Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia-ischemia in neonatal rats.
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 (10mg/kg) or vehicle immediately before HI (n >or= 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-1Beta (IL-1Beta) and tumour necrosis factor-alpha (TNF-alpha); 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.


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


CONCLUSIONS
Taken together, our results suggest the putative clinical potential of DOXY in the management of neonatal cerebral HI injury.
Jantzie
Lauren L
LL
Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alta., Canada.
Todd
Kathryn G
KG
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D008137:Longitudinal Studies; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline