title: The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain.
abstract: 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.
authors.affiliation: Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Manning
authors.forename: Griffin
authors.initials: G
authors.lastname: Boll
authors.forename: Erin
authors.initials: E
authors.lastname: Fitzgerald
authors.forename: Debra B
authors.initials: DB
authors.lastname: Selip
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Volpe
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007969:Leukomalacia, Periventricular / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D021122:Protein Subunits; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D016704:Synapsins; D016291:Dizocilpine Maleate; D008559:Memantine