Tissue-specific coordinate regulation of enzymes of cholesterol biosynthesis: Sciatic nerve versus liver

Exposure of weanling rats to a diet containing the element tellurium results in specific inhibition of squalene epoxidase, an obligate enzyme in cholesterol biosynthesis. Liver responds to the resulting intracellular sterol deficit by up-regulating, in parallel and to the same extent, expression of mRNA for squalene epoxidase and for HMG-CoA reductase, the major rate-limiting enzyme in the pathway. This increased mRNA expression, coupled with additional translational and posttranslational activation of the pathway allows normal levels of cholesterol synthesis in liver despite tellurium-induced inhibition of squalene epoxidase. The response to tellurium challenge in sciatic nerve is very different. In this tissue, cholesterol synthesis is prominent because of the large amount of cholesterol required for synthesis and maintenance of myelin. Although nerve shows an initial (at 1 day) up-regulation of mRNA expression for both enzymes in response to tellurium exposure, this is followed quickly by parallel down-regulation of both enzymes, in concert with down-regulation of mRNA expression for myelin proteins. We suggest that the tellurium-induced deficit in sterols leads to a coordinate down-regulation of synthesis of myelin components. The initial early up-regulation of cholesterol biosynthesis in sciatic nerve due to the cholesterol deficit is countered by down-regulation which is coordinated with overall control of the program of myelin assembly. This tissue-specific control of cholesterol synthesis in sciatic nerve is a point of vulnerability to toxicants, and may be related to the need for coordinate synthesis of all components of myelin

Interleukin-6 (IL-6) receptor/IL-6 fusion protein (Hyper IL-6) effects on the neonatal mouse brain: Possible role for IL-6 trans-signaling in brain development and functional neurobehavioral outcomes

Adverse neurodevelopmental outcomes are linked to perinatal production of inflammatory mediators, including interleukin 6 (IL-6). While a pivotal role for maternal elevation in IL-6 has been established in determining neurobehavioral outcomes in the offspring and considered the primary target mediating the fetal inflammatory response, questions remain as to the specific actions of IL-6 on the developing brain. CD-1 male mice received a subdural injection of the bioactive fusion protein, hyper IL-6 (HIL-6) on postnatal-day (PND)4 and assessed from preweaning until adulthood. Immunohistochemical evaluation of astrocytes and microglia and mRNA levels for pro-inflammatory cytokines and host response genes indicated no evidence of an acute neuroinflammatory injury response. HIL-6 accelerated motor development and increased reactivity to stimulation and number of entries in a light/dark chamber, decreased ability to learn to withhold a response in passive avoidance, and effected deficits in social novelty behavior. No changes were observed in motor activity, pre-pulse startle inhibition, or learning and memory in the Morris water maze or radial arm maze, as have been reported for models of more severe developmental neuroinflammation. In young animals, mRNA levels for MBP and PLP/DM20 decreased and less complexity of MBP processes in the cortex was evident by immunohistochemistry. The non-hydroxy cerebroside fraction of cerebral lipids was increased. These results provide evidence for selective effects of IL-6 signaling, particularly trans-signaling, in the developing brain in the absence of a general neuroinflammatory response. These data contribute to our further understanding of the multiple aspects of IL-6 signaling in the developing brain

Normal metabolism but different physical properties of myelin from mice deficient in proteolipid protein

