Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of granulocytic lineage cells. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction. The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for spinal cord injury (SCI) in mice. We found that G-CSF is neuroprotective against glutamate-induced cell death of cerebellar granule neurons in vitro. Moreover, we used a mouse model of compressive SCI to examine the neuroprotective potential of G-CSF in vivo. Histologic assessment with cresyl violet staining revealed that the number of surviving neurons in the injured spinal cord was significantly increased in G-CSF-treated mice. Immunohistochemistry for neuronal apoptosis revealed that G-CSF suppressed neuronal apoptosis after SCI. Moreover, administration of G-CSF promoted hindlimb functional recovery. Examination of signaling pathways downstream of the G-CSF receptor suggests that G-CSF might promote functional recovery by inhibiting neuronal apoptosis after SCI. G-CSF is currently used in the clinic for hematopoietic stimulation, and its ongoing clinical trial for brain infarction makes it an appealing molecule that could be rapidly placed into trials for patients with acute SCI.
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PMID:Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. 1788 16

The ability to culture functional adult mammalian spinal cord neurons represents an important step in the understanding and treatment of a spectrum of neurological disorders including spinal cord injury. Previously, the limited functional recovery of these cells, as characterized by a diminished ability to initiate action potentials and to exhibit repetitive firing patterns, has arisen as a major impediment to their physiological relevance. In this report, we demonstrate that single temporal doses of the neurotransmitters serotonin, glutamate (N-acetyl-DL-glutamic acid) and acetylcholine-chloride lead to the full electrophysiological functional recovery of adult mammalian spinal cord neurons, when they are cultured under defined serum-free conditions. Approximately 60% of the neurons treated regained their electrophysiological signature, often firing single, double and, most importantly, multiple action potentials.
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PMID:Temporal neurotransmitter conditioning restores the functional activity of adult spinal cord neurons in long-term culture. 1800 59

Our study followed the changes in thalamic nuclei metabolism, hindlimb sensitivity to thermal stimulation, and locomotor function after spinal cord injury (SCI). MR spectroscopy (MRS) was used to examine the thalamic nuclei of rats 1 day before and 1, 3, 6, and 15 days after SCI or sham surgery. All animals were tested before MRS measurements for motor performance and thermal sensitivity. SCI induced by balloon compression caused complete paraplegia from the first to third day, followed by partial functional recovery during the second week. MRS revealed an increase in N-acetylaspartate (NAA) concentration in the thalamic nuclei on the first day after SCI, which decreased by the third day. The data also showed an increase in inositol (Ins), glutamate, and creatine (Cr) concentrations on the third day postinjury; the Ins concentration remained elevated on the sixth day. In sham-operated animals an increase in NAA concentration was observed on the sixth and fifteenth days after surgery and an increase in Cr concentration on the third day. A positive correlation between Ins concentration and hindlimb sensitivity in both SCI and sham-operated animals suggests changes in glial activity, while changes in NAA levels may indicate the response of thalamic neuronal cells to injury.
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PMID:Metabolic changes in the thalamus after spinal cord injury followed by proton MR spectroscopy. 1821 31

