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Systemic Administration of Mk-801 Protects Against ~=Met~Yl~~-Aspartate* and Quisqualate-Mediated Neurotoxicity in Perinatal Rats

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Systemic Administration of Mk-801 Protects Against ~=Met~Yl~~-Aspartate* and Quisqualate-Mediated Neurotoxicity in Perinatal Rats Neatroscience Vol. 36, No. 3. pp. 589-599, 1990 0306-4522j90 $3.00 f 0.00 Printed in Great Britain Pergamon Press plc 0 1990 IBRO SYSTEMIC ADMINISTRATION OF MK-801 PROTECTS AGAINST ~=MET~YL~~-ASPARTATE* AND QUISQUALATE-MEDIATED NEUROTOXICITY IN PERINATAL RATS J. W. MCDONALD,* F. S. .%LvERS~IN,~$ II. Chmo~~,$ C. HmmN,$ R. CWEN~and M. V. JoHNsToN*~$$IIB *Neuroscience Training Program and Departments of TPediatrics and SNeurotogy, Medical SchooI, and &%nter for Human Growth and Development, University of Michigan, Ann Arbor, MI 48Io4, U.S.A. ~~~Fa~rnen~ of Neurology and Pediatrics, Johns Hopkins Un~~~~~ty Schoot of Medicine and the Kennedy Institute, Baltimore, MD 21205, U.S.A. Abstract-MK-801, a non-competitive antagonist of N-methy&aspartate-type glutamate receptors, was tested for its abiiity to antagonize excitotoxic actions of ~-methyl-~-as~~ate or quisqualic acid injected into the brains of seven-day-old rats, Stereotaxic injection of ~“me~yi-~aspa~ate (25 nmol/OS ai) or quisqualic acid (100 nmol/l.O ~1) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies, ~-Methyl-~aspa~ate produced severe, mntluent neuronal destruction while quisquaiic acid typicatty caused more selective neuronaf necrosis. Intraperitoneal administration of MK-801 (0.1-1.0 mg/kg) 30 min before N-methyl-D-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. A 1 mg/kg dose of MK-801 given as pre-treatment completely protected the infant brain. The same dose of MK-801 was also completely protective when administers 30 or 40 min after ~-methyl-~-as~rtate and afforded partial protection when given 2 h later. MK-801 pre-treatment also prevented the electrically confirmed behavioral seizures induced by N-methyl-D-aspartate. The drug significantly reduced striatal but not hippocampal or neocortical injury when given as two doses (I mg/kg) 30 min prior to and immediately following quisqualic acid injection. The data indicate that systemic admin~stra~on of MK-8Of can prevent ~-methyl-D-aspar~te-indu~ neuronal injury in perinatsl rat brain even when administered after the initial insult. MK-801 also partially antagonized quisqualic acid-mediated neurotoxicity, suggesting that quisqualic acid-induced toxicity is, in part, mediated through N-methyl+aspartate receptor activation. The sensitivity of the developing brain to the toxicity of N-methyl-D-aspartate provides a sensitive and reproducible in uivo model for exploring these issues and for screening prospective neuroprot~tive drugs that act at the N-methyl-D- aspartate receptor-channel complex. The excitatory amino acid @AA) receptor subtypes, and biochemicalfy (for review see Ref. 8). NMDA specific for IV-methyl-D-aspartate (NMDA), quis- activates a calcium-permeable cationic channel26 qualate and kainate are uniquely distributed in the that is gated by Mg2+ 30*40in a voltage-dependent developing and mature brain and are distinguished manner.1t,27 The NMDA response is enhanced by by biochemical,i5v24*2selectrophysiologicalS.~o,3s,52 and glycine22 and is non-competitively blocked in a use- pharmacological criteria.8.‘8~19*37Each of the receptor dependent manner by phencyclidine receptor ligands subtypes may mediate physiologic excitatary neur- including (( + )-Smethyt- 10,l I -dihydro-SH-dibenzo- onal responses but under conditions of excessive ~~~~~y~Iohepten-~,~O-i~ne meleate) (MK-S01)6 and receptor activation, agonists for these receptors are the dissociative anesthetic ciass of compounds.29*‘4 capable of initiating a cascade of events resulting in Furthermore, the distributions of NMDA and phen- neuronal death in both the adult39*42.Mand immature cyclidine receptors in the mammalian forebrain are brain.7*33”h49The NM~A-prefer~ng receptor subtype identical.” This finding, taken together with pharma- has been best characterized el~trophysiolog~ca~~y cological evidence of interactions between these __I.. two receptor sites, suggests that NMDA and phen- fiTo wham correspondence should be addressed. cyclidine receptors may be components of the same Abbreufatfons: APN, 7-~~nophosphonoh~~noic acid; receptor-ion channel complex. EAA, excitatory amino acid; EEG, eleetroencepha- Excessive NMDA receptor activation has been iogram; MK-801, f( +)-5-methyl-iO,I i-dihydro-5I%di- benzo[a,dicycloheaten-5, IO-imine meleatel: NMDA. implicated in neuron4 damage resulting from N-meihyl:D-aspariate; PBF, phosphate-buf&red forma; hypoxia-ischemia; 31.36*45*47hypoglycemias3 and sus- lin; PBS, phosphate-buffered saline. tained seizures.3S48 Simon et al.