Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.
 ...
PMID:Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease. 1595 16

This study was performed to test the hypothesis that fragments of amyloid precursor protein are able to enter the injured blood-brain barrier (BBB) following brain ischemia. We observed chronic disruption of the BBB after ischemia. The BBB changes did not increase in intensity and frequency with longer periods of recirculation. As an effect of BBB injury, we noted a visible connection of diffuse amyloid plaques with neurovasculature in rats. This pathology appears to have a similar distribution as in Alzheimer's disease, hippocampal and cortical changes being most severe.
 ...
PMID:Pathological opening of the blood-brain barrier to horseradish peroxidase and amyloid precursor protein following ischemia-reperfusion brain injury. 1600 69

Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases.
 ...
PMID:Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. 1611 Mar 45

Beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease (AD). Several lines of evidence support that Abeta-induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Thus, agents that scavenge ROS level may usefully impede the development or progress of AD. Green tea extract has been known to have such antioxidant properties. Our previous studies demonstrate that green tea extract protected ischemia/reperfusion-induced brain cell death by scavenging oxidative damages of macromolecules. In this study, we investigated the effects of green tea extract on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with Abeta25-35 (10-50 microM) showed intracellular ROS elevation, the formation of 8-oxodG (an oxidized form of DNA), and underwent apoptotic cell death in a dose-dependent manner. Abeta(25-35) treatment upregulated pro-apoptotic p53 at the gene level, and Bax and caspase-3 at the protein level, but downregulated anti-apoptotic Bcl-2 protein. Interestingly, co-treated green tea extract (10-50 microg/ml) dose-dependently attenuated Abeta(25-35) (50 microM)-induced cell death, intracellular ROS levels, and 8-oxodG formation, in addition to p53, Bax, and caspase-3 expression, but upregulated Bcl-2. Furthermore, green tea extract prevented the Abeta(25-35)-induced activations of the NF-kappaB and ERK and p38 MAP kinase pathways. Our study suggests that green tea extract may usefully prevent or retard the development and progression of AD.
 ...
PMID:Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. 1615 42

Nitric oxide (NO) and arachidonic acid (AA) and also its metabolites are very important inter- and intracellular second messengers. They are involved in mechanisms of learning and memory. However, liberated in excessive amount in brain ischemia, Parkinson and Alzheimer diseases they are responsible for cell degeneration and death. Previously, we could show that Alzheimer disease's amyloid-beta protein enhanced nitric oxide liberation. The role of NO in AA metabolism is till now not well understood. Therefore, the aim of the present study was to investigate the mechanisms of NO-evoked activation of AA release and inhibition of AA incorporation into phospholipids of cortical rat brain synaptoneurosomes. The studies were carried out using NO donors, butyryl-cGMP (b-cGMP) and H2O2. All these compounds enhanced AA liberation from phosphatydilinositol (PI) and phosphatidylcholine (PC). Protein kinase ERK1/2, protein kinase C (PKC), cGMP-dependent protein kinase G (PKG) were involved in basal and NO-induced cytosolic phospholipase A2 (cPLA2) activation. Moreover, NO donors, b-cGMP and hydrogen peroxide (H2O2) exerted inhibitory effect on AA incorporation into PI and PC influencing arachidonyl-CoA transferase (AA-CoA-T) activity. AA-CoA synthase (AA-CoA-S) activity did not change. Specific inhibitors of protein kinase ERK1/2 (UO126), PKC (GF109203X), PKG (KT5823) had no effect on NO-mediated lowering of AA incorporation into PI and PC but inhibited the basal AA-CoA-S activity. Our data indicated that AA (10 microM) itself markedly decreased AA incorporation by about 50% into phospholipids of synaptoneurosomes membranes. Increasing release of AA and its metabolites causes the lowering of AA incorporation evoked by NO, b-cGMP and H2O2. Antioxidant, Resveratrol (100 microM) prevented NO- and cGMP-evoked inhibition of AA incorporation. These results suggest that NO affects the intracellular level of AA through alteration of cPLA2 and AA-CoA acyltransferase activities and may have an important implication in alterations of nerve endings properties and function.
 ...
PMID:Nitric oxide alters arachidonic acid turnover in brain cortex synaptoneurosomes. 1621 87

