Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cochlear ischemia and acoustic trauma result in an immediate hearing loss accompanied by the complete disruption of the terminal dendrites of primary auditory neurons postsynaptic to the sensory inner hair cells (IHCs). This synaptic uncoupling, due to an acute glutamate (IHC neurotransmitter) excitotoxicity process, can be mimicked by glutamate agonists. Thus, we have followed over a 5-day period the responses of guinea-pig cochleas to a local application of 200 microM AMPA. This application immediately results in a destruction of all postsynaptic endings of the auditory nerve, resulting in a total loss of cochlear potentials. Twenty-four hours after this excitotoxic injury, the inner hair cells were contacted by repaired postsynaptic dendrites and the cochlear potential had partially recovered. This process of neo-synaptogenesis was completed and the potentials were fully restored at 5 days post exposure. As shown by in situ hybridization, an up-regulation of NMDA and metabotropic glutamate receptors in the primary auditory neurons occurred during this process of recovery. This process of neo-synaptogenesis and functional recovery probably accounts for restoring hearing after temporary losses due to excitotoxic-related pathologies.
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PMID:Synaptic regeneration and functional recovery after excitotoxic injury in the guinea pig cochlea. 753 93

This study's goal is to identify adaptations involving striatal glutamate (GLU) or dopamine (DA) receptors that may contribute to recovery of function following cortical injury. Unilateral aspiration of the medial agranular region of frontal cortex (AGm) in rats produces neglect of contralateral stimuli. Pharmacological and immunocytochemical studies suggest that glutamatergic and dopaminergic processes within striatum may contribute to spontaneous recovery from this neglect. This study examined by autoradiography radioligand binding to striatal GLU and DA receptor subfamilies in AGm-ablated rats surviving 5 days (unrecovered) or 3 or more weeks (recovered) postsurgery. Density of radioligand binding was quantified in striatal subregions by computerized image analysis. Compared to striatal binding densities in the intact hemisphere, [3H]kainate binding and [3H]GLU binding to NMDA receptors were decreased in the lesioned hemisphere of unrecovered AGm-ablated rats, but normalized (for kainate) or increased (for NMDA) in the lesioned hemisphere of recovered rats. Ablation of AGm did not affect [3H]AMPA binding or the binding of [3H]SCH23390, [3H]spiperone, or [3H]mazindol to dopaminergic D1 or D2 receptor subfamilies, or to DA uptake sites, respectively. The results suggest that a small percentage of NMDA and kainate receptors are located on corticostriatal axon terminals, and that over time an upregulation of striatal NMDA and/or kainate receptors may offset the loss of cortical glutamatergic input caused by cortical injury. These time-dependent alterations in GLU receptors may contribute to the recovery of function and normalizations of immediate early gene expression seen weeks after AGm ablation. Upregulation of striatal dopamine receptors was not evident, and thus is unlikely to mediate recovery from neglect produced by cortical injury.
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PMID:Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors. 876 70

We examined the role of glutamatergic mechanisms in acute injury to rat spinal cord white matter. Compound action potentials (CAPs) were recorded from isolated dorsal column segments in vitro. Under control conditions (Ringer's solution), the CAPs decreased to 71.4 +/- 2.0% of preinjury values after compression injury with a clip exerting a closing force of 2 g. The combination of the NMDA receptor blocker APV (50 microM) and the AMPA/kainate (KA) receptor blocker CNQX (10 microM) resulted in significantly improved recovery of CAP amplitude postinjury; however, the NMDA receptor antagonist APV alone did not enhance postinjury recovery, and infusion of NMDA (10 microM) did not affect recovery of the CAPs. In contrast, the AMPA/KA receptor blockers NBQX (10 microM) or CNQX (10 microM) significantly enhanced the recovery of CAP amplitude postinjury. The agonists AMPA (100 microM) or KA (100 microM) resulted in significant attenuation of CAP amplitude postinjury. Coapplication of AMPA/KA plus NBQX and CNQX was also associated with improved functional recovery. After incubation with AMPA and KA, Co(2+)-positive glia were visualized in spinal cord white matter. Similar results were seen after compressive injury but not in control cords. Immunohistochemistry and Western blot analysis demonstrated AMPA (GluR4)- and KA (GluR6/7 and KA2)-positive astrocytes in spinal cord white matter. In summary, non-NMDA ionotropic glutamate receptors seem to be involved in the pathophysiology of traumatic spinal cord injury. The presence of AMPA (GluR4) and KA (GluR6/7 and KA2) receptors on periaxonal astrocytes suggests a role for these cells in glutamatergic white matter injury.
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PMID:Role of NMDA and non-NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury. 899 60

