Glycosaminoglycan C3 protects against AF64A-induced cholinotoxicity in a dose-dependent and time-dependent manner

Several studies revealed that proteoglycans (PGs) and glycosaminoglycans (GAGs) play a pivotal role in the pathogenesis of Alzheimer's disease (AD). PGs have affinity to amyloid beta (Abeta) and protect it against proteolysis, and the consequent aggregation is the cause of neurotoxicity. This effect is believed to be attenuated by GAGs. Moreover, a low-molecular-weight GAG C3 derived from unfractionated heparin has been reported to protect against Abeta-induced tau-2 immunoreactivity and cholinergic damage induced by a cholinotoxin, AF64A, in rat. However, the optimal dose and the timeframe of administration of C3 are still unknown. In our studies, we revealed the concentration-dependent and time-dependent effects of C3 on AF64A-induced cholinergic lesion in rat. C3 was administered orally in 5, 10, and 25 mg/kg/day concentration, 7 days before and/or 7 days after intracerebroventricular (i.c.v.) AF64A administration. Our results have shown that 25 mg/kg/day C3 effectively protects against AF64A-generated cholinotoxicity if administered both 7 days before and 7 days after the AF64A injection. In contrast to these findings, administration of 5 or 10 mg/kg/day C3 or 25 mg/kg/day C3, given 7 days before or 7 days after stereotaxic AF64A injection, did not show cholinoprotective effects. In conclusion, the time-dependent effects of C3 on AF64A-induced cholinergic lesion suggest that C3 may act via the processes of both neuroprotection and neurorepair. Moreover, the effects of C3 depend largely on the administered dose of this low-molecular-weight GAG. The present findings also indicate that C3, administered in the effective concentration and timeframe, may play a pivotal role in the treatment of AD.