John W. McDonald

Physiological and pathophysiological roles of excitatory amino acids during central nervous system development

Recent studies suggest that excitatory amino acids (EAAs) have a wide variety of physiological and pathophysiological roles during central nervous system (CNS) development. In addition to participating in neuronal signal transduction, EAAs also exert trophic influences affecting neuronal survival, growth and differentiation during restricted developmental periods. EAAs also participate in the development and maintenance of neuronal circuitry and regulate several forms of activity-dependent synaptic plasticity such as LTP and segregation of converging retinal inputs to tectum and visual cortex. Pre- and post-synaptic markers of EAA pathways in brain undergo marked ontogenic changes. These markers are commonly overexpressed during development; periods of overproduction often coincide with times when synaptic plasticity is great and when appropriate neuronal connections are consolidated. The electrophysiological and biochemical properties of EAA receptors also undergo marked ontogenic changes. In addition to these physiological roles of EAAs, overactivation of EAA receptors may initiate a cascade of cellular events which produce neuronal injury and death. There is a unique developmental profile of susceptibility of the brain to excitotoxic injury mediated by activation of each of the EAA receptor subtypes. Overactivation of EAA receptors is implicated in the pathophysiology of brain injury in several clinical disorders to which the developing brain is susceptible, including hypoxia-ischemia, epilepsy, physical trauma and some rare genetic abnormalities of amino acid metabolism. Potential therapeutic approaches may be rationally devised based on recent information about the developmental regulation of EAA receptors and their involvement in the pathogenesis of these disorders.

Spinal-cord injury

PURPOSE This article is an overview of the newer therapeutic interventions employed in the care of the spinal cord injured individual and the theoretical rationale supporting them. ISSUE Spinal Cord Injury (SCI) care was, until recently, a maintenance type treatment, addressing systems mostly affected by complications of the original injury (e.g. bladder, skin, spasiticity). CONCLUSION With the recent advances in the neuroscience field, more aggressive interventions geared at secondary injury prevention, neuronal regeneration and functional restoration are emerging.

Neurotoxicity of N-methyl-d-aspartate is markedly enhanced in developing rat central nervous system

The neurotoxic lesion produced by direct injection of 25 nmol ofN-methyl-d-aspartate (NMDA) into the corpus striatum of 7-day-old rats was compared to the effects of injecting 75 nmol into the striatum or hippocampus of adults. The area of histopathology in the immature striatum was 21 × larger than the striatal lesions in adults. Damage from NMDA injected into the immature striatum also extended into the dorsal hippocampus and produced an area of destruction which was 16 × larger than observed after direct injection into the adult hippocampus. Several studies have implicated excessiveN-methyl-d-aspartate receptor activation in the pathogenesis of hypopoxic-ischemic and hypoglycemic injury and our results suggest that this neurotoxic mechanism is extremely active in the immature brain.

MK-801 protects the neonatal brain from hypoxic-ischemic damage

Enhanced synaptic release of excitatory amino acid neurotransmitters may contribute to brain injury from hypoxia-ischemia (Meldrum, 1985; Simon et al., 1984). To examine this hypothesis in neonatal brain we tested MK-80I , a novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, using an in vivo experimental model of hypoxic-ischemic forebrain injury (Johnston, 1983). To induce injury, seven day old rats were anesthetized with ether and the right carotid was ligated (N = 63), after which they recovered with the dam for 2 h. The pups were then placed in a warmed (37°C) chamber and exposed to 8% oxygen balance nitrogen for 3 h, a procedure which resulted in hemispheric necrosis ipsilateral to the side of ligation. Effect of treatment was assessed using three MK-801 treatment protocols: administration of 1 dose of MK-801 (1 m g / k g ) before hypoxia (N = 10), a single dose during hypoxia (N = 18), or two doses, one before and another after 1.25 h of hypoxia (N = 9). In the second group, the timing of treatment was varied to determine if there was a critical time threshold for efficacy: a single dose was given after 1.25 h (N = 5), 1.5 h (N = 6) or 2.5 h (N = 7). Pups received one or two intraperitoneal injections of M K = 801 (N = 37) or phosphate buffered saline (N = 26); a group of untreated litter-mates served as additional controls (N = 5). Pups were sacrificed 5 days after

