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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Age-associated immunodeficiency and cognitive deterioration are two predominant features of the aging process, but the mutual influences between them are not clear yet. Research on the neuroendocrine immunomodulation (NIM) network indicate reciprocal interactions between the neuroendocrine and the immune systems mediated by neurotransmitters, neuropeptides, hormones and cytokines, which form an integrated network to maintain normal physiological functions of the body. An imbalance in the NIM network is believed to accelerate the aging process, in which the thymus plays an important role. We recently discovered that thymectomy in mice not only reduces the immune response, but also deteriorates learning performances. Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor, and corticosterone affect the induction of hippocampal long-term potentiation, a synaptic model of memory. Clinical studies have demonstrated that Alzheimer's patients show disordered immune function in addition to cognitive deficit, and the brain lesions of Alzheimer's patients may be associated with abnormal immune reactions occurring in the brain. With these findings, it is speculated that the disordered immune function may induce an imbalance in the NIM network, which consequently influences central cognitive function.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:Thymectomy-induced deterioration of learning and memory. 1129 51

Plasmalogens are glycerophospholipids of neural membranes containing vinyl ether bonds. Their synthetic pathway is located in peroxisomes and endoplasmic reticulum. The rate-limiting enzymes are in the peroxisomes and are induced by docosahexaenoic acid (DHA). Plasmalogens often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety. The receptor-mediated hydrolysis of plasmalogens by cytosolic plasmalogen-selective phospholipase A2 generates AA or DHA and lysoplasmalogens. AA is metabolized to eicosanoids. The mechanism of signaling with DHA is not known. The plasmalogen-selective phospholipase A2 differs from other intracellular phospholipases A2 in molecular mass, kinetic properties, substrate specificity, and response to glycosaminoglycans, gangliosides, and sialoglycoproteins. A major portion of [3H]DHA incorporated into neural membranes is found at the sn-2 position of ethanolamine glycerophospholipids. Studies with a mutant cell line defective in plasmalogen biosynthesis indicate that the incorporation of DHA is reduced in this RAW 264.7 cell line by 50%. In contrast, the incorporation of AA remains unaffected. This is reversed completely when the growth medium is supplemented with sn-1-hexadecylglycerol, suggesting that DHA can be selectively targeted for incorporation into plasmalogens. We suggest that deficiencies of DHA and plasmalogens in peroxisomal disorders, Alzheimer's disease (AD), depression, and attention deficit hyperactivity disorders (ADHD) may be responsible for abnormal signal transduction associated with learning disability, cognitive deficit, and visual dysfunction. These abnormalities in the signal-transduction process can be partially corrected by supplementation with a diet enriched with DHA.
J Mol Neurosci
PMID:Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. 1147 81

The use of hormonal therapies for the treatment of breast cancer is common, yet few studies have examined the possible cognitive effects. Several regions of the brain, important in memory and cognition, are rich in oestrogen receptors. As a result, the long-term use of anti-oestrogens may have potential consequences for cognition. This project aims to establish whether significant cognitive deficit exists in women receiving hormone therapy for breast cancer and to develop a cognitive package that is sensitive to the potential effects of oestrogen deficiency on cognition. Cognitive assessments measured a range of memory and attention functions in patient and control groups to identify whether cognitive impairment, if apparent, occurs at a widespread or function specific level. Ninety-four patients from the anastrozole, tamoxifen and combined (ATAC) trial and 35 non-cancer controls were assessed. Groups did not differ significantly in age or estimated full-scale intelligence. The patient group did not differ from controls on measures of working memory, attention and visual memory but was significantly impaired compared to the control group on measures of verbal memory (P=0.026) and processing speed (P=0.032). Cognitive performance in the patient group was not significantly related to length of time on trial or measures of psychological morbidity. As more and more hormonal agents are used in clinical trials of both adjuvant and preventive settings it is of vital importance that any potentially deleterious effects on cognitive function are measured adequately. Preliminary results from this study suggest that anti-oestrogen therapy may cause a specific deficit in verbal memory that corroborates the links between oestrogen levels and verbal memory often reported in studies of the cognitive benefits of hormone replacement therapy.
J Steroid Biochem Mol Biol 2003 Sep
PMID:The effects of hormone therapy on cognition in breast cancer. 1462 38

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.
Mol Psychiatry 2007 Feb
PMID:Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. 1703 31

The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.
J Cell Mol Med
PMID:X-linked mental retardation and epigenetics. 1712 86

