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The effect of sustained activation of excitatory amino acid receptors on neuronal survival was studied using slices of adult rat hippocampus and light and electron microscopy. Kainate, N-methyl-D-aspartate, quisqualate, and ibotenate all produce signs of severe neurotoxicity within 90 min. Neuronal damage occurs in the form of perikaryal and dendritic swelling, cytoplasmic and nucleoplasmic disintegration, and plasma and nuclear membrane ruffling and collapse. The toxicity is restricted to intrinsic neuronal somata, dendrites and spines, while afferent axons, boutons and glia are spared. Although damage is generally distributed throughout all areas of hippocampus, kainate has little effect on pyramidal neurons in the CA2 region. Quantitative analysis of neuronal survival indicates that agonists induce dose-dependent damage over concentration ranges known to be excitatory. Based on selective antagonism by DL-aminophosphonoheptanoate and the patterns of damage produced by each, N-methyl-D-aspartate, kainate, and quisqualate trigger neurotoxicity by acting on distinct receptor classes. It is concluded that, in hippocampal slices, excitatory amino acids induce neurotoxicity in a similar manner to their actions in vivo. The results support the hypothesis that hippocampal neurotoxicity is initiated by excessive excitation, and provide another example of the capacity of adult hippocampal neurons for rapid structural modification.
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PMID:Excitatory amino acid neurotoxicity in the hippocampal slice preparation. 305 May 89

Two weeks after daily topical application of hexachlorophene, a 4-week-old female kitten developed cardiovascular collapse, corneal ulcers, trembling, lethargy, and weakness. The kitten was euthanatized. At necropsy, the tissues appeared macroscopically normal; however, microscopic examination of tissue specimens indicated status spongiosis, astrocytosis, and microgliosis of the cerebral and cerebellar white matter and corticospinal tracts. Neuronal cell bodies forming the affected white matter were intact, indicating that demyelination may have been the cause of the lesions. The neurologic lesions were considered compatible with those of hexachlorophene-induced toxicosis.
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PMID:Neurotoxicosis associated with the use of hexachlorophene in a cat. 358 87

Lung volume was altered setting the mean air pressure within a closed spirometer system to +5, +10, -5 or -10 cm H2O. In many respiratory modulated neurons (RMN) the duration of discharge changed in the same direction as the duration of the corresponding half cycle, but changes of duration of neuronal discharge were often larger. This was the case in many EI neurons for the duration of discharge during expiration, in many I units at high lung volume for the duration during inspiration and in many IE and E cells at low lung volume for the duration of discharge during expiration. The responses to inflation or collapse, however, differed in magnitude. At all lung volumes in part of the IE and E neurons and at low lung volume in part of the I units the duration of discharge during inspiration changed in opposite direction as the duration of inspiration. Neuronal desactivation at high lung volume or activation at low volume was termed alpha-type response; it occurred in many I neurons at high lung volume and for the inspiratory part of discharge of many EI units. Neuronal activation at high lung volume or desactivation at low volume was denoted as beta-type response; it was observed in many I neurons at low lung volume and in E, EI and IE cells for the expiratory part of discharge. In a large majority of all phase types of RMN, incidence of maximum spike density within the burst discharge was delayed in time when the corresponding half cycle was prolonged and vice versa; the shift of time incidence often exceeded the change of duration of inspiration or expiration.
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PMID:Bulbar respiratory neurons during artificial lung distension or collapse in spontaneously breathing rabbits. 725 97

