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)

Brain plasticity and the mechanisms controlling plasticity are central to learning and memory as well as the recovery of function after brain injury. While it is clear that neurotrophic factors are one of the molecular classes that continue to regulate brain plasticity in the adult central nervous system (CNS), less appreciated but equally profound is the role of cell adhesion molecules (CAMs) in plasticity mechanisms such as long term potentiation, preservation of neurons and regeneration. Ironically, however, CAMs can also reorganize the extra-cellular space and cause disturbances that drive the development of brain pathology in conditions such as Alzheimer's disease and multiple sclerosis. Candidate molecules include the amyloid precursor protein which shares many properties of a classical CAM and beta-amyloid which can masquerade as a pseudo CAM. Beta-Amyloid serves as a nidus for the formation of senile plaques in Alzheimer's disease and like CAMs provides an environment for organizing neurotrophic factors and other CAMs. Inflammatory responses evolve in this environment and can initiate a vicious cycle of perpetuated neuronal damage that is medicated by microglia, complement and other factors. Certain CAMs may converge on common signal transduction pathways involving focal adhesion kinases. Thus a breakdown in the organization of key CAMs and activation of their signal transduction mechanisms may serve as a new principle for the generation of brain pathology.
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PMID:Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations? 967 Feb 24

In the present study plastic neural responses to N-methyl-D-aspartate-induced excitotoxic lesions and the neuroprotective effects of the L-type voltage-dependent Ca(2+) channel antagonist nimodipine were investigated in the rat magnocellular nucleus basalis. Assessment of spontaneous behaviour in the elevated plus maze and small open-field paradigms on day 5 and day 14 post-surgery indicated anxiety and persistent hypoactivity of N-methyl-D-aspartate-lesioned rats, as compared with sham-operated controls. Nimodipine administration significantly alleviated the behavioural deficits. Quantitative histochemical analysis of acetylcholinesterase-positive fibre innervation of the somatosensory cortex and determination of the numbers of choline-acetyltransferase-positive proximal fibre branches of cholinergic projection neurons in the magnocellular nucleus basalis demonstrated a severe cholinergic deficit as a consequence of the excitotoxic lesion 14 days post-surgery. Nimodipine pre-treatment significantly attenuated the loss of cortical cholinergic innervation and preserved the functional integrity of cholinergic projection neurons in the magnocellular nucleus basalis. Double-labelling immunocytochemistry demonstrated increased amyloid precursor protein expression in shrinking and presumably apoptotic choline-acetyltransferase-positive neurons, whereas surviving cholinergic nerve cells were devoid of excessive amyloid precursor protein immunoreactivity. Moreover, as a consequence of N-methyl-D-aspartate infusion, rim-like accumulation of amyloid precursor protein-positive astrocytes was visualized in a penumbra-like zone of the excitotoxic injury. Furthermore, abundant sprouting of serotonergic projection fibres invading the damaged magnocellular nucleus basalis subdivision was demonstrated. Pharmacological blockade by the Ca(2+) antagonist nimodipine significantly attenuated both neuronal and glial amyloid precursor protein immunoreactivity and serotonergic fibre sprouting following N-methyl-D-aspartate infusion. The present data characterize plastic endogenous glial and neuronal responses in the magnocellular nucleus basalis model of acute excitotoxic brain damage. The increased amyloid precursor protein expression may indicate effective means of intrinsic neuroprotection, as secreted amyloid precursor protein isoforms are suggested to play a role in neuronal rescue following excitotoxic injury. From a pharmacological point of view, extensive sprouting of serotonergic projections in the damaged magnocellular nucleus basalis may also counteract N-methyl-D-aspartate excitotoxicity via serotonin-induced inhibition of Ca(2+) currents and membrane hyperpolarization. Hence, lesion-induced changes in spontaneous animal behaviour, such as anxiety and novelty-induced hypoactivity, may well be attributed to the considerable re-distribution of serotonergic projections in the basal forebrain. In conclusion, our present data emphasize a role of neuron-glia and neurotransmitter-system interactions in functional recovery after acute excitotoxic brain injury, and the efficacy of L-type Ca(2+) channel blockade by the selective 1,4-dihydropyridine antagonist nimodipine.
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PMID:Increased amyloid precursor protein expression and serotonergic sprouting following excitotoxic lesion of the rat magnocellular nucleus basalis: neuroprotection by Ca(2+) antagonist nimodipine. 1106 40

