Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia

Abstract

Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer's type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit antiinflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents.

Characterization of currently marketed heparin products: Analysis of heparin digests by RPIP-UHPLC–QTOF-MS

“…Heparin is a linear molecule with alternating building blocks where an uronic acid residue and a glucosamine residue are sequentially linked from the uronate carbon at position 1 to the glucosamine carbon at position 4 via an ether bond with a ␤-configuration. Each disaccharide pair is further linked (1)(2)(3)(4) to form the longer heparin chains. In addition, the heparin chains also vary in the number of sulfates present: Osulfation can occur on either C2 position of the uronic acid residues or the C3/C6 position of the glucosamine residues.…”

“…Heparin was put into human trials in 1935 and has been widely used as an anticoagulant since 1937 [2]. Recently, potential pharmaceutical applications of heparin in other diseases, including senile dementia [3], angiogenesis [4], diabetic nephropathy [5], and cancer treatment [6], have been reported. Currently, heparin is marketed in multiple forms: unfractionated heparin (UFH, heparin sodium, MW ∼17 kDa), low molecular weight heparins (LMWH, MW ∼4-6 kDa) of which three types are approved for the US market (dalteparin, tinzaparin and enoxaparin) and a synthetic heparin-like pentamer (fondaparinux, MW = 1508.3 Da) [7].…”

Immune Functions of Glia and Neurons in the Central Nervous System

“…Nevertheless, the CNS has been previously known to regulate innate immune responses through hormonal and neuronal circuits [37,38]. The neuroendocrine Glutamate, dopamine [35] NO, ATP; Substance P [35]; MMPs [78] HMGB1, Heat-shock proteins [38,75] TLRs [76] IL-4, IL-10, IFN-, TGF- [13][14][15]17] BDNF, GDNF [40] TIMPs [78] CD45, CD91, CD200R, CD172a [15,55] CX3CR1 [45], TREM-2 [62], FasL, Fas [71,72] IL-4, IL-10, IFN-, TGF- [10,23,26] Proteoglycans [79,80] BDNF, GDNF [40] TIMPs [78] FasL [70,71], Complement inhibitors [23] TGF- [39,42], CX3CL1 (fractalkine) [44] GABA [50], VIP [41,49], Proteoglycans [79,80] NGF, BDNF, NT3, GDNF, CNTF [40] CD22 [52] CD47 [53], CD200 [55] ICAM-5 [36,63], FasL [70] stress response generally inhibits innate immune responses at the systemic level …”

β-Amyloid Fibrillation and/or Hyperhomocysteinemia Modify Striatal Patterns of Hyaluronic Acid and Dermatan Sulfate: Possible Role in the Pathogenesis of Alzheimers Disease

“…Furthermore, few studies have been performed on the relationship between hyperhomocysteinemia and extracellular matrix (ECM) modifications with specific regard to the GAG component [20,21]. On the other hand, the characterization of the chemical GAGs structures might be useful to understand the molecular basis related to the enhancing of -amyloid fibrillogenesis and to possibly "design" specific poly(oligo) saccharides able to block this process by competing with the endogenous polymer(s) [22].…”