Tibetan medical interpretation of myelin lipids and multiple sclerosis.

Tibetan medicine integrates diet, lifestyle, herbs, and accessory therapies to increase health and longevity. A comparison of the three humor theory of Tibetan medicine and the three thermodynamic phase properties of myelin lipids exemplifies how integrating medical systems can increase understanding of complex chronic disabling conditions. As a correlative study to microscopically better understand multiple sclerosis (MS) from the view of Tibetan medicine, the physical disruption of central nervous system myelin membranes in MS is interpreted from the theory of the three humors (vital energies) of Tibetan medicine: rLung (Wind), MKhris pa (Bile), and Bad gen (Phlegm). The three classes of myelin lipids--phospholipids, sphingolipids, and cholesterol--are interpreted as one of three humors based on Langmuir isotherm thermodynamic measurements. The nature of rLung is movement or change. Myelin sphingolipids have rLung properties based on thermodynamic observations of changes in phase organization. MKhris pa is fire, energetic. Phospholipids have MKhris pa properties based on thermodynamic observations of being energetic membrane lipids with fast molecular motions and fluid-like properties. The nature of Bad gen is substance and form; it dominates body structure. Cholesterol relates to Bad gen because it dominates membrane structure. We propose a theoretical relationship whereby demyelination in MS is viewed as a continuum of imbalance of the three humors as understood in Tibetan medicine. Myelin lipid data is presented to support this theoretical relationship. Clinically, MS is, in general, a rLung-MKhrispa disorder in women and a Bad gen-MKhrispa disorder in men, with rLung-MKhrispa excess in both genders during exacerbation, inflammation, and demyelination. Studying Tibetan medicine in its traditional context will create an integrative model for the treatment of MS and other chronic conditions.

Tibetan medicine and regeneration.

An overview of the concept of regeneration in Tibetan medicine is presented with descriptions of detoxification and tonification longevity protocols. The body must be fortified before receiving stronger treatments for regeneration. All disease is brought into balance with understanding of the interplay of the five elements, three humors, and their qualities and locations. The example of multiple sclerosis (MS) is given. The macroscopic three-humor interpretation of MS agrees with the microscopic three-humor description of demyelination, providing a new framework for the understanding and treatment of MS. Treatments for MS and other chronic conditions are based on age, season, time of day, and the individual's three-humor and hot (excess) and cold (deficiency) balance. Treatments to promote regeneration include nutrition, gentle exercise, herbal formulas, accessory therapies such as herbal baths and oils, and meditation. It is built into the theory of Tibetan medicine to have predictions about outcome and distinguish different disease patterns in patients with MS and other disorders. Taking into account daily and seasonal variations coupled with the changing nature of MS, it is critical to frequently evaluate people with MS and other chronic conditions for monitoring and adjustment of treatment for regeneration.

Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein.

Force-distance measurements between supported lipid bilayers mimicking the cytoplasmic surface of myelin at various surface coverages of myelin basic protein (MBP) indicate that maximum adhesion and minimum cytoplasmic spacing occur when each negative lipid in the membrane can bind to a positive arginine or lysine group on MBP. At the optimal lipid/protein ratio, additional attractive forces are provided by hydrophobic, van der Waals, and weak dipolar interactions between zwitterionic groups on the lipids and MBP. When MBP is depleted, the adhesion decreases and the cytoplasmic space swells; when MBP is in excess, the bilayers swell even more. Excess MBP forms a weak gel between the surfaces, which collapses on compression. The organization and proper functioning of myelin can be understood in terms of physical noncovalent forces that are optimized at a particular combination of both the amounts of and ratio between the charged lipids and MBP. Thus loss of adhesion, possibly contributing to demyelination, can be brought about by either an excess or deficit of MBP or anionic lipids.

Synergistic interactions of lipids and myelin basic protein.

This report describes force measurements and atomic force microscope imaging of lipid-protein interactions that determine the structure of a model membrane system that closely mimics the myelin sheath. Our results suggest that noncovalent, mainly electrostatic and hydrophobic, interactions are responsible for the multilamellar structure and stability of myelin. We find that myelin basic protein acts as a lipid coupler between two apposed bilayers and as a lipid "hole-filler," effectively preventing defect holes from developing. From our protein-mediated-adhesion and force-distance measurements, we develop a simple quantitative model that gives a reasonably accurate picture of the molecular mechanism and adhesion of bilayer-bridging proteins by means of noncovalent interactions. The results and model indicate that optimum myelin adhesion and stability depend on the difference between, rather than the product of, the opposite charges on the lipid bilayers and myelin basic protein, as well as on the repulsive forces associated with membrane fluidity, and that small changes in any of these parameters away from the synergistically optimum values can lead to large changes in the adhesion or even its total elimination. Our results also show that the often-asked question of which membrane species, the lipids or the proteins, are the "important ones" may be misplaced. Both components work synergistically to provide the adhesion and overall structure. A better appreciation of the mechanism of this synergy may allow for a better understanding of stacked and especially myelin membrane structures and may lead to better treatments for demyelinating diseases such as multiple sclerosis.

Role of lipid interactions in autoimmune demyelination.

A morphological transformation involving loss of adhesion between myelin lamellae and formation of myelin vesicles has been described as a mechanism for demyelination in multiple sclerosis and marmoset experimental allergic encephalomyelitis (EAE). Although protein interactions are involved in maintaining normal myelin structure, we describe here how lipids contribute to myelin stability and how lipid changes in EAE, including increases in lipid polyunsaturation and negatively charged phosphatidylserine (PS), promote demyelination. Three physico-chemical techniques were used to identify these changes: (1) Langmuir monolayer isotherms indicated that EAE white matter lipids were significantly more "expanded" (fluid) than controls. (2) NMR spectroscopy indicated that EAE myelin lipids were more polyunsaturated than controls. (3) High-performance liquid chromatography (HPLC) with an evaporative light scattering detector indicated increased PS in EAE compared to controls, while sphingomyelin (SM), sulfatides and phosphatidylcholine (PC) were decreased. We present a physical model considering electrostatic, van der Waals and undulation forces to quantify the effect of these changes on myelin adhesion at the extracellular interface. Taken together, the isotherm, NMR, HPLC and modeling results support a mechanism for autoimmune demyelination whereby the composition of myelin lipids is altered in a manner that increases myelin fluidity, decreases myelin adhesion, increases membrane curvature, and promotes vesiculation.

Structure of hydroxylated galactocerebrosides from myelin at the air-water interface.

Hydroxy-galactocerebrosides (mixed chain length, constituent of myelin membranes) from bovine brain are investigated as monolayers at the air-water interface with isotherms, fluorescence microscopy, x-ray reflectivity and grazing incidence diffraction. With grazing incidence diffraction a monoclinic tilted chain lattice is found in the condensed phase. According to x-ray reflectivity, the longest chains protrude above the chain lattice and roughen the lipid/air interface. On compressing the chain lattice, the correlation length increases by approximately 65%; obviously, the sugar headgroups are flexible enough to allow for lattice deformation. With fluorescence experiments, small coexisting fluid and ordered domains are observed, and there is lipid dissolution into the subphase as well. The dissolved hydroxy-galactocerebroside molecules reenter on monolayer expansion. The electron density profiles derived from x-ray reflectometry (coherent superposition) show that the chain-ordering transition causes the molecules to grow into the subphase.