Multiple molecular, cellular, structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively, or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g., protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (alpha-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E(4), have more subtle effects on brain aging. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
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PMID:Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. 1208 31

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
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PMID:Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior. 1239 75

During the course of Alzheimer's disease (AD), neurons undergo extensive remodeling, contributing to the loss of function observed in the disease. Many brain regions in patients with AD show changes in axonal and dendritic fields, dystrophic neurites, synapse loss, and neuron loss. Accumulation of amyloid-beta protein, a pathological hallmark of the disease, contributes to many of these alterations of neuronal structure. Areas of the brain displaying a high degree of plasticity are particularly vulnerable to degeneration in Alzheimer's disease. This article describes neuronal changes that occur in AD, reviews evidence that amyloid-beta contributes to these changes, and finally discusses the recovery of amyloid-induced changes in the brains of transgenic mice, lending hope to the idea that therapeutic strategies which reduce amyloid-beta production will lead to functional recovery in patients with AD.
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PMID:Neuronal structure is altered by amyloid plaques. 1552 51

Alzheimer's disease (AD) is a common cause of dementia, resulting from accumulated beta-amyloid protein deposits in the brain. As the population ages the incidence of AD is also on the rise. The incidence is very high in the developed countries where life expectancy is high, but it is also rising rapidly in the developing countries. Caring for patients suffering from AD is a major economic burden. The mechanisms underlying the neuropathology of AD are slowly being unravelled. Here we explore the many models and theories, which have been proposed over the years. We then discuss a potential therapeutic agent, vaccinia virus complement control protein (VCP), involved in modulating the complement system in AD. VCP has been shown in in vitro studies to block the complement activation caused by the beta peptide. Traumatic injuries to the brain are well known risk factors associated with the development of AD. VCP can also enhance functional recovery resulting from traumatic brain injury and may be able to slow the progression of traumatic brain injury to AD. Here we describe strategies for testing this hypothesis and evaluating other agents such as VCP.
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PMID:Molecular mechanisms, emerging etiological insights and models to test potential therapeutic interventions in Alzheimer's disease. 1597 58

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only recently coming to light. Potential mechanisms include changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Behaviorally, aged rats are more severely impaired by stroke than are young rats, and they also show diminished functional recovery. Infarct volume does not differ significantly in young and aged animals, but critical differences are apparent in the cytological response to stroke, most notably an age-related acceleration of the establishment of the glial scar. The early infarct in older rats is associated with a premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration, and accelerated apoptosis. Regeneration-associated mechanisms in the rat brain are active throughout life, albeit at lower levels in the aged animals. However; after stroke in aged rats, neuroepithelial marker-positive cells emanating largely from capillaries did not make a significant contribution to neurogenesis in the infarcted cortex of aged animals. Furthermore, the expression of plasticity-associated proteins, such as MAP1B, was delayed in aged rats. Tissue recovery was further delayed by the upregulation of Nogo, ephrin-A5 and MAG, which exert a powerful negative effect on axonal sprouting in the aged peri-infarct cortex, and by an age-related increase in the amount of the neurotoxic C-terminal fragment of the beta-amyloid precursor protein (betaAPP) at 2 wks post-stroke. Our findings indicate that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis of this phenomenon in the aging brain could yield novel approaches to neurorestoration following stroke or head injury in the elderly.
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PMID:The response of the aged brain to stroke: too much, too soon? 1769 75