In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth/maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and beta-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, beta-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.
 ...
PMID:Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. 1634 Jan 57

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.
 ...
PMID:Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. 1636 7

Our study demonstrates that ischemia-reperfusion brain injury induces an increase in blood-brain barrier (BBB) permeability in the periventricular white matter. This chronic insufficiency of BBB may allow entry of neurotoxic fragments of amyloid precursor protein (APP) and other blood components such as platelets into the perineurovascular white matter tissue. These components may have secondary and chronic harmful effects on the ischemic myelin and axons and can intensify the phagocytic activity of microglial cells. Pathological accumulation of toxic fragments of APP in myelinated axons and oligodendrocytes appears after ischemic BBB injury and seem to be concomitant with, but independent of neuronal injury. It seems that ischemia-reperfusion disturbances may play important roles, both directly and indirectly, in the pathogenesis of white matter lesions. This pathology appears to have distribution similar to that of sporadic Alzheimer's disease. We noted micro-BBB openings in ischemic white matter lesions that probably would act as seeds of future Alzheimer's-type pathology.
 ...
PMID:Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation in white matter after ischemic brain injury in long-lived rats. 1667 68

Phospholipase A2 (PLA2) generates arachidonic acid, docosahexaenoic acid, and lysophospholipids from neural membrane phospholipids. These metabolites have a variety of physiological effects by themselves and also are substrates for the synthesis of more potent lipid mediators such as eicosanoids, platelet activating factor, and 4-hydroxynonenal (4-HNE). At low concentrations, these mediators act as second messengers. They affect and modulate several cell functions, including signal transduction, gene expression, and cell proliferation, but at high concentrations, these lipid mediators cause neurotoxicity. Among the metabolites generated by PLA2, 4-HNE is the most cytotoxic metabolite and is associated with the apoptotic type of neural cell death. Levels of 4-HNE are markedly increased in neurological disorders such as Alzheimer disease, Parkinson disease, ischemia, spinal cord trauma, and head injury. The purpose of this review is to summarize and integrate the vast literature on metabolites generated by PLA2 for a wider audience. The authors hope that this discussion will jump-start more studies not only on the involvement of PLA2 in neurological disorders but also on the importance of PLA2-generated lipid mediators in physiological and pathological processes.
 ...
PMID:Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. 1668 69

In recent years endothelin-converting enzyme (ECE-1) has been suggested to play an important role in amyloid-beta peptide metabolism as one of the amyloid-degrading enzymes. In this connection, the analysis of the levels of expression and distribution of ECE-1 in the brain under normal and pathologic conditions could be important in neurodegeneration and pathogenesis of Alzheimer disease. In our previous studies, we have demonstrated that expression of ECE-1 was significantly reduced in the cortex of adult rats after 15 mins of global ischemia. It was also significantly reduced in the striatum of rats subjected to prenatal hypoxia. In the present study, we analyzed effects of hypoxia and oxidative stress on ECE-1 in human neuroblastoma NB7 cells and effects of the cholinergic agonist carbachol and the phorbol ester, phorbol 12-myristate 13-acetate (PMA). We have found that chronic (24 hrs) hypoxia and oxidative stress resulted in 30% and 20% decrease in expression of ECE-1 at the protein level, respectively, although at the level of ECE-1 mRNA there were no statistically significant changes. Serum withdrawal from the incubation medium as well as addition of carbachol or PMA for 24 hrs also led to a significant reduction of the levels of ECE-1 protein in NB7 cells. Further study of the downstream signaling cascades involved in downregulation of ECE expression in NB7 cells and primary neuronal cells might provide us with new insights into possible therapeutic strategies for prevention or treatment of Alzheimer disease in elderly patients and those who suffer from stroke or cerebrovascular disorders.
 ...
PMID:Regulation of endothelin-converting enzyme-1 expression in human neuroblastoma cells. 1674 Oct 47


<< Previous 1 2 3 4 5 6 7 8 9 10