New aspects of cholesterol in the central nervous system

Cholesterol is a multifacetted molecule, which serves as essential membrane component, as cofactor for signaling molecules and as precursor for steroid hormones. Despite intense research on the diverse aspects of cholesterol, the role of cholesterol in the nervous system is still little understood. Our recent studies on primary cultures of highly purified neurons from the rodent central nervous system (CNS) suggest that during development, neurons reduce or even abandon cholesterol synthesis and import cholesterol from astrocytes via lipoproteins. Neurons use the glia-derived cholesterol to form numerous and efficient synapses. This provokes new ideas about the role of astrocytes as cholesterol producers and about the function of cholesterol in the CNS and its involvement in neurodegenerative diseases.     

DNA synthesis in the embryonic chick central nervous system

Summary DNA synthesis has been studied in chick embryos age between 2 and 10 days, using labelling with tritiated thymidine and stripping film autoradiography. The observations made earlier in the literature on a premitotic migration of the nuclei in the neural epithelium have been verified. In young stages (before day 7) peripherally migrated cells do not synthesize DNA, but after day 7 such a synthesis occurs. In spite of this, few mitoses are seen. The interpretation of these facts is discussed.The costs of this investigation were defrayed by grants from the Swedish Medical Research Council, the Medical Faculty of Lund, and the Royal Physiographic Society.     

Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system

The nuclear oxysterol receptors liver X receptor-alpha [LXRalpha (NR1H3)] and LXRbeta (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer's and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.     

"2-6-11" motif in heat shock protein 60 and central nervous system antigens: a preliminary study in multiple sclerosis patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with unknown etiology and pathogenesis. A local autoimmune process involving activation of autoreactive T cells against CNS protein components is likely crucial in the development of MS lesions. Myelin-reactive T cells are believed to be primed in the periphery during infections by antigens of bacterial or viral origin via molecular mimicry, a postulated mechanism that might account for the trigger of an autoimmune response on the basis of sequence homology between foreign and self determinants. Immune responses to heat shock proteins (hsp) have been implicated in the initiation or progression of a number of autoimmune diseases. Hsp may function as immunodominant targets during the immune response evoked by pathogens, and theoretically a cross-reactive response to sequences shared by these immunogens and autoantigens in the CNS may contribute to the pathogenesis of MS. We examined the immune response of peripheral blood mononuclear cells (PBMNc) from MS patients and healthy subjects elicited by peptides derived from hsp60 containing a common structural motif ("2-6-11" motif) already described, which is also present in CNS putative antigens. This structural pattern consists of an apolar residue or Lys at position 2, Pro always at position 6, and Glu, Asp or Lys at residue 11. Results reported here are indicative of maturation of peripheral blood monocytes towards a differentiated CD14(+)CD16(+)DR(+) cell and release of pro-inflammatory cytokines consistent with a Th1-like pattern. These are typical features exhibited by immune cells implicated in autoimmune responses.     

Bombesin affects the central nervous system to produce hyperglycemia in rats

Bombesin, a peptide isolated from frog skin, acts through the central nervous system to produce hyperglycemia in rats. Bombesin induced hyperglycemia may be mediated via adrenomedullary-catecholamine induced changes in insulin and glucagon secretion resulting in enhanced hepatic glucose output.     

Neuroprotective effect of mexiletine in the central nervous system of diabetic rats

Both experimental and clinical studies suggests that oxidative stress plays an important role in the pathogenesis of diabetes mellitus type 1 and type 2. Hyperglycaemia leads to free radical generation and causes neural degeneration. In the present study we investigated the possible neuroprotective effect of mexiletine against streptozotocin-induced hyperglycaemia in the rat brain and spinal cord.30 adult male Wistar rats were divided into three groups: control, diabetic, and diabetic-mexiletine treated group. Diabetes mellitus was induced by a single injection of streptozotocin (60 mg/kg body weight). Mexiletine (50 mg/kg) was injected intraperitoneally every day for six weeks. After 6 weeks the brain, brain stem and cervical spinal cord of the rats were removed and the hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for biochemical analysis (the level of Malondialdehide [MDA], Nitric Oxide [NO], Reduced Glutathione [GSH], and Xanthine Oxidase [XO] activity). MDA, XO and NO levels in the hippocampus, cortex, cerebellum, brain stem and spinal cord of the diabetic group increased significantly, when compared with control and mexiletine groups (P < 0.05). GSH levels in the hippocampus, cortex, cerebellum, brain stem and spinal cord of the diabetic group decreased significantly when compared with control and mexiletine groups (P < 0.05).This study demonstrates that mexiletine protects the neuronal tissue against the diabetic oxidative damage.     

