Myelin Sheaths In White Matter Research Articles

Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.

STEREOLOGICAL EVIDENCE FOR DE/RE-GENERATION OF MYELIN SHEATHS IN AGED BRAIN WHITE MATTER OF FEMALE RATS

Studies have provided qualitative evidence of de-myelination and re-myelination in aged brain white matter. However, there have been no quantitative evidences of degeneration and regeneration of myelin sheaths in white matter. The present study was designed to investigate the quantitative changes in myelin sheaths using unbiased stereological techniques and qualitative changes using electron microscopy in aged brain white matter. Results obtained showed that in brain white matter, the total volume of myelin sheaths of old-age female rats was not significantly different from that of young female rats, but the total length of myelinated fibers in old female rats was significantly decreased by 46.1% when compared with that of young female rats. Myelin sheath volume per unit length of myelinated fibers of old female rats was significantly increased by 43.4% compared with that of young female rats. The mean thickness of myelin sheaths in the white matter of the old rats was significantly increased by 33.3%, when compared with that of young female rats. In age-related loss of myelinated fibers, most fibers had diameters less than 1.4 μm, and myelin sheath thicknesses less than 0.14 μm, but the length of myelinated fibers with diameters more than 0.6 μm and myelin sheath thicknesses more than 0.22 μm increased with age. Myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter less than 0.21 were significantly lower in elderly rats than in young rats. However, the total length of myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter more than 0.23 was higher in aged rats than in young rats. About 6.58% of myelin sheaths showed degenerative alterations, while 0.88% myelin sheaths showed regenerative alterations. This study provides stereological evidence not only for degeneration but also regeneration of myelin sheaths in aged white matter.

Stereological Methods for Estimating the Myelin Sheaths of the Myelinated Fibers in White Matter

In the present study, efficient and unbiased stereological techniques to investigate the myelin sheaths of the myelinated fibers in rat white matter were established. In the present design, four tissue blocks were obtained from the entire white matter of rat brain in a uniform, random fashion. Isotropic, uniform random (IUR) sections were ensured by the use of the isector technique. One section with the thickness of 60 nm was cut from the center of each epon block. Eight to 10 fields of vision were randomly photographed under a transmission electron microscope. The total length of the myelinated fibers and the total volume of the myelin sheaths in the white matter were the products of the length density, volume density, and the volume of the white matter obtained with the Cavalieri principle. The mean areas of the myelinated fibers profiles and myelin sheaths were estimated with the point counting technique. The inner and outer perimeters of the myelin sheaths were estimated by the use of a line grid, and the thickness of the myelin sheaths was estimated by direct orthogonal measurements in uniform, random locations. The described methods will provide very useful tools for future quantitative studies of changes in the myelin sheaths of white matter in various experimental conditions and in various neurodegenerative diseases.

The myelinated fiber changes in the white matter of aged female Long‐Evans rats

Age-related changes of the white matter and the myelinated fibers in white matter of female Long-Evans rats were investigated by the use of design-based stereological methods. The white matter volume in middle-aged rats was not significantly different from that in young rats, but the white matter volume in aged rats was significantly decreased by 42.7% and 37.7%, respectively, when compared with young and middle-aged rats. When compared with young rats, the total volumes of the myelinated fibers and myelin sheaths in white matter of aged rats were significantly decreased by 26.7% and 30.7%, respectively. When compared with young and middle-aged rats, the total length of the myelinated fibers in white matter of aged rats was significantly decreased by 52.5% and 48.6%, respectively. The mean diameter of the myelinated fibers in white matter of aged rats was significantly increased by 37.5% when compared with young rats. The absolute diameter distributions of the myelinated fiber length in the white matter of young, middle-aged, and aged rats indicated that the age-related loss of the myelinated fiber length in the white matter of aged rats was mainly as a result of the marked loss of the myelinated fibers with smaller diameter. The age-related changes of the white matter and the myelinated fibers in white matter may have important implications for age-related cognitive impairments.

Dose-dependent neuroprotective effects of melatonin on experimental spinal cord injury in rats

Background This report examines the dose-dependent effects of melatonin on early lipid peroxidation levels, ultrastructural changes, and neurological function in experimental spinal cord injury (SCI) by comparing them with therapeutic levels of methylprednisolone in rats. Methods SCI was performed by an aneurysm clip placed extradurally at the level of T10. Rats were randomly divided into 6 groups of 10 rats each. Group 1 (sham) received only laminectomy; group 2 (control) received SCI; group 3 (placebo) received SCI and physiological saline; group 4 received methylprednisolone (30 mg/kg); groups 5 and 6 received melatonin at doses of 50 or 100 mg/kg, respectively, after SCI. Rats were neurologically tested 24 hours after trauma. Spinal cord samples were harvested for both lipid peroxidation levels and ultrastructural histopathological evaluation. Results Neurological scores of rats were not different in SCI groups. Lipid peroxidation levels are significantly restricted only in methylprednisolone group at 24 hours. Melatonin-treated groups showed more ultrastructural improvement on electron microscopic studies when compared with methylprednisolone group. However, the therapeutic effects of melatonin were mainly observed on white matter of spinal cord in ultrastructural investigation. There was significant difference between melatonin dose groups increasing with dose. Conclusions Results showed that melatonin has no significant dose-dependent effects on early lipid peroxidation but rather some neuroprotective effects on both axons and myelin sheaths of white matter in ultrastructural observations when compared with methylprednisolone. These effects significantly augmented with dose increase.