An increase in the number of activated microglia in the brain is a key feature of neuroinflammation after a hypoxic-ischemic insult to the preterm neonate and can contribute to white matter injury in the brain. Minocycline is a potent inhibitor of microglia and may have a role as a neuroprotective agent that ameliorates brain injury after hypoxia-ischemia in neonatal animal models. However to date large doses, pre-insult administration and short periods of treatment after hypoxia-ischemia have mostly been investigated in animal models making it difficult to translate minocycline's potential applicability to protect the human preterm neonatal brain exposed to hypoxia-ischemia. We investigated whether repeated doses of minocycline can minimize white matter injury and neuroinflammation one week after hypoxia-ischemia (right carotid artery ligation and 30 min 6% O(2)) in the post-natal day 3 rat pup. Two dosage regimens of minocycline were administered for one week; a high dose of 45 mg/kg 2h after hypoxia-ischemia then 22.5 mg/kg daily or a low dose 22.5 mg/kg 2h after hypoxia-ischemia then 10 mg/kg. Post-natal day 3 hypoxia-ischemia significantly reduced myelin content, numbers of O1- and O4-positive oligodendrocyte progenitor cells and increased activated microglia one week later on post-natal day 10. The low dose minocycline regimen was as effective as the high dose in ameliorating neuroinflammation after post-natal day 3 hypoxia-ischemia. However only the high dose regimen significantly attenuated reductions in O1- and O4-positive oligodendrocyte progenitor cells and myelin content. The low dose only significantly attenuated the reduction in O1-positive oligodendrocyte cell counts. Repeated, daily, post-insult treatment with minocycline abolished neuroinflammation and may provide neuroprotection to white matter for up to one week after hypoxia-ischemia in a rodent preterm model. The present findings suggest the potential clinical relevance of a repeated, daily minocycline treatment strategy, administered after a hypoxia-ischemia insult, as a therapeutic intervention for hypoxia-ischemia-affected preterm neonates.

Minocycline is a second-generation tetracycline and a potential neuroprotective intervention following brain injury. However, despite the recognized beneficial effects of minocycline in a multitude of adult disease states, the clinical application of minocycline in neonates is contentious. Tetracyclines, as a class, are not usually administered to neonates, but there is compelling evidence that minocycline reduces brain injury after neonatal hypoxic-ischemic brain injury. This Review focuses on the evidence for minocycline use in neonates by considering aspects of pharmacology, drug regimens, functional outcomes, and mechanisms of action.

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Hypoxic-ischemic (HI) injury in the preterm neonate incurs numerous functional deficits, however little is known about the neurochemically-defined brain nuclei that may underpin them. Key candidates are the brainstem catecholamine neurons. Using an immature animal model, the postnatal day (P)-3 (P3) rat pup, we investigated the effects of HI on brainstem catecholamine neurons in the locus coeruleus, nucleus tractus solitarius (NTS), and ventrolateral medulla (VLM). On P21, we found that prior P3 HI significantly reduced numbers of catecholaminergic neurons in the locus coeruleus, NTS, and VLM. Only locus coeruleus A6, NTS A2, and VLM A1 noradrenergic neurons, but not NTS C2 and VLM C1 adrenergic neurons, were lost. There was also an associated reduction in dopamine-beta-hydroxylase-positive immunolabeling in the forebrain. These findings suggest neonatal HI can affect specific neurochemically-defined neuronal populations in the brainstem and that noradrenergic neurons are particularly vulnerable to HI injury. (Pediatr Res 63: 364-369, 2008) P rematurity and hypoxia-ischemia (HI) in newborn infants are critical risk factors contributing to perinatal mortality and neurologic morbidity. Perinatal HI in the preterm neonate can lead to long-term brain injury and a broad range of neurologic deficits that include motor disabilities, autonomic dysfunction, epilepsy, memory, and attention disorders (1,2). Premature neonates are particularly susceptible to white matter injury in the brain. Neuronal injury in the brain also ensues and damage to certain areas of the brain may be associated with neurologic impairments in adults or children who have experienced HI as a neonate. However, very little is known about how perinatal HI affects neurochemically-defined groups of neurons in the immature preterm brain. It is therefore difficult to ascertain which specific brain nuclei and neuronal networks might be responsible for, or at least contribute to, the long-term functional deficits observed and how different neurons vary in their susceptibility to HI injury.Injury to the brainstem after HI may be a critical contributor to autonomic and cardiorespiratory dysfunction in premature infants and neonatal animals (3-5). The brainstem consists of well-defined neurochemical groups of neurons, in particular the catecholamine neurons, serving as critical integratory sites in the brain. Distinct populations of brainstem catecholamine neurons reside in the locus coeruleus (A6 noradrenergic neurons), nucleus tractus solitarius (NTS) (A2 noradrenergic and C2 adrenergic neurons), and ventrolateral medulla (VLM) (A1 noradrenergic and C1 adrenergic neurons). These neuronal populations constitute the major sources of noradrenergic and adrenergic networks in the brain. The NTS and VLM catecholamine neurons, located in the medulla oblongata, have major roles in cardiovascular and respiratory control mechanisms, gastrointestinal, vasomotor tone, and neuroendocrine regulation (6,7). The locus coeruleus A6 noradrenergic neurons in the pont...

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LE is characterized by locally increased facilitation of pain, as measured by TS, but this is not associated with severity of pain or disability.

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