heparitin-sulfate and Central-Nervous-System-Diseases

We have described the age-related deposition of fibrillar material in brains of B6 mice and SAM. Since in other inbred strains similar deposits were absent or occurred only occasionally and only in aged individuals, a genetic predisposition of B6 mice and SAM to accumulate the fibrillar material is suggested. The deposits are mostly associated with astrocytic processes and have been referred to as astrocytic inclusions. HSPG- and laminin-like molecules have been identified as components of the fibrillar material. The deposits have similarities with CA in humans, but they also show some important differences; thus there is presently insufficient evidence to consider the deposits the murine equivalent of CA. Although the physiological significance of the fibrillar material is not yet clear, the awareness of the deposits appears pertinent because they might contribute to various aspects of CNS function of susceptible strains of mice, and therefore could lead to possible misinterpretations of the results of studies employing these strains. Future directions of our research will determine the potential of the murine deposits to model aspects of human neuropathology, in particular, whether the deposits may mimic the deposition of ECM molecules as an early-event in the pathogenesis of amyloid plaque formation.

Topics: Aging; Animals; Biomarkers; Brain Diseases; Central Nervous System Diseases; Disease Models, Animal; Female; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Laminin; Male; Mice; Mice, Inbred Strains; Neurofibrils; Proteoglycans; Species Specificity

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

Topics: Animals; Central Nervous System Diseases; Corpus Callosum; Cuprizone; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Heparitin Sulfate; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Sulfates

Glycosaminoglycans (GAGs) were recovered from human cerebral spinal fluid (CSF) and after their conversion to disaccharides using polysaccharide lyases were analyzed by liquid chromatography tandem mass spectrometry using multiple reaction monitoring. CSF showed ng/mL levels of heparan sulfate, chondroitin sulfates and hyaluronan. The amounts and disaccharide composition of these GAGs differed from those found in human plasma. This approach may offer a new method for the discovery of biomarkers for diseases of the central nervous system.

Topics: Biomarkers; Central Nervous System Diseases; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Tandem Mass Spectrometry

The lack of endogenous repair following spinal cord injury (SCI) accounts for the frequent permanent deficits for which effective treatments are absent. Previously, we demonstrated that low sulfated modified heparin mimetics (LS-mHeps) attenuate astrocytosis, suggesting they may represent a novel therapeutic approach. mHeps are glycomolecules with structural similarities to resident heparan sulfates (HS), which modulate cell signaling by both sequestering ligands, and acting as cofactors in the formation of ligand-receptor complexes. To explore whether mHeps can affect the myelination and neurite outgrowth necessary for repair after SCI, we created lesioned or demyelinated neural cell co-cultures and exposed them with a panel of mHeps with varying degrees and positions of their sulfate moieties. LS-mHep7 enhanced neurite outgrowth and myelination, whereas highly sulfated mHeps (HS-mHeps) had attenuating effects. LS-mHeps had no effects on myelination or neurite extension in developing, uninjured myelinating cultures, suggesting they might exert their proregenerating effects by modulating or sequestering inhibitory factors secreted after injury. To investigate this, we examined conditioned media from cultures using chemokine arrays and conducted an unbiased proteomics approach by applying TMT-LC/MS to mHep7 affinity purified conditioned media from these cultures. Multiple protein factors reported to play a role in damage or repair mechanisms were identified, including amyloid betaA4. Amyloid beta peptide (1-42) was validated as an important candidate by treating myelination cultures and shown to inhibit myelination. Thus, we propose that LS-mHeps exert multiple beneficial effects on mechanisms supporting enhanced repair, and represent novel candidates as therapeutics for CNS damage.

Topics: Amyloid beta-Peptides; Animals; Animals, Newborn; Antimetabolites; Cell Proliferation; Cells, Cultured; Central Nervous System Diseases; Culture Media, Conditioned; Cytokines; Demyelinating Diseases; Deoxyuridine; Embryo, Mammalian; Heparitin Sulfate; Intercellular Signaling Peptides and Proteins; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; Neurites; Neuroglia; Neurons; Oligodendroglia; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord