dizocilpine-maleate and Leukomalacia--Periventricular

The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been demonstrated to be protective in a rat model of PVL, without effects on normal myelination or cortical growth. To further evaluate the safety of memantine in the developing brain, we demonstrate here that, in contrast to MK-801, memantine at neuroprotective doses does not increase neuronal constitutive apoptosis. In addition, there are no long-term alterations in the expression of NMDAR subunits, AMPAR subunits, and two markers of synaptogenesis, Synapsin-1 and PSD95. Evaluating clinically approved drugs in preclinical neonatal animal models of early brain development is an important prerequisite to considering them for clinical trial in preterm infants and early childhood.

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; In Situ Nick-End Labeling; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Leukomalacia, Periventricular; Male; Memantine; Membrane Proteins; Neuroprotective Agents; Protein Subunits; Rats; Rats, Long-Evans; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapsins

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight-day-old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31-day-old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre-treatment with the NMDA receptor antagonist MK-801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.

Topics: Animals; Animals, Newborn; Brain; Brain Stem; Cell Death; Cerebellum; Corpus Callosum; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Infant, Newborn; Leukomalacia, Periventricular; Male; Mice; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Shaken Baby Syndrome; Time Factors