Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

作者：O. Arteaga Cabeza, Zhi Zhang, Elizabeth Smith Khoury, R. Ann Sheldon, Anjali Sharma, Fan Zhang, Barbara S. Slusher, Rangaramanujam M. Kannan, Sujatha Kannan, Donna M. Ferriero · 发表于：Neurobiology of Disease · 年份：2020 · DOI：10.1016/j.nbd.2020.105201 · 被引用次数：40 · 研究领域：Neonatal and fetal brain pathology、Neuroinflammation and Neurodegeneration Mechanisms、Traumatic Brain Injury and Neurovascular Disturbances

The result of a deprivation of oxygen and glucose to the brain, hypoxic–ischemic encephalopathy (HIE), remains the most common cause of death and disability in human neonates globally and is mediated by glutamate toxicity and inflammation. We have previously shown that the enzyme glutamate carboxypeptidase (GCPII) is overexpressed in activated microglia in the presence of inflammation in fetal/newborn rabbit brain. We assessed the therapeutic utility of a GCPII enzyme inhibitor called 2-(3-Mercaptopropyl) pentanedioic acid (2MPPA) attached to a dendrimer (D-2MPPA), in order to target activated microglia in an experimental neonatal hypoxia-ischemia (HI) model using superoxide dismutase transgenic (SOD) mice that are often more injured after hypoxia-ischemia than wildtype animals. SOD overexpressing and wild type (WT) mice underwent permanent ligation of the left common carotid artery followed by 50 min of asphyxiation (10% O2) to induce HI injury on postnatal day 9 (P9). Cy5-labeled dendrimers were administered to the mice at 6 h, 24 h or 72 h after HI and brains were evaluated by immunofluorescence analysis 24 h after the injection to visualize microglial localization and uptake over time. Expression of GCPII enzyme was analyzed in microglia 24 h after the HI injury. The expression of pro- and anti-inflammatory cytokines were analyzed 24 h and 72 h post-HI. Brain damage was analyzed histologically 7 days post-HI in the three randomly assigned groups: control (C); hypoxic-isch...