Linked Life Data

19368823

Source:http://linkedlifedata.com/resource/pubmed/id/19368823

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
2009-4-20
pubmed:abstractText
We previously demonstrated that the progesterone (PROG) metabolite allopregnanolone (AP) is more potent than PROG in the treatment of traumatic brain injury (TBI) and stroke, but the mechanisms for this differential effect are little understood. The mitochondrial permeability transition pore (mtPTP) appears to be a key player in the intrinsic pathway of apoptosis-induced loss of neurons. Its activation is accompanied by the release of cytochrome c (cyt c) from the intermembrane gap and subsequent cell death. We investigated whether mtPTP is implicated in the mechanisms of PROG and AP neuroprotection following traumatic and ischemic brain injury. To assess the neurosteroids' direct effects on mtPTP activity at the single-channel level, recordings from the inner mitochondrial membrane were obtained by a patch-clamp approach in rat liver mitoplasts. AP but not PROG strongly inhibited mtPTP currents. Interaction of AP with the PTP was further supported by a swelling assay demonstrating that AP inhibited Ca(2+)-triggered swelling in functionally intact rat liver and brain mitochondria. If AP inhibits the mtPTP, it should prevent the mitochondrial cyt c release seen in stroke and TBI. To test this idea, we subjected one group of rats to cortical contusion injury (CCI) and another to transient middle cerebral artery occlusion (MCAO). AP-treated animals showed substantially decreased cyt c release and AP was more potent than PROG in inhibiting mitochondrial cyt c release at 24 h post-CCI and -MCAO. Our results demonstrate that AP inhibits the mtPTP current. This may help to explain its more potent anti-apoptotic and neuroprotective effects compared to PROG.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1872-6240
pubmed:author
pubmed:issnType
Electronic
pubmed:day
31
pubmed:volume
1263
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
165-73
pubmed:meshHeading
pubmed-meshheading:19368823-Animals, pubmed-meshheading:19368823-Brain, pubmed-meshheading:19368823-Brain Injuries, pubmed-meshheading:19368823-Calcium, pubmed-meshheading:19368823-Cell Membrane Permeability, pubmed-meshheading:19368823-Cytochromes c, pubmed-meshheading:19368823-Infarction, Middle Cerebral Artery, pubmed-meshheading:19368823-Liver, pubmed-meshheading:19368823-Male, pubmed-meshheading:19368823-Membrane Potential, Mitochondrial, pubmed-meshheading:19368823-Mitochondria, pubmed-meshheading:19368823-Mitochondria, Liver, pubmed-meshheading:19368823-Mitochondrial Membrane Transport Proteins, pubmed-meshheading:19368823-Mitochondrial Membranes, pubmed-meshheading:19368823-Neuroprotective Agents, pubmed-meshheading:19368823-Patch-Clamp Techniques, pubmed-meshheading:19368823-Pregnanolone, pubmed-meshheading:19368823-Progesterone, pubmed-meshheading:19368823-Rats, pubmed-meshheading:19368823-Rats, Wistar
pubmed:year
2009
pubmed:articleTitle
Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone.
pubmed:affiliation
Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA 30322, USA. isayeed@emory.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural