Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia–ischemia in neonatal rats

Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia–ischemia in neonatal rats

PDF

J Psychiatry Neurosci 2010;35(1):20-32

Lauren L. Jantzie, PhD; Kathryn G. Todd, PhD

Jantzie, Todd — Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alta.; Jantzie —Department of Neurology, Children’s Hospital Boston and Harvard Medical School, Boston, Mass.

Abstract

Background: Neonatal hypoxia–ischemia (HI) is a major cause of perinatal brain injury and is associated with a spectrum of neuropsychiatric disorders. Although very few treatment options are currently available, doxycycline (DOXY) has been reported to be neuroprotective in neontatal HI. Our objective was to investigate the effects of DOXY on neonatal brain development in normal and HI rat pups. We hypothesized that DOXY would inhibit microglial activation but that developmentally important processes, including cytogenesis and trophic responses, would not be impaired.

Methods: To investigate the putative neurodevelopmental consequences of DOXY administration in a clinically relevant animal model of HI, we performed a time-course analysis such that postnatal rat pups received DOXY(10 mg/kg) or vehicle immediately before HI (n ≥ 6). We then assessed cytogenesis, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinases regionally and longitudinally.

Results: We found that DOXY significantly inhibits neuroinflammation in the frontal cortex, striatum and hippocampus; decreases interleukin-1Β (IL-1Β) and tumour necrosis factor-α (TNF-α); and augments BDNF following HI. In addition, DOXY-treated pups have significantly fewer 2-bromo-5-deoxyuridine (BrdU)-positive cells in the subventricular zone 6 hours post-HI. However, DOXY does not persistently affect cytogenesis in the subventricular zone or dentate gyrus up to 7 days post-HI. The BrdU-positive cells not expressing markers for mature neurons colabel with nestin, an intermediate filament protein typical of neuronal precursors.

Limitations: Our study investigates “acute” neurodevelopment over the first 7 days of life after HI injury. Further long-term investigations into adulthood are underway.

Conclusion: Taken together, our results suggest the putative clinical potential of DOXY in the management of neonatal cerebral HI injury.


Acknowledgments: The experiments described were funded by the Davey Fund for Brain Injury Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Stollery Children’s Hospital Foundation and the Canadian Institutes of Health Research. L.L. Jantzie held a Canada Graduate Scholarship from the Natural Science and Engineering Research Council of Canada and an Incentive Award from the Alberta Heritage Foundation for Medical Research. The technical assistance of Aaron Lai is gratefully acknowledged, as well as the input and helpful discussions provided by Dr. Frances Jensen.

Competing interests: None declared.

Contributors: Dr. Jantzie acquired the data. Both Drs. Jantzie and Todd designed the study, analyzed the data, wrote and reviewed the article and approved its publication.

Submitted May 25, 2009; Revised Aug. 10, 2009; Accepted Aug. 17, 2009.

Correspondence to: Dr. K.G. Todd, 12-127 Clinical Sciences Bldg., Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton AB T6G 2R7; fax 780 492-6841; kgtodd@ualberta.ca