Cerebral ischaemia leads to a transient accumulation of beta-amyloid precursor protein (APP) and beta-amyloid (Abeta) peptides adjacent to the ischaemic lesion. There is conflicting evidence that APP/Abeta fragments may either enhance neuronal plasticity or be neurotoxic. The aim of the current study was to assess the effect of overexpression of human APP in rats on functional recovery following cerebral ischaemia. Adult APP-overexpressing (hAPP695 Tg) rats subjected to transient middle cerebral artery occlusion (MCAO) had significantly smaller infarct volumes than non-transgenic littermates, yet did not perform better on a series of sensorimotor or learning tests during a 6-month follow-up period. In fact, transgenic animals were found to be significantly more impaired in both the beam-walking and Morris water maze tests following MCAO. Immunohistochemistry showed human Abeta-positive staining in the cortex and hippocampus of APP transgenic rats. The present data suggest that while overexpression of APP in rats may provide some histological neuroprotection in the event of cerebral ischaemia, this does not translate into significant functional recovery.
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PMID:Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. 1789 95

Clinically, spinal cord injuries (SCI) in infants are different from SCIs in adults. SCI is rarer in infants, and the most common types of associated spinal column injury are different for adults and infants. Initially, infants tend to have higher injury severities and mortality; however, young survivors of SCI typically have greater and more rapid functional recovery. The objective of this study was to contrast the biomechanics and neuropathology of SCI in adult and neonatal rats to investigate these differences. Thoracolumbar vertebrae of anaesthetized rats were dislocated laterally (T12 held stationary and L1 displaced laterally, with T13 between these levels) by 10 mm at 250 mm/sec in adults and by 4 mm at 100 mm/sec in neonates (13-15 days), and rats were euthanized 6 h later. Spinal cord sections were stained to detect hemorrhage (with hematoxylin and eosin [H&E]), axonal injury (with beta-amyloid precursor protein [betaAPP]), and neuronal nuclei (with NeuN). Maximum load was significantly higher in adults (25.7 +/- 2.4N) than neonates (11.0 +/- 2.4N; p < 0.001). Adult and neonatal hemorrhage volumes were not significantly different for either the raw or normalized data sets (p = 0.064 for normalized dataset). Un-normalized axonal injury densities were similar for adults and neonates, but normalized axonal injury density was significantly higher in neonates (p < 0.001). Reduction of NeuN immunoreactivity was significantly lower in neonates, for both un-normalized (p < 0.004) and normalized (p < 0.001) data sets. The findings of this study may explain the different common types of spinal column injury associated with SCI, and the greater initial severity of SCI in infants.
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PMID:Contrasting biomechanics and neuropathology of spinal cord injury in neonatal and adult rats following vertebral dislocation. 1862 58

In this study, we examined whether ischemia-induced amyloidogenesis could be modulated by environmental "experience," and whether this modulation is associated with improved cognitive functioning. Rats were subjected to either global ischemia or sham surgery and then were randomly assigned to either enriched environment housing (EE) or socially paired housing (controls). After 14 days of differential environmental housing, the rats were tested in the water maze. Our results show decreased C-terminal fragments of the beta-amyloid precursor protein (betaAPP) and decreased amyloid beta (Abeta) load in the ischemic EE rats compared to the ischemic control animals. In addition, Abeta oligomerization was significantly decreased in the ischemic EE animals compared to the ischemic control rats. Further, significantly increased levels of neprilysin, but not insulin-degrading enzyme, amyloid-degrading enzymes, were seen in the ischemic EE rats compared to the ischemic control animals. Behavioral analyses showed that ischemic EE rats performed significantly better on the memory task compared to the ischemic control group. These results suggest that use of multi-sensory environmental enrichment following cerebral ischemia may reduce the accumulation of Abeta peptide in the more pathologic oligomeric form, and consequently may enhance functional recovery.
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PMID:Environmental experience modulates ischemia-induced amyloidogenesis and enhances functional recovery. 2773 69


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