NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia.
Hypoxia-ischemia (H/I) in the premature infant leads to white matter injury termed periventricular leukomalacia (PVL), the leading cause of subsequent neurological deficits. Glutamatergic excitotoxicity in white matter oligodendrocytes (OLs) mediated by cell surface glutamate receptors (GluRs) of the AMPA subtype has been demonstrated as one factor in this injury. Recently, it has been shown that rodent OLs also express functional NMDA GluRs (NMDARs), and overactivation of these receptors can mediate excitotoxic OL injury. Here we show that preterm human developing OLs express NMDARs during the PVL period of susceptibility, presenting a potential therapeutic target. The expression pattern mirrors that seen in the immature rat. Furthermore, the uncompetitive NMDAR antagonist memantine attenuates NMDA-evoked currents in developing OLs in situ in cerebral white matter of immature rats. Using an H/I rat model of white matter injury, we show in vivo that post-H/I treatment with memantine attenuates acute loss of the developing OL cell surface marker O1 and the mature OL marker MBP (myelin basic protein), and also prevents the long-term reduction in cerebral mantle thickness seen at postnatal day 21 in this model. These protective doses of memantine do not affect normal myelination or cortical growth. Together, these data suggest that NMDAR blockade with memantine may provide an effective pharmacological prevention of PVL in the premature infant.
Manning
Simon M
SM
Department of Neurology, Children's Hospital, Boston, Massachusetts 02115, USA.
Talos
Delia M
DM
Zhou
Chengwen
C
Selip
Debra B
DB
Park
Hyun-Kyung
HK
Park
Chang-Joo
CJ
Volpe
Joseph J
JJ
Jensen
Frances E
FE
D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014855:Wallerian Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control
D000943:Antigens, Differentiation; D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D004676:Myelin Basic Protein; D016194:Receptors, N-Methyl-D-Aspartate; C488961:oligodendrocyte O antigen, rat; D008559:Memantine