Objective: This study investigated the hypothesis that ceftriaxone preconditioning ameliorates brain damage in neonatal animals through glutamate transporter 1 (GLT-1) upregulation. Study design: Sprague Dawley rats were pretreated with ceftriaxone, erythromycin, minocycline, or saline for 5 consecutive days starting from postnatal day 2 (P2), and GLT-1/glutamate-aspartate transporter (GLAST) messenger RNA (mRNA) and protein levels were examined in the P7 brains. After ceftriaxone or saline preconditioning, the P7 rats underwent hypoxic-ischemic (H-I) procedure or sham operation. One week after the procedure (P14), hematoxylin-eosin staining, microtubule-associated protein 2 (MAP-2) immunostaining, and transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay were used to examine neuronal damage and possible neurotoxicity. Results: Repeated ceftriaxone injections significantly increased GLT-1 mRNA and protein levels but not GLAST. Following such treatment and H-I procedure, the MAP-2-positive area increased and TUNEL-positive cells decreased. Conclusion: Antenatal ceftriaxone may help to provide neuroprotection in the immature brain and become a new prophylactic strategy to reduce neonatal encephalopathy in clinical perinatal medicine.
TanakaKWataseKManabeT. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276(5319):1699–1702.
7.
RothsteinJDDykes-HobergMPardoCA. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16(3):675–686.
8.
RothsteinJDJinLDykes-HobergMKunclRW. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci U S A. 1993;90(14):6591–6595.
9.
McDonaldJWSilversteinFSJohnstonMV. Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res. 1988;459(1):200–203.
10.
TremblayERoisinMPRepresaACharriaut-MarlangueCBen-AriY. Transient increased density of NMDA binding sites in the developing rat hippocampus. Brain Res. 1988;461(2):393–396.
11.
McDonaldJWJohnstonMVYoungAB. Ontogeny of the receptors comprising the NMDA receptor complex. Soc Neurosci Abstr. 1989;15(3):198.
12.
RepresaATremblayEBen-AriY. Transient increase of NMDA-binding sites in human hippocampus during development. Neurosci Lett. 1989;99(1-2):61–66.
13.
FurutaARothsteinJDMartinLJ. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci. 1997;17(21):8363–8375.
14.
KuglerPSchleyerV. Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus. Hippocampus. 2004;14(8):975–985.
15.
McDonaldJWSilversteinFSJohnstonMV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol. 1987;140(3):359–361.
16.
OlneyJWIkonomidouCMosingerJLFrierdichG. MK-801 prevents hypobaric-ischemic neuronal degeneration in infant rat brain. J Neurosci. 1989;9(5):1701–1704.
17.
IkonomidouCBoschFMiksaM. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–74.
18.
StefovskaVCzuczwarMSmitkaM. Sedative and anticonvulsant drugs suppress postnatal neurogenesis. Ann Neurol. 2008;64(4):434–445.
KonCSoon-TaeLDong-InS. Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke. 2007;38(1):177–182.
21.
VermaRMishraVSasmalDRaghubirR. Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury. Eur J Pharmacol. 2010;638(1-3):65–71.
22.
HagbergHBonaEGillandEPuka-SundvallM. Hypoxia-ischemia model in the 7-day-old rat: possibilities and shortcomings. Acta Paediatr Suppl. 1997;442:85–88.
23.
BrambrinkAMKoernerIPDiehlKStrobelGNoppensRKempskiO. The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning). Anesthesiology. 2006;104(6):1208–1215.
24.
FoxCDingmanADeruginN. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2005;25(9):1138–1149.
25.
RiceJEVannucciRCBrierleyJB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9(2):131–141.
26.
KitagawaKMatsumotoMNinobeM. Microtubule-associated protein 2 as a sensitive marker for cerebral ischemic damage-immunohistochemical investigation of dendritic damage. Neuroscience. 1989;31(2):401–411.
27.
TomimatsuTFukudaHKanagawaTMuJKanzakiTMurataY. Effects of hyperthermia on hypoxic-ischemic brain damage in the immature rat: its influence on caspase-3–like protease. Am J Obstet Gynecol. 2003;188(3):768–773.
28.
NizzardoMNardiniMRonchiD. Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms. Exp Neurol 2011;229(2):214-225. 2011; In press;
29.
GoodmanLSHardmanJGLimbirdLE. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics.2001;New York, NY: McGraw-Hill,
30.
CriderKSClevesMAReefhuisJ. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163(11):978–985.
31.
NauRPrangeHWMuthP. Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges. Antimicrob Agents Chemother. 1993;37(7):1518–1524.
32.
KafetzisDABraterDCFanourgakisJEVoyatzisJGeorgakopoulosP. Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk postpartum. Antimicrob Agents Chemother. 1983;23(6):870–873.
33.
SidhuSTuorUIDel BingioMR. Nuclear condensation and fragmentation following cerebral hypoxia-ischemia occurs more frequently in immature than older rats. Neurosci Lett. 1997;223(2):129–132.
34.
HuBRLiuCLOuyangYBlomgrenKSiesjöBK. Involvement of caspase-3 in cell death after hypoxic-ischemic declines during brain maturation. J Cereb Blood Flow Metab. 2000;20(9):1294–1300.
35.
FukudaHTomimatsuTWatanabeN. Post-ischemic hypothermia blocks caspase-3 activation in the newborn rat brain after hypoxia-ischemia. Brain Res. 2001;910(1-2):187–191.
BrooksWJSarkisianMYangYHoriAHelmersSLMikatiM. Effect of chronic administration of NMDA antagonists on synaptic development. Synapse. 1997;26(2):104–113.
MurryCEJenningsRBReimerKA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–1136.
40.
HagbergHDammannOMallardCLevitonA. Preconditioning and the developing brain. Semin Perinatol. 2004;28(6):389–395.
41.
GiddayJMFitzgibbonsJCShahARParkTS. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett. 1994; 168(1-2):221–224.
42.
IkedaTIkenoueTXiaXYXiaYX. Important role of 72-kd heat shock protein expression in the endothelial cell in acquisition of hypoxic-ischemic tolerance in the immature rat. Am J Obstet Gynecol. 2000;182(2):380–386.
43.
GustavssonMAndersonMFMallardCHagbergH. Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats. Pediatr Res. 2005;57(2):305–309.
44.
SalterMGFernR. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438(7071):1167–1171.
45.
BackSAHanBHLuoNL. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci. 2002;22(2):455–463.
46.
FollettPLDengWDaiW. Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci. 2004; 24(18): 4412–4420.