The over-expression of excitotoxic neurotransmitter, such as glutamate, is an important mechanism of secondary injury after spinal cord injury. The authors examined the neuroprotective effect of pregabalin (GP) which is known as to reduce glutamate secretion, in a rat model of spinal cord injury. Thirty-two male Sprague-Dawley rats were randomly allocated to four groups; the control group (contusion injury only), the methylprednisolone treated group, the minocycline treated group and the GP treated group. Spinal cord injury was produced by contusion using the New York University impactor (25 g-cm, at the 9th-10th thoracic). Functional evaluations were done using the inclined plane test and a motor rating scale. Anti-apoptotic and anti-inflammatory effects were evaluated by in situ nick-end labeling staining technique (TUNEL) and immunofluorescence staining of cord tissues obtained at 7 days post-injury. Pregabalin treated animals showed significantly better functional recovery, and anti-apoptotic and anti-inflammatory effects. Mean numbers of TUNEL positive cells in the respective groups were 63.5 +/- 7.4, 53.6 +/- 4.0, 44.2 +/- 3.9 and 36.5 +/- 3.6. Double staining (TUNEL and anti-CC1) for oligodendrocyte apoptosis, was used to calculate oligodendrocyte apoptotic indexes (AI), using the following formula AI = (No. of doubly stained cells/No. of anti-CC1 positive cells) x 100. Mean group AIs were 88.6, 46.7, 82.1 and 70.3%, respectively. Mean numbers of activated microglia (anti-OX-42 positive cells) in high power fields were 29.8 +/- 3.9, 22.7 +/- 4.1, 21.0 +/- 3.9 and 17.8 +/- 4.3, respectively. This experiment demonstrates that GP can act as a neuroprotector after SCI in rats, and its anti-apoptotic and anti-inflammatory effects are related to its neuroprotective effect. Further studies are needed to unveil the specific mechanism involved at the receptor level.
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PMID:Pregabalin as a neuroprotector after spinal cord injury in rats. 1835

Rasmussen syndrome (RS) and non-herpetic acute limbic encephalitis (NHALE) have pathophysiological background related with autoimmunity to glutamate receptors (GluRs) after infections. RS and NHALE were reviewed, depending mainly on our recent studies. RS is the prototype of autoimmune-mediated epilepsy. In patients with RS, several kinds of autoantibodies against neuronal molecules, for example, GluR3, GluRepsilon2 (NMDA-R2B), etc., are reported. These autoantibodies are not specific for RS. About autoantibodies against GluR3, significance and stimulating effects to GluR3 are controversial. Autoantibodies against GluRepsilon2 were detected in all patients within six months from epilepsy onset, and in some patients at chronic stage. These data suggest that autoantibodies against GluRepsilon2 may be involved in the pathological mechanisms in the early stage, but we could not confirm the effect of the autoantibodies from RS patients on excitatory postsynaptic NMDA current using patch clump methods. However, anti-double-stranded DNA antibodies in patients with SLE are reported to cross-react with n-terminal of GluRepsilon2, and cause neuronal apoptosis in rat hippocampus, ensuing memory impairment, and emotional behavior impairment in mice. Therefore, autoantibodies against GluRepsilon2 may contribute to the cognitive and behavioral changes in RS. Concerning about cellular immunity in RS, lymphocytes stimulating tests revealed peripheral lymphocytes sensitized by antigens containing GluRepsilon2. Cytotoxic T cells (CTLs) excreting Granzyme B were reported in resected brain tissue, and we confirmed the elevated levels of Granzyme B, not in sera, but in CSF. These data suggest that CTLs activated by infection invade into CNS, and recognize neural antigens, and excrete Granzyme B. The incidence of NHALE is 4.1/1 million/year in Japanese adults. Our study in 91 adult patients with NHALE revealed the following characteristics. Mean onset age was 35.2 +/- 16.9 years old, and preceding infections existed in 68.7% of patients, and predominant symptoms at the onset were psychiatric symptoms (33.3%) and convulsions (25.0%). CSF showed slightly elevated cell counts (55.5 +/- 139.9), protein levels (48.1 +/- 36.0 mg/dl), and IgG levels (4.5 +/- 3.9 mg/dl). MRI lesions with high intensity were found in 40.8% (DWI) and 54.2% (FLAIR) of patients in various stages after onsets. Autoantibodies against GluRepsilon2 in sera were detected in approximately 60% of NHALE patients from acute to chronic stages, and the autoantibodies in CSF were detected in 51.8% (acute stage), 41.4% (recovery stage), 28.6% (chronic stage) of patients and included epitopes to n-terminal of GluRepsilon2 (NT1). These data suggest that autoantibodies against GluRepsilon2 produced in sera after infection infiltrate into CNS through damaged BBB in acute stages, and affect n-terminal of GluRepsilon2. In chronic stage, recovery of function of BBB reduces levels of the autoantibodies in CSF. Because BBB in hippocampi and amygdala are vulnerable, autoantibodies against GluRepsilon2 including epitopes to n-terminal may contribute to the limbic symptoms around onset. Among several autoantibodies related with NHALE, autoantibodies against GluRepsilon2 were found in patients around 15-34 years old, autoantibodies against VGKC were around 50.4 years old, autoantibodies against NAE were around 59 years old, autoantibodies against Hu were around 61.5 years old. These data suggest that autoantibodies related with NHALE have age-dependent heterogeneity.
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PMID:[Rasmussen encephalitis and non-herpetic acute limbic encephalitis]. 1840 35