In some cochlear pathologies, temporary hearing loss can be followed by complete or partial functional recovery. Our previous findings suggest the involvement of an excitotoxic (glutamate-related) disruption of inner hair cell (IHC)-auditory nerve synapses, followed by synaptic regeneration. It is essential to understand the molecular mechanisms responsible for this synaptic repair if new therapeutic strategies are to be developed. In guinea pig cochleas, acute synaptic excitotoxic damage (mimicking what occurs with acoustic trauma or local ischemia) is achieved by locally applying AMPA, a glutamate agonist. This results in a total disruption of all IHC-auditory dendrite synapses, together with a disappearance of cochlear potentials. Within the next 5 days, however, a recovery of both the normal pattern of IHC innervation and the physiological responses is observed. The fact that the blockage of the NMDA receptors during functional recovery delayed the regrowth of neurites and the restoration of hearing suggests that glutamate plays a neurotrophic role via activation of NMDA receptors. Experiments are in progress to investigate, among other factors, the role of other glutamate receptor subunits. A reversible in vivo antisense strategy is being developed to overcome the lack of specificity of some antagonists. First results bode well for future pharmacological therapies in cochlear pathologies where glutamatergic synapses are likely to be involved; i.e., noise trauma, ischemia-related sudden deafness, and neural presbycusis.
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PMID:Synaptic repair mechanisms responsible for functional recovery in various cochlear pathologies. 910 52

The immunoreactivity of glutamate receptor subunits 2/3 (GluR2/3) and 4 (GluR4) was studied following neurectomy of the hypoglossal nucleus (NH). After a short period of survival (at 1, 2, and 7 days postoperation, dpo), GluR2/3 immunoreactivity was barely dectectable in the operated side of HN. During these periods, GluR4 immunoreactivity was present, but was greatly reduced when compared with the GluR4 immunoreactivity in the unoperated side. The data suggest that of the 4 subunits of the AMPA receptor, GluR2/3 is the most susceptible receptor to the early stage of hypoglossal neurectomy, and GluR4 tolerated the lesion more than the others. It is also suggested that both GluR2/3 and 4 may play a very important neuroprotective role in the early stage of neuronal degeneration after axotomy, especially the former. Following a midterm survival period (14, 21, and 35 dpo), GluR2/3 immunoreactivity gradually reappeared in some neurons on the operated side of HN, which may indicate functional recovery. However, the number of GluR4-immunopositive neurons on the operated side of HN was greatly reduced. The reason for such a reduction is not known, but, from the speculative point of view, it is possible that the disappearance of GluR4-positive neurons may be related to their excitotoxic property, especially at 35 dpo, when neuronal cell death had already occurred. Following a long-term period of survival (i.e., 56, 90, and 120 dpo), the numbers of surviving neurons remained fairly constant, suggesting the possible cessation of neuronal death.
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PMID:Expression of glutamate receptor subunits 2/3 and 4 in the hypoglossal nucleus of the rat after neurectomy. 943 13

