ABSTRACT
We investigated the effect of long-term, peripheral treatment with enoxaparin, a low molecular weight heparin, in transgenic mice overexpressing human amyloid precursor protein(751). Enoxaparin (6 IU per mouse intraperitoneally, three times a week for 6 months) significantly lowered the number and the area occupied by cortical beta-amyloid deposits and the total beta-amyloid (1-40) cortical concentration. Immunocytochemical analysis of glial fibrillary acid protein-positive cells showed that enoxaparin markedly reduced the number of activated astrocytes surrounding beta-amyloid deposits. In vitro, the drug dose-dependently attenuated the toxic effect of beta-amyloid on neuronal cells. Enoxaparin dose-dependently reduced the ability of beta-amyloid to activate complement and contact systems, two powerful effectors of inflammatory response in AD brain. By reducing the beta-amyloid load and cytotoxicity and proinflammatory activity, enoxaparin offers promise as a tool for slowing the progression of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Enoxaparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Plaque, Amyloid/drug effects , Alzheimer Disease/pathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/toxicity , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Complement Activation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Glial Fibrillary Acidic Protein/biosynthesis , Male , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , PC12 Cells , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Peptide Fragments/toxicity , Plaque, Amyloid/pathology , RatsABSTRACT
C1-inhibitor (C1-INH) is a major regulator of the complement classical pathway. Besides this action, it may also inhibit other related inflammatory systems. We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery. C1-INH induced a dose-dependent reduction of ischemic volume that, with the dose of 15 U/mouse, reached 10.8% of the volume of saline-treated mice. Four days after ischemia the treated mice had significantly lower general and focal neurological deficit scores. Fluoro-Jade staining, a marker for neuronal degeneration, showed that C1-INH-treated mice had a lower number of degenerating cells. Leukocyte infiltration, as assessed by CD45 immunostaining, was also markedly decreased. We then investigated the response to ischemia in C1q(-/-) mice. There was a slight, nonsignificant decrease in infarct volume in C1q(-/-) mice (reduction to 72.3%) compared to wild types. Administration of C1-INH to these mice was still able to reduce the ischemic volume to 31.4%. The study shows that C1-INH has a strong neuroprotective effect on brain ischemia/reperfusion injury and that its action is independent from C1q-mediated activation of classical pathway.
