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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen receptor beta (ERbeta) is expressed at high levels in both neurons and glial cells of the central nervous system. The development of ERbeta knockout (BERKO) mice has provided a model to study the function of this nuclear receptor in the brain. We have found that the brains of BERKO mice show several morphological abnormalities. There is a regional neuronal hypocellularity in the brain, with a severe neuronal deficit in the somatosensory cortex, especially layers II, III, IV, and V, and a remarkable proliferation of astroglial cells in the limbic system but not in the cortex. These abnormalities are evident as early as 2 mo of age in BERKO mice. As BERKO mice age, the neuronal deficit becomes more pronounced, and, by 2 yr of age, there is degeneration of neuronal cell bodies throughout the brain. This is particularly evident in the substantia nigra. We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain.
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PMID:Morphological abnormalities in the brains of estrogen receptor beta knockout mice. 1122 19

Newly developed insulin-sensitizing agents, which target the nuclear receptor peroxisome proliferator-activated receptor-gamma have recently been appreciated to exhibit potent anti-inflammatory actions. Since stroke is associated with an intense inflammatory response, we reasoned that these agents may ameliorate injury from stroke. We report that administration of troglitazone or pioglitazone 24 h before and at the time of cerebral infarction dramatically reduced infarction volume and improved neurological function following middle cerebral artery occlusion in rats. Furthermore, we find that delayed therapy also significantly reduced infarct volume. The brains of the drug-treated animals displayed reduced inflammation as evidenced by decreased immunoreactivity for microglial/macrophage markers and reduced protein and mRNA for interleukin-1beta, cyclooxygenase-2 and inducible nitric oxide synthase. We argue that the beneficial effects of these drugs are likely due to reduced expression of these inflammatory mediators, which are known to exacerbate ischemic injury following stroke. These results are of particular relevance to diabetic patients chronically treated with these agents who may benefit from the neuroprotective actions of these drugs.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. 1559 Jan 52

Cardiovascular diseases are the leading cause of morbidity and mortality in the US. Proper management and/or prevention of atherosclerosis and hypertension, two complex and chronic disorders, would significantly reduce the risk for cardiovascular events such as myocardial infarction and stroke, but this requires an understanding of the mechanisms underlying their development and progression. Whereas a great deal has been learned and applied toward the management of these disorders, especially hypertension, morbidity and mortality remains unacceptably high, most likely because there are disease-causing mechanisms that have yet to be fully recognized. Understanding these disease mechanisms is necessary so that novel management strategies can be developed. One of these novel mechanisms centers on peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a member of the nuclear receptor superfamily of ligand-activated transcription factors known to play a role in glucose homeostasis and adipocyte differentiation and, more recently, has been shown to have anti-inflammatory, antiatherogenic, and antihypertensive effects. Thiazolidinediones, a class of drugs used in the treatment of type 2 diabetes mellitus, are high-affinity ligands for PPAR-gamma. In this review, the anti-inflammatory, anti-atherosclerotic, and anti-hypertensive mechanisms by which PPAR-gamma and its agonists are thought to exert protective effects on the cardiovascular system are discussed. Ongoing clinical trials using PPAR-gamma activators for the management of cardiovascular diseases, especially in patients with type 2 diabetes mellitus, are summarized.
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PMID:Peroxisome proliferator-activated receptor-gamma and its agonists in hypertension and atherosclerosis : mechanisms and clinical implications. 1625 27

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: alpha, beta (sometimes called delta), and gamma. The better studied are PPARalpha and PPARgamma, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARbeta and that its selective activation inhibits platelet aggregation. PPARbeta is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARbeta ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARbeta is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARbeta as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.
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PMID:Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARbeta. 1636 17

Diseases of the central nervous system present a challenge for the development of new therapeutic agents. Nuclear receptors are ligand-activated transcription factors that have proven to be valuable targets for development of new drugs owing to their ability to directly regulate gene expression. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), has been investigated for its action in ameliorating the development and progression of a number of CNS diseases. PPARgamma agonists exhibit potent anti-inflammatory effects and appear to have direct neuroprotective actions. PPARgamma agonists have been shown to be efficacious in animal models of Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis. The availability of FDA-approved agonists of this receptor will facilitate the rapid translation of these findings into clinical trials for a number of CNS diseases.
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PMID:PPARgamma as a therapeutic target in central nervous system diseases. 1676 86

1. Stroke is accompanied by a robust inflammatory response, glutamate-mediated excitotoxicity, release of reactive oxygen species and apoptosis. Thiazolidinediones, which target the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-g, have been reported recently to exhibit potent anti-inflammatory and anti-oxidant actions and inhibit both neural excitotoxicity and apoptosis. 2. The present study was conducted to determine whether rosiglitazone, a potent thiazolidinedione for PPAR-g, would show efficacy against the cerebral infarction and neurological dysfunctions induced by embolic middle cerebral artery (MCA) occlusion in the rat. 3. Focal ischaemic injury was induced by embolizing a preformed clot into the MCA. Rosiglitazone was dissolved in dimethyl sulphoxide and injected i.p. 1 h before MCA occlusion at doses of 0.33, 0.1, 0.3 or 1 mg/kg. In addition, 1 mg/kg rosiglitazone was used immediately or 4 h after embolization. Forty-eight hours after MCA occlusion, brains were removed, sectioned and stained with a 2% solution of 2,3,5-triphenyltetrazolum chloride and analysed using a commercial image-processing software program. 4. When rosiglitazone was administered 1 h before embolization, it significantly reduced infarct volume by 48.2, 68.4% and 70.3% at doses of 0.1, 0.3 and 1 mg/kg, respectively (P < 0.001). Administration of rosiglitazone (1 mg/kg) immediately or 4 h after stroke also reduced infarct volume by 67 and 50.8%, respectively (P < 0.001). Rosiglitazone-treated rats also demonstrated improved neurological functions. However, there were no statistically significant differences between control and treated groups in terms of brain oedema at 48 h after ischaemic injury. 5. The findings of the present study may support the idea of a potential benefit of thiazolidinediones in the management of ischaemic stroke.
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PMID:Rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, reduces infarction volume and neurological deficits in an embolic model of stroke. 1704 14

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and function as ligand-modulated transcription factors that regulate gene expression in many important biological processes. The PPARdelta subtype has the highest expression in the brain and is postulated to play a major role in neuronal cell function; however, the precise physiological roles of this receptor remain to be elucidated. Herein, we show that the high-affinity PPARdelta agonists L-165041 [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxyl]phenoxy]-acetic acid] and GW501516 [2-methyl4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-triazol-5-yl)-methylsulfanyl)phenoxy acetic acid] protect against cytotoxin-induced SH-SY5Y cell injury in vitro and both ischemic brain injury and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in vivo. In the SH-SY5Y studies, treatment with L-165041 or GW501516 significantly and concentration-dependently attenuated cell death following thapsigargin, 1-methyl-4-phenylpyridinium, or staurosporine exposure, with the extent of damage correlated with the level of caspase-3 inhibition. In the transient (90 min) middle cerebral artery occlusion model of ischemic brain injury in rats, i.c.v. infusion of L-165041 or GW501516 significantly attenuated the ischemic brain damage measured 24 h after reperfusion. Moreover, the PPARdelta agonists also significantly attenuated MPTP-induced depletion of striatal dopamine and related metabolite contents in mouse brain. These results demonstrate that subtype-selective PPARdelta agonists possess antiapoptotic properties in vitro, which may underlie their potential neuroprotective potential in in vivo experimental models of cerebral ischemia and Parkinson's disease (PD). These findings suggest that PPARdelta agonists could be useful tools for understanding the role of PPARdelta in other neurodegenerative disorders, as well as attractive therapeutic candidates for stroke and neurodegenerative diseases such as PD.
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PMID:Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. 1716 70

The peroxisome proliferator activated receptors (PPARs), which belong to the nuclear receptor superfamily, are key regulators of glucose and fat metabolism. The PPAR-gamma isoform is involved in the regulation of cellular glucose uptake, protection against atherosclerosis and control of immune reactions. In addition, the activation of PPAR-gamma effectively attenuates neurodegenerative and inflammatory processes in the brain. Here, we review a novel aspect of beneficial and clinically relevant PPAR-gamma actions: neuroprotection against ischemic injury mediated by intracerebral PPAR-gamma, which is expressed in neurons and microglia. Together with the recent observation that the PPAR-gamma ligand pioglitazone reduces the incidence of stroke in patients with type 2 diabetes, this review supports the concept that activators of PPAR-gamma are effective drugs against ischemic injury.
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PMID:PPAR-gamma: therapeutic target for ischemic stroke. 1741 24

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor gamma, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.
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PMID:NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. 1752 20

Normal physiological processes are under control of circadian rhythms. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. Recent observations demonstrate a causal relationship between alterations in circadian rhythmicity and metabolic disorders. Disruption of clock genes results in dyslipidemia, insulin resistance and obesity, all predisposing to atherosclerosis. The nuclear receptor Rev-erb alpha is part of the clock circuitry and plays an important role in keeping proper timing of the clock. Rev-erb alpha also regulates lipid metabolism, adipogenesis and vascular inflammation. Interestingly, Rev-erb alpha also cross-talks with several other nuclear receptors involved in energy homeostasis. Therefore Rev-erb alpha may serve to couple metabolic and circadian signals.
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PMID:Rev-erb alpha gives a time cue to metabolism. 1776 29


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