Doxycycline reduces cleaved caspase-3 and microglial activation in an animal model of neonatal hypoxia-ischemia

Lauren L. Jantzie, Po Yin Cheung, Kathryn G. Todd

Research output: Contribution to journalArticlepeer-review

Abstract

Neonatal hypoxia-ischemia (HI) is a major contributor to many perinatal neurologic disorders and, thus, the search for therapies and effective treatments for the associated brain damage has become increasingly important. The tetracycline derivative, doxycycline (DOXY), has been reported to be neuroprotective in adult animal models of cerebral ischemia. To investigate the putative neuroprotective effects of DOXY in an animal model of neonatal HI, a time-course study was run such that pups received either DOXY (10 mg/kg) or VEH immediately before hypoxia, 1, 2, or 3 hours after HI (n=6). At 7 days after injury, the pups were euthanized, and the brains were removed and processed for immunohistochemical and Western blot analyses using antibodies against specific markers for neurons, apoptotic markers, microglia, oligodendrocytes, and astrocytes. Results showed that in vulnerable brain regions including the hippocampal formation, thalamus, striatum, cerebral cortex and white matter tracts, DOXY significantly decreased caspase-3 immunoreactivity (a marker of apoptosis), promoted neuronal survival, inhibited microglial activation and reduced reactive astrocytosis compared with VEH-treated HI pups. These effects were found to occur in a time-dependent manner. Taken together, these results strongly suggest that doxycycline has potential as a pharmacological treatment for mild HI in neonates.

Original languageEnglish (US)
Pages (from-to)314-324
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Keywords

  • Apoptosis
  • Caspases
  • Doxycycline
  • Hypoxia-ischemia
  • Inflammation
  • Microglia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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