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Dendrimer-Conjugated Glutamate Carboxypeptidase II Inhibitor Restores Microglial Changes in a Rabbit Model of Cerebral Palsy.
Sah, Nirnath; Zhang, Zhi; Chime, Alicia; Fowler, Amanda; Mendez-Trendler, Antonio; Sharma, Anjali; Kannan, Rangaramanujam M; Slusher, Barbara; Kannan, Sujatha.
Afiliación
  • Sah N; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Zhang Z; Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan, USA.
  • Chime A; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Fowler A; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Mendez-Trendler A; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Sharma A; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Kannan RM; Department of Chemistry, Washington State University, Pullman, Washington, USA.
  • Slusher B; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Kannan S; Johns Hopkins Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Dev Neurosci ; 45(5): 268-275, 2023.
Article en En | MEDLINE | ID: mdl-36990069
We have previously shown that maternal endotoxin exposure leads to a phenotype of cerebral palsy and pro-inflammatory microglia in the brain in neonatal rabbits. "Activated" microglia overexpress the enzyme glutamate carboxypeptidase II (GCPII) that hydrolyzes N-acetylaspartylglutamate to N-acetylaspartate and glutamate, and we have shown previously that inhibiting microglial GCPII is neuroprotective. Glutamate-induced injury and associated immune signaling can alter microglial responses including microglial process movements for surveillance and phagocytosis. We hypothesize that inhibition of GCPII activity could alter microglial phenotype and normalize microglial process movement/dynamics. Newborn rabbit kits exposed to endotoxin in utero, when treated with dendrimer-conjugated 2-(phosphonomethyl)-pentanedioic acid (D-2PMPA), a potent and selective inhibitor of microglial GCPII, showed profound changes in microglial phenotype within 48 h of treatment. Live imaging of hippocampal microglia in ex vivo brain slice preparations revealed larger cell body and phagocytic cup sizes with less stable microglia processes in CP kits compared to healthy controls. D-2PMPA treatment led to significant reversal of microglial process stability to healthy control levels. Our results emphasize the importance of microglial process dynamics in determining the state of microglial function in the developing brain and demonstrate how GCPII inhibition specifically in microglia can effectively change the microglial process motility to healthy control levels, potentially impacting migration, phagocytosis, and inflammatory functions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parálisis Cerebral / Dendrímeros Límite: Animals Idioma: En Revista: Dev Neurosci Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parálisis Cerebral / Dendrímeros Límite: Animals Idioma: En Revista: Dev Neurosci Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza