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Neuronal Death Enhanced by N-Methyl-D- Aspartate Antagonists

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Neuronal Death Enhanced by N-Methyl-D- Aspartate Antagonists Neuronal death enhanced by N-methyl-D- aspartate antagonists Chrysanthy Ikonomidou*†, Vanya Stefovska*, and Lechoslaw Turski‡ *Department of Pediatric Neurology, Children’s Hospital, Charite´-Virchow Clinics, Humboldt University, Augustenburger Platz 1, D-13353 Berlin, Germany; and ‡Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, London, WC1E 6BT, United Kingdom Communicated by Martin Lindauer, University of Wu¨rzburg, Wu¨rzburg, Germany, August 28, 2000 (received for review May 23, 2000) Glutamate promotes neuronal survival during brain development thesia. 3NP was infused at 12 or 24 mg͞kg per d for 28 days. and destroys neurons after injuries in the mature brain. Glutamate Dizocilpine (MK801; 0.3 mg͞kg per d), memantine (24 mg͞kg antagonists are in human clinical trials aiming to demonstrate per d), 3-((Ϯ)-2-carboxypiperazin-4-yl)propyl-1-phosphonate limitation of neuronal injury after head trauma, which consists of (CPP; 24 mg͞kg per d), 2,3-dihydroxy-6-nitro-7-sulfamoylben- both rapid and slowly progressing neurodegeneration. Further- zo(f)quinoxaline (NBQX; 24 mg͞kg per d), [1,2,3,4-tetrahydro- more, glutamate antagonists are considered for neuroprotection in 7-morpholinyl-2,3-dioxo-6-(trifluoromethyl)quinoxalin-1- chronic neurodegenerative disorders with slowly progressing cell yl]methylphosphonate (MPQX; 24 mg͞kg per d), or vehicle were death only. Therefore, humans suffering from Huntington’s dis- administered s.c. by means of osmotic minipumps either simul- ease, characterized by slowly progressing neurodegeneration of taneously with 3NP, 12 mg͞kgperdor24mg͞kg per d, or alone. the basal ganglia, are subjected to trials with glutamate antago- Intrastriatal microinjections. Wistar rats were anesthetized with nists. Here we demonstrate that progressive neurodegeneration sodium pentobarbital (50 mg͞kg i.p.) and subjected to bilateral in the basal ganglia induced by the mitochondrial toxin 3-nitro- microinjection of 3NP, 100, 250, or 500 nmol, into the striatum propionate or in the hippocampus by traumatic brain injury is at coordinates derived from the stereotaxic atlas of Swanson enhanced by N-methyl-D-aspartate antagonists but ameliorated by (10). The coordinates were: AP (anterior͞posterior) 7.63; L ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonists. (lateral) 2.0; V (ventral) 3.2. To assess effect of NMDA antag- These observations reveal that N-methyl-D-aspartate antagonists may increase neurodestruction in mature brain undergoing slowly onists on neurodegeneration induced by 3NP, CPP, 250 nmol, progressing neurodegeneration, whereas blockade of the action of was coadministered with 3NP, 250 nmol, into one striatum. The ␣ contralateral side received 3NP alone and served as control. glutamate at -amino-3-hydroxy-5-methyl-4-isoxazole-propionate ␮ receptors may be neuroprotective. Drugs were delivered into the striatum in a volume of 2 lata rate of 0.1 ␮l͞min. Neurologic assessment. The following scoring system was used lutamate antagonists were demonstrated to be neuropro- to grade neurologic impairment in rats subjected to treatment Gtective in stroke and head trauma in rodents and nonhuman with 3NP: 0, no observable motor deficits; 1, reduction of primates (1, 2). Accordingly, the excitatory neurotransmitter spontaneous locomotor activity; 2, unsteady, wobbly gait, ataxia; glutamate has been pathogenetically linked to cell death in acute and 3, severe depression of movement and loss of righting reflex. neurodegenerative disorders in humans such as stroke or trau- Scores were taken three times a week by a single observer under matic brain injury (1). This inference prompted the assumption blinded conditions. Shown are mean Ϯ SEM maximal scores that glutamate antagonists must be neuroprotective in chronic neurodegenerative disorders in humans (3, 4). However, whether registered during the entire observation period. Morphology. glutamate antagonists limit neurodegeneration in slowly pro- For morphological examination, rats were anes- gressing neurodegenerative disorders is not known. Neverthe- thetized with an overdose of pentobarbital and perfused with a less, clinical trials in humans suffering from Huntington’s dis- fixative containing 1% paraformaldehyde and 1.5% glutaralde- ease, Parkinson’s disease, and severe dementia using glutamate hyde in pyrophosphate buffer (for combined light and electron N-methyl-D-aspartate (NMDA) antagonists are in progress (5). microscopy), or containing 10% acetic acid, 10% formaldehyde, Neuronal loss in the basal ganglia is the hallmark pathological 80% methanol (for paraffin embedding). Serial coronal sections ␮ feature of Huntington’s disease and can be reproduced in rodents of the whole brain were cut 10 m thick, and every 20th section and primates by administration of the succinate dehydrogenase was mounted on a glass slide and stained with cresyl violet, or by inhibitor 3-nitropropionate (3NP) (6). Intrastriatal administration Fink and Heimer technique (11). For electron microscopy of 3NP produces in rodents rapid neuronal death and dystonia striatal tissue was processed in osmium tetroxide, dehydrated in resembling that seen in humans suffering from moldy sugarcane graded ethanols, cleared in toluene, embedded in araldite, and poisoning (7). Systemic administration of 3NP produces slowly examined by transmission electron microscope. progressing neuronal death in the striatum of rodents and primates Quantification of neuronal damage in the striatum. The volume with symptoms of chorea developing with a considerable delay (8). of the striatum in rats subjected to systemic treatment with 3NP, Similarly, traumatic head injury causes immediate death of neurons glutamate antagonists, or vehicle was measured 3 days after at impact in the cortex and slowly progressing neurodegeneration termination of continuous administration of drugs, by using an at sites distant to the impact such as hippocampus (9). image analysis system. To provide an estimate for the overall Here we demonstrate that slowly progressing neuronal death induced by systemic treatment with 3NP in the striatum or by traumatic brain injury in the hippocampus is enhanced by Abbreviations: AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionate; CPP, 3-((Ϯ)-2- NMDA but ameliorated by ␣-amino-3-hydroxy-5-methyl-4- carboxypiperazin-4-yl)propyl-1-phosphonate; MK801, dizocilpine; MPQX, [1,2,3,4- tetrahydro-7-morpholinyl-2,3-dioxo-6-(trifluoromethyl)quinoxalin-1-yl]methylphospho- isoxazole-propionate (AMPA) antagonists in mature rodent nate; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline; NMDA, N-methyl-D- brain. Rapidly progressing neuronal death induced by intrastri- aspartate; 3NP, 3-nitropropionate; Nv, numerical density. atal treatment with 3NP or by traumatic brain injury in the cortex †To whom reprint requests should be addressed. E-mail: [email protected]. is decreased by NMDA antagonists. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Materials and Methods §1734 solely to indicate this fact. 3NP. Systemic delivery. Wistar rats (24–28 months old, 750–950 g) Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073͞pnas.220412197. PHARMACOLOGY were implanted s.c. with osmotic minipumps under ether anes- Article and publication date are at www.pnas.org͞cgi͞doi͞10.1073͞pnas.220412197 PNAS ͉ November 7, 2000 ͉ vol. 97 ͉ no. 23 ͉ 12885–12890 Downloaded by guest on September 24, 2021 striatal neuronal loss over the treatment period of 28 days, administration of vehicle, CPP, or NBQX. The pH, arterial numerical densities (Nv) of striatal neurons were determined by oxygen, carbon dioxide, glucose, and bicarbonate levels were means of the stereologic disector (12, 13) and the total number determined by using automated diagnostic procedures. A rectal of neurons remaining in the striatum were calculated. The temperature probe was connected to a temperature controller volume of the striatum and striatal damage resulting from coupled to a heating pad maintained at 37.5 Ϯ 0.5°C throughout intrastriatal microinjections of 3NP was estimated volumetrically surgery. After surgery, animals were transferred to individual 4 h after administration by using image analysis. To provide an home cages that were kept on heated tables set at 36.5–37.5°C for estimate for neuronal loss after microinjection of 3NP, CPP, or up to 24 h. During the following 48 h animals were individually vehicle into the striatum, Nv of normal neurons were determined housed under standard environmentally controlled conditions (6 in striatum by means of the stereologic disector and the numbers a.m. to 6 p.m.; 12-hr light͞dark cycle; 24–25°C) and were of neurons lost in the striatum were calculated. permitted free access to food and water. Body weight was monitored by means of a Sartorius model U6100 balance. Traumatic Brain Injury. Contusing device. The contusing device Morphometric analysis in cortex and hippocampus. The volume consisted of a stainless steel tube, 40 cm in length, perforated at of the damage in the cortex was determined stereologically 3 1-cm intervals to prevent air compression in the tube. Fischer 344 days after traumatic injury by using an image analysis. The rats, 230–270 g, were anesthetized with tribromoethanol, 260 damage in the hippocampal CA3 subfield was determined mg͞kg i.p. A craniotomy over the right hemisphere
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