Department Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver BC, Canada V6T 1Z3.
Curr Alzheimer Res. 2013 Mar;10(3):252-60. doi: 10.2174/1567205011310030004.
We have examined the anti-angiogenic compound, angiostatin as a modulator of inflammatory reactivity and vascular responses and for neuroprotection in an animal model of Alzheimer's disease (AD). Intra-hippocampal amyloidbeta (Aβ₁₋₄₂) injection, relative to controls phosphate buffer saline (PBS) or reverse peptide Aβ₄₂₋₁, increased gliosis in the molecular layer (ML) of rat hippocampus. Vascular remodeling was indicated from increased microvessel immunoreactivity (ir) in ML suggesting the possibility of an angiogenic response to peptide injection. Administration of Aβ₁₋₄₂ also induced a loss of neurons in the granule cell region of hippocampus relative to controls. Treatment of peptide-injected rats with angiostatin was associated with a spectrum of modulatory effects including reduced microgliosis (by 34%), diminished microvessel ir (by 36%) and increased neuronal viability (by 31%) compared with peptide injection alone. Angiostatin treatment was ineffective in reducing astrogliosis induced by Aβ₁₋₄₂ and applied alone the compound had no significant effect to alter gliosis, microvessel ir or neuronal viability compared with PBS control. In vitro, angiostatin significantly attenuated secretion of the pro-angiogenic agent, vascular endothelial growth factor (VEGF) in lipopolysaccharide (LPS)-stimulated THP-1 cells. Our findings provide novel evidence for a broad spectrum of angiostatin effects in an animal model of AD including actions to reduce inflammatory reactivity, stabilize vascular remodeling and confer neuroprotection. The overall effects of angiostatin are consistent with actions of the compound to inhibit microglial secretion of VEGF.
我们研究了抗血管生成化合物血管抑素作为阿尔茨海默病（AD）动物模型中炎症反应和血管反应的调节剂和神经保护剂。与对照的磷酸盐缓冲盐水（PBS）或反向肽 Aβ₄₂₋₁相比，海马内淀粉样β（Aβ₁₋₄₂）注射增加了大鼠海马分子层（ML）中的神经胶质增生。血管重塑表明 ML 中小血管免疫反应性（ir）增加，提示肽注射可能引起血管生成反应。Aβ₁₋₄₂的给药还导致海马颗粒细胞区神经元的丧失，与对照相比。与单独注射肽相比，血管抑素治疗肽注射大鼠与一系列调节作用相关，包括减少小胶质细胞增生（34%）、减少微血管 ir（36%）和增加神经元活力（31%）。与 Aβ₁₋₄₂诱导的星形胶质细胞增生相比，血管抑素治疗无效，并且与 PBS 对照相比，单独应用该化合物对改变神经胶质增生、微血管 ir 或神经元活力没有明显影响。在体外，血管抑素显著减弱脂多糖（LPS）刺激的 THP-1 细胞中促血管生成剂血管内皮生长因子（VEGF）的分泌。我们的研究结果为 AD 动物模型中血管抑素的广泛作用提供了新的证据，包括减少炎症反应、稳定血管重塑和提供神经保护的作用。血管抑素的总体作用与该化合物抑制小胶质细胞分泌 VEGF 的作用一致。