The toxicity of released glutamate contributes substantially to secondary cell death following spinal cord injury (SCI). In this work, the extent and time courses of glutamate-induced losses of neurons and oligodendrocytes are established. Glutamate was administered into the spinal cords of anesthetized rats at approximately the concentration and duration of its release following SCI. Cells in normal tissue, in tissue exposed to artificial cerebrospinal fluid and in tissue exposed to glutamate were counted on a confocal system in control animals and from 6 h to 28 days after treatment to assess cell losses. Oligodendrocytes were identified by staining with antibody CC-1 and neurons by immunostaining for Neuronal Nuclei (NeuN) or Neurofilament H. The density of oligodendrocytes declined precipitously in the first 6 h after exposure to glutamate, and then relatively little from 24 h to 28 days post-exposure. Similarly, neuron densities first declined rapidly, but at a decreasing rate, from 0 h to 72 h post-glutamate exposure and did not change significantly from 72 h to 28 days thereafter. The nuclei of many cells strongly and specifically stained for activated caspase-3, an indicator of apoptosis, in response to exposure to glutamate. Caspase-3 was localized to the nucleus and may participate in apoptotic cell death. However, persistence of caspase-3 staining for at least a week after exposure to glutamate during little to no loss of oligodendrocytes and neurons demonstrates that elevation of caspase-3 does not necessarily lead to rapid cell death. Beyond about 48 h after exposure to glutamate, locomotor function began to recover while cell numbers stabilized or declined slowly, demonstrating that functional recovery in the experiments presented involves processes other than replacement of oligodendrocytes and/or neurons.
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PMID:Glutamate-induced losses of oligodendrocytes and neurons and activation of caspase-3 in the rat spinal cord. 1842 97

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.
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PMID:Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for ischemic brain injury. 1853 71

Loss of function and subsequent spontaneous recovery after ischaemic stroke are associated with functional and structural alterations in brain tissue. Acute functional tissue damage involves distortion of key metabolic processes, such as oxidative glycolysis and neurotransmitter metabolism. Nevertheless, initially perturbed metabolism may be restored at later stages, e.g. in perilesional areas, which could play a key role in post-stroke recovery of brain function. The pattern of metabolic recovery in relation to ischaemic tissue damage, however, is basically unknown. The goal of our study was to reveal changes in glycolysis and glutamatergic neurotransmitter metabolism that could underlie post-stroke changes in functional status. We performed in vivo (1)H/(13)C magnetic resonance spectroscopic imaging (MRSI) during (13)C-labelled glucose infusion, and MRI, at 24 h (n = 6) and 3 weeks (n = 8) after stroke in a rat model to characterize alterations in baseline metabolite levels, glutamate (Glu) and glutamine (Gln) turnover, and active lactate (Lac) formation in areas with different degrees of ischaemic injury. Inside the lesion, we detected significant reductions in baseline metabolite levels, ongoing Lac formation and seriously diminished Glu and Gln turnover at both time points, indicative of irreversible functional tissue damage. In perilesional areas, significant decrease of N-acetyl aspartate (NAA) levels, and Glu and Gln turnover indicated neuronal dysfunction at 24 h. After 3 weeks, when animals showed significant neurological improvement, anaerobic glycolysis had ceased, NAA levels were normalized, Glu turnover was maintained and Gln turnover had recovered. These findings point out that early metabolic impairment in the lesion borderzone can be restored over time. Alterations in brain metabolism in perilesional areas probably contribute significantly to changes in functional status in stroke subjects, and may provide a gateway for therapeutic strategies directed at improvement of functional recovery after stroke.
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PMID:1H/13C MR spectroscopic imaging of regionally specific metabolic alterations after experimental stroke. 1866 96

