Elsevier

Neuroscience

Volume 137, Issue 2, 2006, Pages 425-435
Neuroscience

Research paper
Developmental neuroscience
Minocycline alleviates hypoxic–ischemic injury to developing oligodendrocytes in the neonatal rat brain

https://doi.org/10.1016/j.neuroscience.2005.09.023Get rights and content

Abstract

The role of minocycline in preventing white matter injury, in particular the injury to developing oligodendrocytes was examined in a neonatal rat model of hypoxia–ischemia. Hypoxia–ischemia was achieved through bilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen) for 15 min in postnatal day 4 Sprague–Dawley rats. A sham operation was performed in control rats. Minocycline (45mg/kg) or normal phosphate-buffered saline was administered intraperitoneally 12 h before and immediately after bilateral carotid artery occlusion+hypoxia and then every 24 h for 3 days. Nissl staining revealed pyknotic cells in the white matter area of the rat brain 1 and 5 days after hypoxia–ischemia. Hypoxia–ischemia insult also resulted in apoptotic oligodendrocyte cell death, loss of O4+ and O1+ oligodendrocyte immunoreactivity, and hypomyelination as indicated by decreased myelin basic protein immunostaining and by loss of mature oligodendrocytes in the rat brain. Minocycline significantly attenuated hypoxia–ischemia-induced brain injury. The protective effect of minocycline was associated with suppression of hypoxia–ischemia-induced microglial activation as indicated by the decreased number of activated microglia, which were also interleukin-1β and inducible nitric oxide synthase expressing cells. The protective effect of minocycline was also linked with reduction in hypoxia–ischemia-induced oxidative and nitrosative stress as indicated by 4-hydroxynonenal and nitrotyrosine positive oligodendrocytes, respectively. The reduction in hypoxia–ischemia-induced oxidative stress was also evidenced by the decreases in the content of 8-isoprostane in the minocycline-treated hypoxia–ischemia rat brain as compared with that in the vehicle-treated hypoxia–ischemia rat brain. The overall results suggest that reduction in microglial activation may protect developing oligodendrocytes in the neonatal brain from hypoxia–ischemia injury.

Section snippets

Chemicals

Unless otherwise stated, all chemicals used in this study were purchased from Sigma (St. Louis, MO, USA). Monoclonal mouse antibodies against O4, O1, glial fibrillary acidic protein (GFAP), neuron-specific nuclear protein (NeuN) or nitrotyrosine (NT), rabbit anti-caspase-3 (the active form) antibody, and the terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) staining kit were purchased from Chemicon (Temecula, CA, USA). Mouse anti-myelin

Minocycline attenuated HI-induced brain injury

BCAO followed by 15 min hypoxic exposure resulted in cell death, as indicated by many pyknotic cells shown by the Nissl staining, in the cingulum, the subventricular areas and the subcortical white matter tract of 82% of the rat brain 24 h after the HI insult (Fig. 1B and Table 1). In some more severely injured brains, pyknotic cells were not limited to the white matter area and they were also found in the adjacent cortical gray matter. No pyknotic cells were found in the SH rat brain (Fig. 1A)

Discussion

The protective effect of doxycycline, a similar tetracycline compound as minocycline, on ischemic brain injury was first found in rabbits (Clark et al., 1994). Minocycline was later reported to protect the adult gerbil brain from injury induced by global ischemia (Yrjanheikki et al., 1998) and the adult rat brain from focal ischemic injury (Xu et al 2004, Yrjanheikki et al 1999). Minocycline has also been found to markedly protect the neonatal rat brain against HI injury (Arvin et al., 2002).

Conclusion

In summary, we showed that minocycline attenuates HI-induced injury to developing OLs and hypomyelination in the neonatal rat brain. The protective effect of minocycline in the present study is associated with its ability to reduce microglial activation.

Acknowledgment

This work was supported by HD 35496 and NS 54278.

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