‘? first reported that 590 J. W. MCDONALD et ul. pre-treatment with the competitive NMDA receptor ately following intrastriatal quisqualic acid administration antagonist 7-aminophosphonoheptanoic acid (APH) (n = 6). Four-additional groips served as controls: intra- striatal NMDA + in. PBS (n = 28). intrastriatal vehicle + reduced acute ischemic hippocampal damage in i.p. PBS (n = S), intiastriatal vehicle + i.p. MK-801 (n = 7) r,itw. Recent reports indicate that MK-801, a non- and intrastriatal quisquaiic acid f i.p. PBS (n = 4). Appro- competitive NMDA antagonist acting at the phen- priate littermate controls were included in each experiment cyclidine site associated with the NMDA receptor- on each day. All pups were subsequently returned to the dam for channel complex, is a potent neuroprotectant, five days and were decapitated on day 12. A five-day reducing hypoxic-ischemic damage in uiw even when survival period allows sufficient time for brain edema to given after the initiation of the insult in both the resolve (unpublished obseffatjons). Their brains were immature” and adult brain.” Furthermore, MK-801 removed and placed sequentially into 10% phosphate- selectively attenuates neuronal damage in adult rats buffered formalin (PBF) followed by a 30% sucrose/PBF solution. Fifty-micron frozen microtome coronal sections caused by intracerebral injection of NMDA but not were stained for Nissl substance with Cresyl Violet. Tissue kainic acid.” This evidence suggests that neuronal damage was assessed qualitatively by light microscopy and damage in conditions related to glutamate toxicity quantitated by measurement of cross-sectional areas of is mediated, in part, by excessive NMDA receptor- corpus striatum, dorsal hippocampus and cerebral hemi- sphere using a video-based computer-aided image analyser. channel activation. For each animal, measurements were made bilaterally in Several observations suggest that glutamate recep- four coronal sections through each individual structure tors and the severity of neurotoxicity mediated by corresponding to 0.7, 1.0. 1.3, 1.6 mm (striatum, cerebral glutamate analog undergo major changes during hemisphere) and 2.6. 2.8, 3.0, 3.2 mm (hippocampus) caudal postnatal development. A dense pattern of glutamate to bregma. The four measures for each structure were summed within animals by hemisphere and transformed by receptors in the globus palIidus and basal forebrain the formula 100 x (C -l/C) into a term reflecting the of rodents develops soon after birth and is greatly degree of damage (% damage) of the structure in the diminished in adults.” In contrast to the adult, the injected hemisphere relative to the contralateral structure. C neonatal brain is relatively insensitive to kainic acid’s and I refer to the cross-sectional areas of anatomical structures contralateral (C)and ipsilateral (I) to the lesioned neurotoxic effects.’ However, neonates are relatively hemisphere. The data were expressed as percentage protec- more sensitive to the neurotoxic effects of quisqualic tion (mean + S.E.M.) for each experimental group using the acid and NMDA.33,40 In order to examine the neuro- following formula: protective effects of MK-801 during development. we tested the ability of MK-801 to antagonize NMDA- (C - f)/C MK-801 or quisqualic acid-induced neurotoxicity in neonatal -- --~__- (C - I)/C control I-dtS. )I Values for experimental groups that received MK-801 and EXPERIMENTAL PROCEDURES an excitotoxin were compared with control groups that received an excitotoxin and saline. Seven-day-old male and female Sprague-Dawley albino Cortical electroencephalograms (EEGs) were recorded rat pups (Charles River, MI), maintained on a 12 h:l2 h from seven-day-old rat pups at 1 (n = 12) and 4 (n = 8) h 1ight:dark cycfe, were used for these experiments and were after intracerebral injections of 25 nmoi/0.5 ,ul of NMDA. housed with the dam at all times except for a 2-h experimen- EEG activity was recorded jnde~ndently from each cere- tal period. lntracerebral injections of excitotoxins were bral hemisphere. To prepare pups for EEG recordings, they performed in seven-day-old pups briefly but deeply anes- were briefly anesthetized with ether, the scalp was incised thetized with ether.l” A midline cranial incision was made in the midline and five holes were made into the skull with through the skin to expose the calvarium. Drugs were a 26-gauge needle. Using bregma as a central landmark, administered under stereotaxic guidance (Kopf small animal electrodes were placed bilaterally at AP + 3.75 mm. ML apparatus) using a Hamilton syringe with a 26-gauge needle. 2.5 mm and AP -3.Xmm, ML 2Smm. and the ground Pups were positioned in a plaster of Paris mold of the head was placed at a fifth site anteriorally and adjacent to the and body. All intracerebral injections were directed into the midline. Electrodes were secured at the epidural surface posterior corpus striatum. Coordinates were AP 2.0mm, of the cortex with dental acrylic. ML 2.5 mm, at depth of 4.0 mm from the dura using bregma Electrodes were connected to a Grass P5 11J amplifier and as a landmark.
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