cell entry into the central nervous system

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines

In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the highly specialized endothelial blood-brain barrier (BBB) and gain access to the central nervous system (CNS). It is well established that leukocyte recruitment across this vascular bed is unique due to the predominant involvement of alpha4-integrins in mediating the initial contact to as well as firm adhesion with the endothelium. In contrast, the involvement of the selectins, L-selectin, E- and P-selectin and their respective carbohydrate ligands such as P-selectin glycoprotein (PSGL)-1 in this process has been controversially discussed. Intravital microscopic analysis of immune cell interaction with superficial brain vessels demonstrates a role for E- and P-selectin and their common ligand PSGL-1 in lymphocyte rolling. However, E- and P-selectin-deficient SJL- or C57Bl/6 mice or PSGL-1-deficient C57Bl/6 mice develop EAE indistinguishable from wild-type mice. Considering these apparently discrepant observations, it needs to be discussed whether the molecular mechanisms involved in leukocyte trafficking across superficial brain vessels are irrelevant for EAE pathogenesis or whether the therapeutic efficacy of targeting alpha4-integrins in EAE is truly dependent on the inhibition of leukocyte trafficking across the BBB.

The ventro-medial prefrontal cortex: a major link between the autonomic nervous system, regulation of emotion, and stress reactivity?

ABSTRACT: Recent progress in neuroscience revealed diverse regions of the CNS which moderate autonomic and affective responses. The ventro-medial prefrontal cortex (vmPFC) plays a key role in these regulations. There is evidence that vmPFC activity is associated with cardiovascular changes during a motor task that are mediated by parasympathetic activity. Moreover, vmPFC activity makes important contributions to regulations of affective and stressful situations.This review selectively summarizes literature in which vmPFC activation was studied in healthy subjects as well as in patients with affective disorders. The reviewed literature suggests that vmPFC activity plays a pivotal role in biopsychosocial processes of disease. Activity in the vmPFC might link affective disorders, stressful environmental conditions, and immune function.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Targeting Myc in pediatric malignancies of the central and peripheral nervous system

Myc family genes are often deregulated in embryonal tumors of childhood including medulloblastoma and neuroblastoma and are frequently associated with aggressive, poorly differentiated tumors. The Myc protein is a transcription factor that regulates a variety of cellular processes including cell growth and proliferation, cell cycle progression, differentiation, apoptosis, and cell motility. Potential strategies that either inhibit the proliferation-promoting effect of Myc and/or activate its pro-apoptotic function are presently being explored. In this review, we will give an overview of Myc activation in embryonal tumors and discuss current strategies aimed at targeting Myc for cancer treatment.

Role of the Central Nervous System in the Regulation of Pregnancy, Parturition and Lactation in Beef Heifers

Progesterone secretion is crucial for maintaining pregnancy to parturition in mammalian species, and in cattle the corpus luteum is the primary source of this hormone. This study determined the roles of prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) in the luteotropic process in beef heifers hypophyseal stalk-transected (HST, n = 7) or sham operated on (SOC, n = 9) during midgestation. The main finding was that endogenous PRL and GH maintained progesterone secretion in HST heifers similar to that in SOC throughout pregnancy. Serum PRL averaged 37 vs 187 and GH 2 vs 4 ng/ml in HST compared with SOC, whereas LH abruptly decreased to undetectable levels after HST compared with a modest 0A4 ng/ml in SOC heifers. The second finding was that parturition and lactation occurred in HST heifers with calf delivery induced to occur at the same time as SOC. Milk production in HST animals was severely limited, and postpartum estrus obliterated compared with SOC. The suckling stimulus sustained milk ejection in HST heifers in spite of diminished PRL and GH secretion. The results suggest that PRL, GH and possibly placental lactogen are luteotropic during pregnancy in cattle.

Role of the Central Nervous System in the Regulation of Pregnancy, Parturition and Lactation in Beef Heifers

Progesterone secretion is crucial for maintaining pregnancy to parturition in mammalian species, and in cattle the corpus luteum is the primary source of this hormone. This study determined the roles of prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) in the luteotropic process in beef heifers hypophyseal stalk-transected (HST, n = 7) or sham operated on (SOC, n = 9) during midgestation. The main finding was that endogenous PRL and GH maintained progesterone secretion in HST heifers similar to that in SOC throughout pregnancy. Serum PRL averaged 37 vs. 187 and GH 2 vs. 4 ng/ml in HST compared with SOC, whereas LH abruptly decreased to undetectable levels after HST compared with a modest 0.4 ng/ml in SOC heifers. The second finding was that parturition and lactation occurred in HST heifers with calf delivery induced to occur at the same time as SOC. Milk production in HST animals was severely limited and postpartum estrus obliterated compared with SOC. The suckling stimulus sustained milk ejection in HST heifers in spite of diminished PRL and GH secretion. The results suggest that PRL, GH, and possibly placental lactogen are luteotropic during pregnancy in cattle.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

The Houston Academy of Medicine--Texas Medical Center Library management information system.

A management information system (MIS) provides a means for collecting, reporting, and analyzing data from all segments of an organization. Such systems are common in business but rare in libraries. The Houston Academy of Medicine-Texas Medical Center Library developed an MIS that operates on a system of networked IBM PCs and Paradox, a commercial database software package. The data collected in the system include monthly reports, client profile information, and data collected at the time of service requests. The MIS assists with enforcement of library policies, ensures that correct information is recorded, and provides reports for library managers. It also can be used to help answer a variety of ad hoc questions. Future plans call for the development of an MIS that could be adapted to other libraries' needs, and a decision-support interface that would facilitate access to the data contained in the MIS databases.

Application of real-time fluorescent PCR for quantitative assessment of Neospora caninum infections in organotypic slice cultures of rat central nervous system tissue

The previously described Nc5-specific PCR test for the diagnosis of Neospora caninum infections was used to develop a quantitative PCR assay which allows the determination of infection intensities within different experimental and diagnostic sample groups. The quantitative PCR was performed by using a dual fluorescent hybridization probe system and the LightCycler Instrument for online detection of amplified DNA. This assay was successfully applied for demonstrating the parasite proliferation kinetics in organotypic slice cultures of rat brain which were infected in vitro with N. caninum tachyzoites. This PCR-based method of parasite quantitation with organotypic brain tissue samples can be regarded as a novel ex vivo approach for exploring different aspects of cerebral N. caninum infection.

Potential role of CYP2D6 in the central nervous system

1. Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest that CYP2D6 may have a function in the central nervous system. 2. To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type (WT) C57BL/6 mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including the CYP2D6 gene and 5'- and 3'-flanking sequences. 3. Human CYP2D6 was expressed not only in the liver but also in the brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice, either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of L-carnitine, acetyl-L-carnitine, pantothenic acid, 2'-deoxycytidine diphosphate (dCDP), anandamide, N-acetylglucosaminylamine and a down-regulation of stearoyl-L-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety. 4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function.