Proteolipid protein (PLP) is the primary protein component of CNS myelin, yet myelin from the PLPnull mouse has only minor ultrastructural abnormalities. Might compensation for a potentially unstable structure involve increased myelin synthesis and turnover? This was not the case; neither accumulation nor in vivo synthesis rates for the myelin- specific lipid cerebroside was altered in PLPnull mice relative to wild-type (wt) animals. However, the yield of myelin from PLPnull mice, assayed as levels of cerebroside, was only about 55% of wt control levels. Loss of myelin occurred during initial centrifugation of brain homogenate at 20,000g for 20 min, which is sufficient to sediment almost all myelin from wt mice. Cerebroside-containing fragments from PLPnull mice remaining in the supernatant could be sedimented by more stringent centrifugation, 100,000g for 60 min. Both the rapidly. and the more slowly sedimenting cerebroside-containing membranes banded at the 0.85/0.32 M sucrose interface of a density gradient, as did myelin from wt mice. These results suggest at least some myelin from PLPnull mice differs from wt myelin with respect to physical stability (fragmented into smaller particles during dispersion) and/or density. Alternatively, slowly sedimenting cerebroside-containing particles could be myelin precursor membranes that, lacking PLP, were retarded in their processing toward mature myelin and thus differ from mature myelin in physical properties. If this is so, recently synthesized cerebroside should be preferentially found in these "slower-sedimenting" myelin precursor fragments. Metabolic tracer experiments showed this was not the case. We conclude that PLPnull myelin is physically less stable and/or less dense than wt myelin. (C) 2003 Wiley- Liss, Inc

Myelin Deficits Produced by Early Postnatal Exposure to Inorganic Lead or Triethyltin Are Persistent

: Long‐Evans rat pups were exposed to either inorganic lead (400 mg Pb as lead acetate/kg body weight/day) or triethyltin sulfate (1.0 mg/kg body weight/day), by gastric intubation, from 2 days through 29 days of age. The rats were then weaned and placed on standard lab chow ad libitum. At 30 days of age, leadtreated rats exhibited statistically significant decreases in body and brain weights (22% and 17%, respectively), and the concentration of forebrain myelin was significantly reduced, by 21% relative to the 4.9 mg myelin protein/g brain in control rats. Although these animals recovered from the body weight deficits after several months, the deficits in brain weight and myelin concentration were still present at 120 days of age. This suggests that the lead‐induced myelin deficits were permanent. Lead levels in brain, which were maximal at 30 days of age when the treatment was terminated, decreased more slowly than in other organs and were still 30% of maximal levels at 120 days of age. Triethyltin‐treated animals also had significantly decreased body and brain weights (20% and 11%, respectively) at 30 days of age, and an even more severe reduction in forebrain myelin concentration (33%). These animals also regained a normal body weight by 120 days of age, but again the deficits in brain weight and myelin concentration persisted. Tin levels in brain and other organs had decreased to control levels by 60 days of age. Animals malnourished by maternal deprivation to match the body weights of the treated animals had myelin deficits that were less severe than those in the treated animals at 30 days of age (approximately 11% less than controls); however, these myelin deficits also persisted throughout the subsequent 90‐day recovery period examined. The apparent lack of recovery from CNS myelin deficits produced by neonatal exposure to different heavy metals or to malnutrition reemphasizes the vulnerability of the developing nervous system to a wide range of metabolic insults

Oligodendrocytes and Progenitors Become Progressively Depleted within Chronically Demyelinated Lesions

To understand mechanisms that may underlie the progression of a demyelinated lesion to a chronic state, we have used the cuprizone model of chronic demyelination. In this study, we investigated the fate of oligodendrocytes during the progression of a demyelinating lesion to a chronic state and determined whether transplanted adult oligodendrocyte progenitors could remyelinate the chronically demyelinated axons. Although there is rapid regeneration of the oligodendrocyte population following an acute lesion, most of these newly regenerated cells undergo apoptosis if mice remain on a cuprizone diet. Furthermore, the oligodendrocyte progenitors also become progressively depleted within the lesion, which appears to contribute to the chronic demyelination. Interestingly, even if the mice are returned to a normal diet following 12 weeks of exposure to cuprizone, remyelination and oligodendrocyte regeneration does not occur. However, if adult O4(+) progenitors are transplanted into the chronically demyelinated lesion of mice treated with cuprizone for 12 weeks, mature oligodendrocyte regeneration and remyelination occurs after the mice are returned to a normal diet. Thus, the formation of chronically demyelinated lesions induced by cuprizone appears to be the result of oligodendrocyte depletion within the lesion and not due to the inability of the chronically demyelinated axons to be remyelinated