Serial improvement in myocardial perfusion images from the acute or subacute to the chronic stage of acute myocardial infarction (AMI) has been attributed to improved coronary microcirculation or cell function after acute ischaemia and reperfusion. However, conventionally used non-gated imaging cannot eliminate the effect of improved regional contraction. We studied the possibility that such scintigraphic improvement reflects the functional recovery by using ECG-gated myocardial perfusion imaging with technetium-99m sestamibi. Nineteen AMI patients who received acute reperfusion therapy underwent ECG-gated myocardial single-photon emission tomography (SPET) in the subacute and chronic stages. Serial changes in regional image count distributions were analysed on the non-gated, end-diastolic (ED) and end-systolic (ES) images by using segmental mean percent peak activity (MPA) and AMPA (MPA in chronic stage - MPA in subacute stage) on bull's-eye polar maps. These changes were compared with those in regional wall motion on biplane left ventriculography (LVG) from the acute (just after reperfusion) to the chronic stage. During the follow-up, regional wall motion remained the same in 42 (group A) but improved in 17 (group B) of the 59 ischaemically compromised segments. MPA showed no improvement in group A but significant improvement in group B on the non-gated and ES images (P<0.0001 and P<0.001, respectively). However, MPA on the ED images showed no improvement in either group. In the follow-up study of AMI, the scintigraphic improvement documented on the non-gated myocardial images appears to be mainly related to the recovery of wall thickening and not to a real improvement in myocardial perfusion. Therefore, ECG-gated myocardial imaging, which enables simultaneous assessment of changes in perfusion and contraction, is preferable to conventional non-gated imaging for follow-up of AMI.
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PMID:Use of ECG-gated SPET to assess the evolution of perfusion after acute myocardial infarction. 1085 6

During cerebral ischemia, neurons undergo rapid alterations in dendritic structure consisting of focal swelling and spine loss. We used time-lapse microscopy to determine the fate of dendritic spines that disappeared after brief, sublethal hypoxic or excitotoxic exposures. Dendrite and spine morphology were assessed in cultured cortical neurons expressing yellow fluorescent protein or labeled with the fluorescent membrane tracer, DiI. Neurons exposed to NMDA, kainate, or oxygen-glucose deprivation underwent segmental dendritic beading and loss of approximately one-half of dendritic spines. Most spine loss was observed in regions of local dendritic swelling. Despite widespread loss, spines recovered within 2 hr after termination of agonist exposure or oxygen-glucose deprivation and remained stable over the subsequent 24 hr. Recovery was slower after NMDA than AMPA/kainate receptor activation. Time-lapse fluorescence imaging showed that the vast majority of spines reemerged in the same location from which they disappeared. In addition to spine recovery, elaboration of dendritic filopodia was observed in new locations along the dendritic shaft after dendrite recovery. Spine recovery did not depend on actin polymerization because it was not blocked by application of latrunculin-A, which eliminated filamentous actin staining in spines and blocked spine motility. Throughout spine loss and recovery, presynaptic and postsynaptic elements remained in physical proximity. These results suggest that elimination of dendritic spines is not necessarily associated with loss of synaptic contacts. Rapid reestablishment of dendritic spine synapses in surviving neurons may be a substrate for functional recovery after transient cerebral ischemia.
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PMID:Dendritic spines lost during glutamate receptor activation reemerge at original sites of synaptic contact. 1126 13

