Back to Search
Start Over
Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury
- Source :
- Neurobiology of Disease, Vol 148, Iss, Pp 105201-(2021), Neurobiology of disease
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- 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 50min of asphyxiation (10% O2) to induce HI injury on postnatal day 9 (P9). Cy5-labeled dendrimers were administered to the mice at 6h, 24h or 72h after HI and brains were evaluated by immunofluorescence analysis 24h after the injection to visualize microglial localization and uptake over time. Expression of GCPII enzyme was analyzed in microglia 24h after the HI injury. The expression of pro- and anti-inflammatory cytokines were analyzed 24h and 72h post-HI. Brain damage was analyzed histologically 7days post-HI in the three randomly assigned groups: control (C); hypoxic-ischemic (HI); and HI mice who received a single dose of D-2MPPA 6h post-HI (HI+D-2MPPA). First, we found that GCPII was overexpressed in activated microglia 24h after HI in the SOD overexpressing mice. Also, there was an increase in microglial activation 24h after HI in the ipsilateral hippocampus which was most visible in the SOD+HI group. Dendrimers were mostly taken up by microglia by 24h post-HI; uptake was more prominent in the SOD+HI mice than in the WT+HI. The inflammatory profile showed significant increase in expression of KC/GRO following injury in SOD mice compared to WT at 24 and 72h. A greater and significant decrease in KC/GRO was seen in the SOD mice following treatment with D-2MPPA. Seven days after HI, D-2MPPA treatment decreased brain injury in the SOD+HI group, but not in WT+HI. This reduced damage was mainly seen in hippocampus and cortex. Our data indicate that the best time point to administer D-2MPPA is 6h post-HI in order to suppress the expression of GCPII by 24h after the damage since dendrimer localization in microglia is seen as early as 6h with the peak of GCPII upregulation in activated microglia seen at 24h post-HI. Ultimately, treatment with D-2MPPA at 6h post-HI leads to a decrease in inflammatory profiles by 24h and reduction in brain injury in the SOD overexpressing mice.
- Subjects :
- 0301 basic medicine
Glutamate Carboxypeptidase II
Transgenic
Mice
0302 clinical medicine
Superoxide Dismutase-1
Nanoparticle
Enzyme Inhibitors
Pediatric
Dendrimer
Microglia
biology
Chemistry
Glutamate receptor
Brain
Neuroprotection
Stroke
medicine.anatomical_structure
Neuroprotective Agents
Neurology
Enzyme inhibitor
Hypoxia-Ischemia, Brain
medicine.symptom
Genetically modified mouse
medicine.medical_specialty
Dendrimers
Physical Injury - Accidents and Adverse Effects
Clinical Sciences
Mice, Transgenic
Brain damage
N-acetyl-aspartyl-glutamate
Article
lcsh:RC321-571
Superoxide dismutase
Glutarates
03 medical and health sciences
Glutamate carboxypeptidase
Internal medicine
Hypoxia-Ischemia
medicine
Animals
Sulfhydryl Compounds
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Neurology & Neurosurgery
Neurosciences
N-acetyl-aspartyl-glutamate (NAAG)
Perinatal Period - Conditions Originating in Perinatal Period
Newborn
Neonatal brain injury
Brain Disorders
030104 developmental biology
Endocrinology
Animals, Newborn
biology.protein
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Volume :
- 148
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Disease
- Accession number :
- edsair.doi.dedup.....5d595ca7632dddf9f2998d7d090a4a7c