1. In the guinea-pig, a unilateral labyrinthectomy induces postural disturbances and an ocular nystagmus which abate or disappear over time. These behavioural changes are accompanied by an initial collapse and a subsequent restoration of the spontaneous activity in the neurones of the ipsilateral vestibular nuclei. Recently, it has been shown that the vestibular neuronal activity remained collapsed over at least 10 h whereas its restoration was complete 1 week after the lesion. The aims of this study were to determine when restoration of spontaneous activity in the partially deafferented vestibular neurones started and to compare the time courses of the behavioural and neuronal recoveries in guinea-pigs that had undergone a unilateral labyrinthectomy. 2. Neuronal discharge measurements were made using chronic extracellular recording of single unit activity. After a left labyrinthectomy, electrodes, were placed on the site of the destroyed labyrinth to enable stimulation of the left vestibular nerve. Behavioural measurements included chronic recording of eye movements by the scleral search coli technique. After a left labyrinthectomy, lateral deviation of the head, twisting of the head, and eye velocity of the slow phases of the nystagmus were measured. 3. The neuronal activity of the rostral part of the vestibular nuclear complex on the lesioned side was recorded in alert guinea-pigs over 4 h recording sessions between 12 and 72 h after the lesion. 4. The criterion used to select vestibular neurones for analysis was their recruitment by an electric shock on the vestibular nerve. In addition, in order to explore a uniform population, we focused on neurones recruited at monosynaptic latencies (0.85-1.15 ms). 5. For each recording period, the mean resting rate was calculated animal by animal and the grand mean of these individual resting rate means was calculated. Previously, a decline in the grand mean resting rate from 35.8 +/- 6.0 spikes s-1 (control state) to 7.1 +/- 4.2 spikes s-1 during the first 4 h after labyrinthectomy has been shown. In the present study, the first sign of recovery was observed during the 12-16 h recording period when the resting rate grand mean increased to 16.3 +/- 3.9 spikes s-1. This grand mean activity did not change significantly during the following 12 h. Thereafter, restoration of neuronal activity improved and was complete 1 week after the lesion. 6. Although the abatement of the vestibular symptoms roughly paralleled the restoration of neuronal activity in the vestibular nuclei, some discrepancies between the time courses of both phenomena emerged. An important step in postural recovery (the animals managed to stand up) and a major part of the abatement of the nystagmus occurred before the recovery of vestibular neuronal activity. In addition, lateral deviation of the head disappeared while restoration of the neuronal activity was incomplete, but significant head twisting was still evident when vestibular resting rates had recovered completely. 7. We conclude that restoration of neuronal activity in the ipsilateral vestibular nuclei starts 12 h after the lesion and that restoration of neuronal activity in the ipsilateral vestibular nuclei is not the only mechanism underlying behavioural vestibular compensation.
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PMID:Dissociations between behavioural recovery and restoration of vestibular activity in the unilabyrinthectomized guinea-pig. 914 34

Glutathione (GSH) levels are supposed to determine the vulnerability of many cells towards a wide array of insults. We investigated the effects of chronic inhibition of GSH synthesis and acute depletion of GSH on cerebellar granule neurons in vitro and determined cytoplasmic and mitochondrial GSH with relation to mitochondrial function and generation of reactive oxygen intermediates (ROI). l-buthionine sulfoximine (BSO), which irreversibly blocks gamma-glutamyl-cysteine synthase, led to a time- and concentration-dependent loss of cytoplasmic GSH, while mitochondrial GSH was relatively preserved. No increased generation of ROI was detected over 48 h and the mitochondrial membrane potential was largely maintained. Neuronal degeneration occurred when mitochondrial GSH levels had fallen below 50% of control after 24-36 h. In contrast, direct conjugation of mitochondrial and cytoplasmic GSH with etacrynic acid (EA), resulted in immediate loss of mitochondrial GSH, a large increase of ROI within 2 h, subsequent collapse of the mitochondrial membrane potential and complete cell death within 4-8 h. Electron microscopy studies revealed an as yet unknown change of the chromatin structure to a homogeneous granular pattern after BSO, while EA resulted in typical necrotic changes. No typical features of apoptosis, i.e., no chromatin condensation or DNA fragmentation were detected after GSH depletion after BSO or EA treatment.
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PMID:Glutathione depletion and neuronal cell death: the role of reactive oxygen intermediates and mitochondrial function. 1021 96

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein-coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Galpha12 and Galpha13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity.
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PMID:Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction. 1035 1

In humans, cerebral hypoxia is a common component of severe brain insults, including trauma, stroke, and perinatal asphyxia. Oxidative stress and free radicals incidental to cerebral hypoxia are implicated in damaging macromolecules, leading to collapse of cellular homeostasis and cell death. Neuronal DNA damage, as a direct measurable event, has not been addressed in cerebral hypoxia. Here, we measured hypoxia-induced damage and repair in nuclear and mitochondrial DNA in rat hippocampus and cortex. Two highly sensitive quantitative polymerase chain reaction (QPCR) assays were used to measure DNA damage. One assay measures the integrity of the entire mitochondrial genome and the other the integrity of nuclear DNA. The latter is a novel assay, developed in our laboratory, which utilizes the high copy number of short interspersed DNA elements (SINEs) residing in introns and untranslated regions of mammalian genes. A unique feature of the SINE-mediated QPCR is its ability to amplify simultaneously long random segments of DNA. Consequently, the SINE assay offers sufficient sensitivity for detecting DNA damage at levels that are compatible with the cellular capacity for DNA repair, and are likely to be consistent with cellular survival and therefore adequate for studying the DNA damage response in the brain. In rats, we found that exposure to an atmosphere of 4% oxygen for 30 min resulted in induction of DNA damage in nuclear and to a greater extent, in mitochondrial DNA. Following a 3-hr recovery period in ambient air, dissimilar repair kinetics for nuclear and mitochondrial DNA were measured.
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PMID:Hypoxia-induced mitochondrial and nuclear DNA damage in the rat brain. 1050 82