Emergence in the central nervous system

“Emergence” is an idea that has received much attention in consciousness literature, but it is difficult to find characterizations of that concept which are both specific and useful. I will precisely define and characterize a type of epistemic (“weak”) emergence and show that it is a property of some neural circuits throughout the CNS, on micro-, meso- and macroscopic levels. I will argue that possession of this property can result in profoundly altered neural dynamics on multiple levels in cortex and other systems. I will first describe emergent neural entities (ENEs) abstractly. I will then show how ENEs function specifically and concretely, and demonstrate some implications of this type of emergence for the CNS.     

Endocannabinoids in the central nervous system

The major psychoactive component of cannabis derivatives, delta9-THC, activates two G-protein coupled receptors: CB1 and CB2. Soon after the discovery of these receptors, their endogenous ligands were identified: lipid metabolites of arachidonic acid, named endocannabinoids. The two major main and most studied endocannabinoids are anandamide and 2-arachidonyl-glycerol. The CB1 receptor is massively expressed through-out the central nervous system whereas CB2 expression seems restricted to immune cells. Following endocannabinoid binding, CB1 receptors modulate second messenger cascades (inhibition of adenylate cyclase, activation of mitogen-activated protein kinases and of focal-adhesion kinases) as well as ionic conductances (inhibition of voltage-dependent calcium channels, activation of several potassium channels). Endocannabinoids transiently silence synapses by decreasing neurotransmitter release, play major parts in various forms of synaptic plasticity because of their ability to behave as retrograde messengers and activate non-cannabinoid receptors (such as vanilloid receptor type-1), illustrating the complexity of the endocannabinoid system. The diverse cellular targets of endocannabinoids are at the origin of the promising therapeutic potentials of the endocannabinoid system.     

Tyrosinase-like polypeptides in the uterus and in the central nervous system of rats.

Nuclear and cytosolic fractions of rat uteri and tissues from the central nervous system contain proteins that are recognized by a polyclonal tyrosinase antibody. This antibody eliminates the cresolase activity of uterine nuclear extract when estradiol is used as substrate. Thus, it appears that tyrosinase-like proteins might be present in tissues not generally considered to chain such an enzyme.     

Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats.

Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.     

Lipid class analysis of the central nervous system of myelin-deficient Wistar rats

Brains and spinal cords of myelin-deficient (md) and littermate control rats were analyzed serially for myelin lipids during the period from 13 to 32 days of age. The glycolipids of md rat brains were severely reduced and remained so during the period of study; brain cholesterol and phospholipids increased moderately but never reached the values for control brains. Deficiency of all three lipid classes was marked in the spinal cord and did not change with age. Among the glycolipids of md rats, deficiency was more severe in cerebrosides than sulfatides. The pronounced reduction of cerebrosides in the early stages of myelination suggests that abnormal synthesis of these glycolipids may be the most important biochemical anomaly responsible for myelin deficiency.--Csiza, C.K. Lipid class analysis of the central nervous system of myelin-deficient Wistar rats.     

中枢神经系统D-氨基酸氧化酶的研究进展

新近研究证实,哺乳动物神经系统中存在内源性D-氨基酸氧化酶,参与脑内D-氨基酸的代谢.遗传学研究发现,D-氨基酸氧化酶基因与精神分裂症的发生密切相关.分子生物学研究表明,在D-氨基酸氧化酶基因启动子区域存在一些转录因子的结合位点.这些研究结果提示,中枢神经系统的D-氨基酸氧化酶除了参与D-氨基酸的代谢以外,可能还具有其它的生理功能.本文就中枢神经系统D-氨基酸氧化酶的研究进展作一综述.     

Potassium channels in the Helix central nervous system: preliminary immunohistochemical studies. Short communication

Distribution of the potassium channel of Kv4.3 type was investigated in the central nervous system (CNS) of Helix pomatia by immunohistochemistry. Immunopositive neurons were found widely distributed in the CNS, present mostly in smaller groups in the different central ganglia but not in the visceral ganglion. Labeled fibers were characteristic for not only the neuropils of all ganglia but also the connective tissue sheath around the CNS and the aorta wall were richly innervated. Western blot analysis revealed a clear identity with the mammalian Kv4.3 subunit, suggesting an evolutionary conserved structure of this channel type. Our preliminary results provide a steady basis for further experiments aiming partly at the identification of other potassium channel types and partly the ultrastructural localization of Kv4.3.