Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model.
Hypoxic-ischemic encephalopathy (HIE) is a leading cause of mortality and morbidity during the perinatal period, and currently no therapeutic drug is available. Minocycline, an antibiotic, has recently been shown to have neuroprotective effects distinct from its antimicrobial effect in several neurological disorders including ischemic brain injury. We examined the effect of minocycline on neonatal hypoxic-ischemic brain injury by using histologic scoring in both mouse and rat models. Mouse (C57Bl/6) and rat (SD) pups were exposed to a unilateral hypoxic-ischemic insult at 8 and 7 days of age, respectively. Minocycline hydrochloride was administered according to protocols that were reported to provide neuroprotection in adult or neonatal rats. Seven days after the insult, we examined brain injury in Nissl stained sections. Although minocycline ameliorated brain injury in the developing rat, it increased injury in the developing mouse. This detrimental effect in the mouse was consistent across different regions (cortex, striatum, and thalamus), with both single and multiple injection protocols and with both moderate and high-dose treatment (P < 0.05). The mechanism of the contrasting effects in mouse and rat is not clear and remains to be elucidated. Minocycline has been used as an antibiotic in the clinical setting for decades; therefore, it may be considered for use in infants with hypoxic-ischemic brain damage, based on prior reports of neuroprotection in the rat. However, it is important to examine this drug carefully before clinical use in human infants, taking our data in the mouse model into consideration.
Tsuji
Masahiro
M
Kennedy Krieger Research Institute, Baltimore, MD 21205, USA. Tsuji@kennedykrieger.org
Wilson
Mary Ann
MA
Lange
Mary S
MS
Johnston
Michael V
MV
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D008911:Minocycline