Behavioral and morphological changes were examined for up to 9 days after moderate cerebral ischemia caused by slow compression of a specific brain area in the sensorimotor cortex of Sprague-Dawley rats. Functional deficits after the cerebral ischemia were assessed by daily beam-walking tests, whereas morphological changes were verified using Nissl staining on day 1, 2, 3, 5, and 9, respectively. Rats exposed to cerebral ischemia displayed impaired beam walking performance. Mild hypothermia prevented both the compression-produced functional deficits and the brain damage. Younger (5 weeks) animals showed less neurological deficits than older (9 weeks) animals. Histological examination revealed a pronounced increase in the number of injured pyramidal neurons from day 1 to day 3 in the primarily damaged brain region. Between day 3 and day 5, the number of injured cells remained constant, whereafter there was a slow decline of thionin-positive neurons as examined on day 9. The noncompetitive NMDA receptor antagonist, dizocilpine (MK-801; 3 mg/kg, i.p.), did not alter the neurological impairment on day 1, but improved thereafter the rate of functional recovery and reduced the number of damaged cells. The AMPA receptor antagonist, LY326325 (15 or 30 mg/kg; i.p.), dose-dependently diminished the neurological deficits on day 1, enhanced the rate of recovery, and reduced the number of injured neurons over time. Our data suggest that short-lasting extradural compression of a well-defined brain area in the sensorimotor cortex is a highly reproducible model with a high success rate for the study of functional and morphological consequences after cerebral ischemia as well as for the evaluation of the therapeutic potential of novel, neuroprotective pharmacological agents.
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PMID:Extradural compression of sensorimotor cortex: a useful model for studies on ischemic brain damage and neuroprotection. 1185 80

Glutamate is an important regulator of dendrite development. During cerebral ischemia, however, there is massive release of glutamate reaching millimolar concentrations in the extracellular space. An early consequence of this excess glutamate is reduced dendrite growth. Bone morphogenetic protein-7 (BMP-7) a member of the transforming growth factor-beta (TGF-beta) superfamily has been demonstrated to enhance dendrite output from cerebral cortical and hippocampal neurons in vitro. However, it is not known whether BMP-7can prevent the reduced dendrite growth associated with excess glutamate or enhance dendrite growth after glutamate exposure. Therefore we quantified axon and primary, secondary, and total dendrite growth from embryonic mouse cortical neurons (E18) grown at low density in vitro in a chemically defined medium and exposed to glutamate (1 or 2 mM) for 48 h. Morphology and double immunolabeling (MAP2, NF-H) were used to identify cortical dendrites and axons after 3 DIV. In these short-term cultures, glutamate did not influence neuron survival. The addition of glutamate to cortical neurons, however, significantly attenuated dendrite output. This effect was mimicked by the addition of NMDA but not AMPA agonists and inhibited by the specific NMDA receptor antagonist MK-801. The reduction in dendrite growth mediated by excess glutamate was ameliorated by the administration of 30 or 100 ng/ml of BMP-7. In addition, when administered in a delayed fashion between 1 and 24 h after the initial glutamate exposure, BMP-7 was able to enhance dendrite growth, including primary dendrite number, primary dendrite length, and secondary dendritic branching. These findings demonstrate that BMP-7 can ameliorate reduced dendrite growth from cerebral cortical neurons associated with excess glutamate in vitro and are important because they may help explain why BMP-7 administration is associated with enhanced functional recovery in models of cerebral ischemia.
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PMID:BMP-7 and excess glutamate: opposing effects on dendrite growth from cerebral cortical neurons in vitro. 1209 81

Brief cochlear excitotoxicity produces temporary neural swelling and transient deficits in auditory sensitivity; however, the consequences of long-lasting excitotoxic insult have not been tested. Chronic intra-cochlear infusion of the glutamate agonist AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) resulted in functional deficits in the sound-evoked auditory brainstem response, as well as in behavioral measures of hearing. The electrophysiological deficits were similar to those observed following acute infusion of AMPA into the cochlea; however, the concentration-response curve was significantly shifted as a consequence of the slower infusion rate used with chronic cochlear administration. As observed following acute excitotoxic insult, complete functional recovery was evident within 7 days of discontinuing the AMPA infusion. Distortion product otoacoustic emissions were not affected by chronic AMPA infusion, suggesting that trauma to outer hair cells did not contribute to AMPA-induced deficits in acoustic sensitivity. Results from the current experiment address the permanence of deficits induced by chronic (14 day) excitotoxic insult as well as deficits in psychophysical detection of longer duration acoustic signals.
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PMID:Chronic excitotoxicity in the guinea pig cochlea induces temporary functional deficits without disrupting otoacoustic emissions. 1537 71


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