Advanced nanotherapies to promote neuroregeneration in the injured newborn brain

Arteaga, Olatz; Mikrogeorgiou, Alkisti; Kannan, Sujatha; Ferriero, Donna M.

doi:10.1016/j.addr.2019.10.005

Cited by 7 publications

(2 citation statements)

References 278 publications

(349 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, dendrimers are non-toxic, non-immunogenic and cleared intact through the kidneys. We have previously demonstrated that these dendrimers selectively localize in activated microglia in the retina and the brain in small and large animal models and can deliver drugs specifically to these cells ( Arteaga Cabeza et al, 2019 ; Smith et al, 2019 ). Here we demonstrate that HI leads to overexpression of GCPII in activated microglia in the neonatal mouse brain and treatment with D-2MPPA leads to decreased brain injury.…”

Section: Introductionmentioning

confidence: 99%

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

Arteaga

Zhang

Khoury

et al. 2021

Neurobiology of Disease

View full text Add to dashboard Cite

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% O 2 ) 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 immunoflu orescence 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-ischemic (HI); and HI mice who received a single dose of D-2MPPA 6 h post-HI (HI+D-2MPPA). First, we found that GCPII was overexpressed in activated microglia 24 h after HI in the SOD overexpressing mice. Also, there was an increase in microglial activation 24 h after HI in the ipsilateral hippocampus which was most visible in the SOD+HI group. Dendrimers were mostly taken up by microglia by 24 h 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 72 h. 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 6 h post-HI in order to suppress the expression of GCPII by 24 h after the damage since dendrimer localization in microglia is seen as early as 6 h with the peak of GCPII upregulation in activated microglia seen at 24 h post-HI. Ultimately, treatment with D-2MPPA

show abstract

Section: Introductionmentioning

confidence: 99%

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

Arteaga

Zhang

Khoury

et al. 2021

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…Immunomodulatory agents and antiinflammatory strategies are being investigated to reduce the detrimental effects of neuroinflammation [28]. Growth factors and neurotrophic factors are being explored for their potential to promote neurogenesis and repair damaged neural tissue in experimental animal studies [29]. Nevertheless, in the future, a combination of pharmacological and non-pharmacological brain-focused clinical practices might be considered as the most promising protection and/or treatment provided in clinical practice to neonates at high risk of neuronal injury [30].…”

Section: Neuroprotective Therapiesmentioning

confidence: 99%

Future perspectives on neonatal brain injury

Maria Tzeli,

Maria Tigka,

Nikoletta Pantelaki

et al. 2023

World J. Adv. Res. Rev.

View full text Add to dashboard Cite

Neonatal brain injury (NBI) is a complex and challenging area of research and critical care. Advances in understanding and treating NBI are crucial for improving the long-term adverse neurological outcomes of the affected neonates. Future perspectives in NBI are focused on systematic antenatal education, personalized medicine and profiling, stem cell and neuroprotective therapies, biomarkers in biological fluids with an emphasis on multimodal biomarker panels, collaborative research projects and considerations regarding ethical issues. Although substantial efforts have been made recently to restrain NBI, its incidence is still high on a global scale. Therefore, future management of NBI will involve a multidisciplinary approach that integrates genetics, individualized therapy, and medical advancements, with particular attention to early detection and intervention. The ultimate goal is to reduce the prevalence of NBI and improve the affected neonates' long-term prognosis. It is critical to remember that this field of study is still being investigated, and it could be years before many of these advancements are widely applied in standard clinical practice.

show abstract