Research focused on improving recovery of function, including the reduction of central neuropathic pain (CNP) after spinal cord injury (SCI) is essential. After SCI, regional neuropathic pain syndromes above, at and below the level or spinal injury develop and are thought to have different mechanisms, but may share common dysfunctional glial mechanisms. Detloff et al., [Detloff, M.R., Fisher, L.C., McGaughy, V., Longbrake, E.E., Popovich, P.G., Basso, D.M., Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp. Neurol. (2008), doi: 10.1016/j.expneurol.2008.04.009.] describe events in the lumbar region of the spinal cord after a midthoracic SCI injury, the so called "below-level" pain and compares the findings to peripheral nerve lesion findings. This commentary briefly reviews glial contributions and intracellular signaling mechanisms, both neuronal and glial, that provide the substrate for CNP after SCI, including the persistent glial production of factors that can maintain sensitization of dorsal horn neurons in segments remote from the spinal injury; ie. dorsal horn hyperexcitability to formerly non noxious stimuli that become noxious after SCI resulting in allodynia. The term "gliopathy" is proposed to describe the dysfunctional and maladaptive response of glial cells, specifically astrocytes and microglia, to neural injury that is initiated by the sudden injury induced increase in extracellular concentrations of glutamate and concomitant production of several proinflammatory molecules. It is important to understand the roles that different glia play in "gliopathy", a condition that appears to persist after SCI. Furthermore, targeted treatment of gliopathy will attenuate mechanical allodynia in both central and peripheral neuropathic pain syndromes.
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PMID:Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. 1851 Oct 41

Glycine-proline-glutamate (GPE) is an N-terminal tripeptide endogenously cleaved from insulin-like growth factor-1 in the brain and is neuroprotective against hypoxic-ischemic brain injury and neurodegeneration. NNZ-2566 is an analog of GPE designed to have improved bioavailability. In this study, we tested NNZ-2566 in a rat model of penetrating ballistic-type brain injury (PBBI) and assessed its effects on injury-induced histopathology, behavioral deficits, and molecular and cellular events associated with inflammation and apoptosis. In the initial dose-response experiments, NNZ-2566 (0.01-3 mg/kg/h x 12 h intravenous infusion) was given at 30 min post-injury and the therapeutic time window was established by delaying treatments 2-4 h post-injury, but with the addition of a 10- or 30-mg/kg bolus dose. All animals survived 72 h. Neuroprotection was evaluated by balance beam testing and histopathology. The effects of NNZ-2566 on injury-induced changes in Bax and Bcl-2 proteins, activated microgliosis, neutrophil infiltration, and astrocyte reactivity were also examined. Behavioral results demonstrated that NNZ-2566 dose-dependently reduced foot faults by 19-66% after acute treatments, and 35-55% after delayed treatments. Although gross lesion volume was not affected, NNZ-2566 treatment significantly attenuated neutrophil infiltration and reduced the number of activated microglial cells in the peri-lesion regions of the PBBI. PBBI induced a significant upregulation in Bax expression (36%) and a concomitant downregulation in Bcl-2 expression (33%), both of which were significantly reversed by NNZ-2566. Collectively, these results demonstrated that NNZ-2566 treatment promoted functional recovery following PBBI, an effect related to the modulation of injury-induced neural inflammatory and apoptotic mechanisms.
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PMID:NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury. 1911 17


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