Linked Life Data

19076458

Source:http://linkedlifedata.com/resource/pubmed/id/19076458

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
2008-12-16
pubmed:abstractText
A major challenge for neurological therapeutics is the development of small molecule drugs that can activate a panoply of downstream pathways without toxicity. Over the past decade our group has shown that a family of enzymes that regulate posttranscriptional and transcriptional adaptive responses to hypoxia are viable targets for neuronal protection and repair. The family is a group of iron, oxygen, and 2-oxoglutarate-dependent dioxygenases, known as the HIF prolyl 4-hydroxylases (HIF PHDs). We have previously shown that pluripotent protection offered by iron chelators is mediated, in part, via the ability of these agents to inhibit the HIF PHDs. Our group and others have implicated the transcriptional activator HIF-1 in some of the salutary effects of iron chelation-induced PHD inhibition. While some iron chelators are currently employed in humans for conditions such as hemochromatosis, the diverse utilization of iron in physiological processes in the brain makes the development of HIF activators that do not bind iron a high priority. Here we report the development of a high throughput screen to develop novel HIF activators and/or PHD inhibitors for therapeutic use in the central nervous system (CNS). We show that tilorone, a low-molecular weight, antiviral, immunomodulatory agent is the most effective activator of the HIF pathway in a neuronal line. We also show that tilorone enhances HIF protein levels and increases the expression of downstream target genes independent of iron chelation and HIF PHD inhibition in vitro. We further demonstrate that tilorone can activate an HIF-regulated reporter gene in the CNS. These studies confirm that tilorone can penetrate the blood-brain barrier to activate HIF in the CNS. As expected from these findings, we show that tilorone provides effective prophylaxis against permanent ischemic stroke and traumatic spinal cord injury in male rodents. Altogether these findings identify tilorone as a novel and potent modulator of HIF-mediated gene expression in neurons with neuroprotective properties.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-10027546, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-12032158, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-12220871, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-15511083, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-15723616, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-15921450, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-16227210, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-16527254, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-16623832, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-16686427, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-1689322, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-17342411, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-17392476, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-17420989, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-17555402, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-18043901, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-18157163, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-18199003, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-2180770, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-2433817, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-339405, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-4317923, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-6159505, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-8271028, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-8784138, http://linkedlifedata.com/resource/pubmed/commentcorrection/19076458-8955077
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1749-6632
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
1147
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
383-94
pubmed:dateRevised
2010-9-22
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury.
pubmed:affiliation
Burke-Cornell Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA. rratan@burke.org
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't