Magnesium reduces N-methyl-d-aspartate (NMDA)-mediated brain injury in perinatal rats

We evaluated the neuroprotective effects of systemically administered magnesium against N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Postnatal day (PND) 7 rats received unilateral intrastriatal injections of 25 nmol NMDA followed 15 min later by single or multiple doses of magnesium intraperitoneally (i.p.). Animals were sacrificed five days later and the severity of brain injury was assessed by comparison of the weights of the injected and contralateral cerebral hemispheres. NMDA injection reduced the weight of the injected cerebral hemisphere by 31 +/- 3%. Single doses of magnesium reduced the severity of NMDA-induced brain injury in a dose-dependent fashion (2 mmol/kg, 29 +/- 11% protection; 3 mmol/kg, 52 +/- 12% protection; 4 mmol/kg, 62 +/- 7% protection). Multiple doses of magnesium reduced brain injury by 65 +/- 4%. These data demonstrate that systemically administered magnesium antagonizes the neurotoxic effects of NMDA in vivo in perinatal rats.

Architectural support for fast symmetric-key cryptography

The emergence of the Internet as a trusted medium for commerce and communication has made cryptography an essential component of modern information systems. Cryptography provides the mechanisms necessary to implement accountability, accuracy, and confidentiality in communication. As demands for secure communication bandwidth grow, efficient cryptographic processing will become increasingly vital to good system performance.In this paper, we explore techinques to improve the performance of symmetric key cipher algorithms. Eight popular strong encryption algorithms are examined in detail. Analysis reveals the algorithms are computaionally complex and contain little parallelism. Overall throughput on high-end microprocessor is quite poor, a 600 Mhz processor is incapable of saturation a T3 communication line with 3DES (triple DES) encrypted data.We introduce new instructions taht improve the efficiency of the analyzed algorithms. Our approach adds instruction set support for fast substitutions, general permutations, rotates, and modular arithmetic. Performance analysis of the optimized ciphers shows an overall speedup of 59% over a baseline machine with rotate instructions and 74% speedup over a baseline without rotates. Even higher speedups are demonstrated with optimized subtitutions (SBOXes) and additional functional unit resources. our analyses of the original and optimized algorithms suggest future directions for the design of high-performance programmable cryptographic processors.

Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair.

Purpose of reviewIn this review, we have documented some current research trends in rodent models of spinal cord injury. We have also catalogued the treatments used in studies published between October 2002 and November 2003, with special attention given to studies in which treatments were delayed for at least 4 days after injury. Recent findingsMost spinal cord injury studies are performed with one of three general injury models: transection, compression, or contusion. Although most treatments are begun immediately after injury, a growing number of studies have used delayed interventions. Mice and the genetic tools they offer are gaining in popularity. Some researchers are setting their sights beyond locomotion, to issues more pressing for people with spinal cord injury (especially bladder function and pain). SummaryDelayed treatment protocols may extend the window of opportunity for treatment of spinal cord injury, whereas continued progress in the prevention of secondary cell death will reduce the severity of new cases. The use of mice will hopefully accelerate progress towards useful regeneration in humans. Researchers must improve cross-study comparability to allow balanced decisions about potentially useful treatments.

Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model.

Severe hyperbilirubinemia in neonates with prematurity and/or systemic illnesses such as hemolytic disease, acidosis, and hypoxemia enhances their risk for developing cerebral palsy, paralysis of ocular upgaze, and deafness. This neurologic syndrome has been associated with selective neuronal vulnerability in the basal ganglia, certain brainstem nuclei, and Purkinje cells. However, the mechanism by which bilirubin damages neurons remains unclear. In these studies, we found that intracerebral injection of N-methyl-D-aspartate (NMDA), an excitotoxic analogue of glutamate, caused greater injury in jaundiced 7-day-old Gunn (jj) rat pups than in nonjaundiced heterozygous (Nj) littermate controls. NMDA injection caused even greater injury when protein-bound bilirubin was displaced with the sulfonamide drug sulfadimethoxine in jaundiced homozygous pups. In additional experiments, the acute signs of bilirubin-mediated neuronal injury, induced in homozygous (jj) Gunn rats by treatment with sulfonamide, were reduced by concurrent treatment with the NMDA-type glutamate channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine (MK-801, dizocilpine). The results suggest that bilirubin may cause encephalopathy and neuronal injury, at least in part, through an NMDA receptor-mediated excitotoxic mechanism. This conclusion is consistent with clinical observations that bilirubin encephalopathy is synergistically worsened by hypoxemia, which also shares an excitotoxic mechanism of neuronal injury.

Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development

The excitatory and excitotoxic actions of the endogenous excitatory amino acid (EAA) neurotransmitter, glutamate, are mediated by activation of three common subtypes of EAA receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/quisqualate and kainate receptors. EAA neurotransmitter systems play a number of physiological roles in the regulation and organization of neural systems during development. However, excessive activation of this neurotransmitter system is also implicated in the pathophysiology of several forms of acute and chronic brain injury. In this study, the susceptibility of the developing rat brain to AMPA/quisqualate receptor mediated injury was examined at eight postnatal ages (1-90 days). The receptor agonists, AMPA (25 nmol) or quisqualate (100 nmol), were stereotaxically microinjected unilaterally into the anterior striatum. The severity of resulting brain injury was assessed 5 days later by comparison of reductions in regional cortical and striatal cross-sectional areas. Microinjection of AMPA (25 nmol) produced widespread unilateral forebrain injury in the intermediate postnatal period (days 5-28). The severity of injury resulting from microinjection of a fixed dose of AMPA (25 nmol) transiently exceeded the severity of injury in adults between PND 5-28 with peak sensitivity occurring near PND 10. At PND 1, microinjection of AMPA produced a 24.5 +/- 1.7% reduction in striatal cross-sectional area, which is similar to the response observed in adult animals, and the lesion was confined to the injection site. Susceptibility to AMPA toxicity increased 2-fold from PND 1 to PND 5. At PND 10, the age of maximal sensitivity, the excitotoxic reaction to AMPA extended throughout the entire cerebral hemisphere and the mean striatal cross-sectional area was reduced by 81.7 +/- 3.9%. With advancing postnatal age, the severity of injury progressively diminished and the lesion became confined to the injection site. The developmental pattern of sensitivity to AMPA toxicity in other brain regions differed although peak sensitivity consistently occurred near PND 10. Microinjection of quisqualate produced a developmental pattern of striatal susceptibility similar to AMPA although quisqualate was a considerable less potent neurotoxin. In additional experiments, the in vivo pharmacology of AMPA and quisqualate mediated brain injury was evaluated in a PND 7 rat model in order to determine the neurotoxic characteristics and specificity of these agonists in vivo. The severity of brain injury was assessed 5 days after intrastriatal excitotoxin injection by comparison of cerebral hemisphere weights.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative assessment of neuroprotection against NMDA-induced brain injury

In immature rodent brain, unilateral intrastriatal injections of selected excitatory amino acid (EAA) receptor agonists, such as N-methyl-D-aspartate (NMDA), produce prominent ipsilateral forebrain lesions. In Postnatal Day (PND) 7 rats that receive a right intrastriatal injection of NMDA (25 nmol) and are sacrificed 5 days later, there is a considerable and consistent reduction in the weight of the injected cerebral hemisphere relative to that of the contralateral side (-28.5 +/- 1.9%, n = 6). In animals treated with specific NMDA receptor antagonists, the severity of NMDA-induced damage is markedly reduced. We have previously reported that the efficacy of potential neuroprotective drugs in limiting NMDA-induced lesions can be assessed quantitatively by comparison of hemisphere weights after a unilateral NMDA injection. In this study, we compared three quantitative methods to evaluate the severity of NMDA-induced brain injury and the degree of neuroprotection provided by NMDA receptor antagonists. We characterized the severity of brain injury resulting from intrastriatal injections of 1-50 nmol NMDA in PND 7 rats sacrificed on PND 12 by (i) comparison of cerebral hemisphere weights; (ii) assay of the activity of the cholinergic neuronal marker, choline acetyltransferase (ChAT) activity; and (iii) measurement of regional brain cross-sectional areas. The severity of the resulting brain injury as assessed by comparison of hemisphere weights increased linearly with the amount of NMDA injected into the striatum up to 25 nmol NMDA. The magnitude of injury was highly correlated with the degree of reduction in ChAT activity (r2 = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)