(1) The role of activation of Rho-kinase in the pathogenesis of cognitive deficit and neuronal damage caused by chronic global ischemia is not clear. In this study, hydroxyfasudil, a Rho-kinase inhibitor, was found to improve the learning and memory performance significantly in rats with ischemia induced by chronic cerebral hypoperfusion after permanent bilateral carotid artery ligation (BCAL). This was observed by the administration of hydroxyfasudil (1 mg/kg or 10 mg/kg, once per day for 30 days) to ischemic rats and the measurements of escape latency and time spent in the target quadrant among the ischemic, sham, and ischemic plus hydroxyfasudil rats by the method of Morris water maze. (2) In electrophysiological study, hydroxyfasudil abolished the inhibition of long-term potentiation (LTP) in rats with ischemia. Morphologically, it also markedly reduced pathological changes such as neuronal cells loss and nuclei shrinkage in cortex and hippocampus of ischemic rats. Biochemical analysis showed that the inhibition of Rho-kinase by hydroxyfasudil reduced the amount of MDA and increased the activities of SOD and GPx in ischemic rats that had increased MDA and decreased SOD and GPx activities. (3) To explore mechanism (s) of the beneficial effects of hydroxyfasudil in ischemia, we performed immunohistochemistry and RT-PCR analyses of NMDA NR2B subunit and for the first time found that hydroxyfasudil increased the expression of NR2B in cortex and hippocampus at both protein and mRNA levels. (4) Taken together, our data further support the notion that the inhibition of Rho-kinase provides neuroprotective effects in cerebral ischemia.
Cell Mol Neurobiol 2008 Aug
PMID:Improvement of cognitive deficit and neuronal damage in rats with chronic cerebral ischemia via relative long-term inhibition of rho-kinase. 1755 19

(1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia.
Cell Mol Neurobiol 2008 Feb
PMID:Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor. 1778 50

Knowledge about the effects of physical exercise on brain is accumulating although the mechanisms through which exercise exerts these actions remain largely unknown. A possible involvement of adult hippocampal neurogenesis (AHN) in the effects of exercise is debated while the physiological and pathological significance of AHN is under intense scrutiny. Recently, both neurogenesis-dependent and independent mechanisms have been shown to mediate the effects of physical exercise on spatial learning and anxiety-like behaviors. Taking advantage that the stimulating effects of exercise on AHN depend among others, on serum insulin-like growth factor I (IGF-I), we now examined whether the behavioral effects of running exercise are related to variations in hippocampal neurogenesis, by either increasing or decreasing it according to serum IGF-I levels. Mutant mice with low levels of serum IGF-I (LID mice) had reduced AHN together with impaired spatial learning. These deficits were not improved by running. However, administration of exogenous IGF-I ameliorated the cognitive deficit and restored AHN in LID mice. We also examined the effect of exercise in LID mice in the novelty-suppressed feeding test, a measure of anxiety-like behavior in laboratory animals. Normal mice, but not LID mice, showed reduced anxiety after exercise in this test. However, after exercise, LID mice did show improvement in the forced swim test, a measure of behavioral despair. Thus, many, but not all of the beneficial effects of exercise on brain function depend on circulating levels of IGF-I and are associated to increased hippocampal neurogenesis, including improved cognition and reduced anxiety.
Mol Cell Neurosci 2008 Feb
PMID:The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. 1808 33

A late onset neurological syndrome in carriers of premutation in FMR1 gene was recently described. The condition was named fragile-X-associated tremor/ataxia syndrome (FXTAS) and includes intentional tremor, cerebellar ataxia, parkinsonism, and cognitive deficit. We ascertained the contribution of FMR1 premutation to the phenotypes ataxia, tremor and/or parkinsonism. Sixty-six men over 45 years old presenting these symptoms, isolated or combined, were tested. Also, 74 normal men, randomly chosen in the population, formed the control group. In the patient group, no premutation carrier was found, which is in agreement with other observed frequencies reported elsewhere (0-5% variation). No significant differences were found when comparing gray zone allele frequencies among target and control groups. The FXTAS contribution in patients with phenotypic manifestations of FXTAS was 15/748 (2%). The presence of gray zone alleles is not correlated with FXTAS occurrence.
Genet Mol Res 2008 Jan 29
PMID:Frequency of FMR1 premutation in individuals with ataxia and/or tremor and/or parkinsonism. 1827 22

We previously reported that inhibition of Rho-kinase (ROCK) by hydroxyl fasudil improves cognitive deficit and neuronal damage in rats with chronic cerebral ischemia (Huang et al., Cell Mol Neurobiol 28:757-768, 2008). In this study, fasudil mesylate (FM) was investigated for its neuroprotective potential in rats with ischemia following middle cerebral artery occlusion (MCAO) and reperfusion. The effect of fasudil mesylate was also studied in rat brain cortical and hippocampal slices treated with oxygen-glucose deprivation (OGD) injury. Gross anatomy showed that cerebral infarct size, measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in the FM-treated than in the non-FM-treated ischemic rats. In the brain regions vulnerable to ischemia of ischemic rats, fasudil mesylate was also found to significantly restore the enzyme protein expression level of endothelial nitric oxide synthase (eNOS), which was decreased in ischemia. However, it remarkably reduced the protein synthesis of inducible nitric oxide synthase (iNOS) that was induced by ischemia and reperfusion. In rat brain slices treated with OGD injury, fasudil mesylate increased the neuronal cell viability by 40% for cortex and by 61% for hippocampus, respectively. Finally, in the presence of OGD and fasudil mesylate, superoxide dismutase (SOD) activity was increased by 50% for cortex and by 58% for hippocampus, compared to OGD only group. In conclusion, our in vivo study showed that fasudil mesylate not only decreased neurological deficit but also reduced cerebral infarct size, possibly and at least partially by augmenting eNOS protein expression and inhibiting iNOS protein expression after ischemia-reperfusion.
Cell Mol Neurobiol 2009 Mar
PMID:Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats. 1878


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