Status epilepticus is common and associated with significant mortality and complications. It affects approximately 50 patients per 100,000 population annually and recurs in >13%. History of epilepsy is the strongest single risk factor for generalized convulsive status epilepticus. More than 15% of patients with epilepsy have at least one episode of status epilepticus and low antiepileptic drug levels are a potentially modifiable risk factor. Other risks include young age, genetic predisposition, and acquired brain insults. Fever is a very common risk in children, as is stroke in adults. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Neuronal injury leading to temporal lobe epilepsy is probably mediated by excess excitation via activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and consequent elevated intracellular calcium that causes acute necrosis and delayed apoptotic cell death. Some forms of nonconvulsive status epilepticus may also lead to neuronal injury by this mechanism, but others may not. Based on clinical and experimental observations, complex partial status epilepticus is more likely to result in neuronal injury similar to generalized convulsive status epilepticus. Absence status epilepticus is much less likely to result in neuronal injury, and complications because it may be mediated primarily through excess inhibition. Future research strategies to prevent complications of status epilepticus include the study of new drugs (including NMDA antagonists, new drug delivery systems, and drug combinations) to stop seizure activity and prevent acute and delayed neuronal injury that leads to the development of epilepsy.
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PMID:Status epilepticus: risk factors and complications. 1088 37

Neuronal morphogenesis is regulated, among other factors, by microtubule-associated proteins (MAPs). A family of these proteins, MAP2, which is very abundant in the mammalian nervous system, has been associated with the formation of neurites at early developmental stages and with the dendritic scaffold upon maturation. The function of MAP2 is regulated by its phosphorylation state. One of the phosphorylation sites that has been described is located in the proline-rich region of the protein. It comprises of the residues 1616-1626 and is specifically recognized by the antibody 305. However, little is known about the functional consequences of its modification in vivo. To gain insight into this, we have analysed the expression levels and intracellular distribution of MAP2 phosphorylated at this site (MAP2-P), in primary cultures of rat hippocampal neurons at different developmental stages. Western blot analysis of hippocampal neuron protein extracts revealed that the ratio of MAP2-P:MAP2 was 4:1 at early developmental stages and became 1:4 at later developmental stages, suggesting a role of such phosphorylated forms of the protein in neuritogenesis. Consistent with this view, immunofluorescence microscopy analysis showed that the ratio MAP2-P:MAP2 was 2 in the neurite growth cones, sites where net elongation takes place. A higher presence of phosphorylated MAP2 was observed in growth regions with higher levels of microfilaments, which may be related with the growth region stability. Indeed, when growth-cone collapse was induced in hippocampal neurons after cytochalasin D treatment, which depolymerizes microfilaments, the ratio MAP2-P:MAP2 in these growing regions decreased down to 1. Finally, acceleration of neuronal maturation induced by the activation of glutamate-receptors triggered a dramatic decrease in the phosphorylation of MAP2 at the site recognized by antibody 305. From these results we suggest that the phosphorylation of MAP2 at its proline-rich region is an important event during neuritogenesis.
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PMID:Microtubule-associated protein-2 located in growth regions of rat hippocampal neurons is highly phosphorylated at its proline-rich region. 1111 37

Mammalian brain is a highly oxidative organ and although it constitutes only a small fraction of total body weight it accounts for a disproportionately large percentage of bodily oxygen consumption (in humans about 2 and 20%, respectively). Yet, the partial pressure and concentration of oxygen in the brain are low and non-uniform. There is a large number of enzymes that use O(2) as a substrate, the most important of which is cytochrome c oxidase, the key to mitochondrial ATP production. The affinity of cytochrome c oxidase for oxygen is very high, which under normal conditions ensures undiminished activity of oxidative phosphorylation down to very low P(O(2)). By contrast, many other relevant enzymes have K(m) values for oxygen within, or above, the ambient cerebral gas tension, thus making their operations very dependent on oxygen level in the physiological range. Among its multiple, versatile functions, oxygen partial pressure and concentration control production of reactive oxygen species, expression of genes and functions of ion channels. Limitation of oxygen supply to the brain below a 'critical' level reduces, and eventually blocks oxidative phosphorylation, drastically decreases cellular (ATP) and leads to a collapse of ion gradients. Neuronal activity ceases and if oxygen is not re-introduced quickly, cells die. The object of this review is to discuss briefly the central oxygen-dependent processes in mammalian brain and the short-term consequences of O(2) deprivation, but not the mechanisms of long-term adaptation to chronic hypoxia. Particular emphasis is placed on issues which have been the focus of recent attention and/or controversy.
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PMID:Tissue oxygen tension and brain sensitivity to hypoxia. 1171 58


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