title: Molecular basis of protective effect by crocetin on survival and liver tissue damage following hemorrhagic shock.
abstract: Hemorrhagic shock (HS) causes reduction of cellular energy stores, as measured by levels of ATP and ADP. Furthermore, energy depletion may cause mitochondrial damage, which in turn leads to cell death by apoptosis. The hypothesis of the present study is that by enhancing the recovery of cellular ATP and ADP and mitochondrial damage can be reduced, and the extent of apoptosis minimized. Crocetin, a carotenoid compound, appears to enhance the diffusion of oxygen in aqueous solution, and hence may improve energy stores both to the cell and within it. HS was produced in Sprague-Dawley rats by withdrawing blood from the carotid cannula until a mean arterial pressure of 35-40 mm Hg was reached, and then maintained by further withdrawals of blood for 30 and 60 min. Crocetin was administered 2-4 mg/kg in resuscitation fluid through venus cannula and the animals survived for 24-48 h after HS. Experiments designed to promote tissue reconstitution of ATP using crocetin indicate that these approaches are successful in increasing ATP post-hemorrhage and survival. Crocetin treatment also inhibited cellular damage as indicated by increase of Bcl-2 following decrease in cytosolic cytochrome c and caspase-3 after resuscitation. The prolonged energy deficit seen after hemorrhagic shock can produce late damage and rapid restoration of ATP levels to baseline can reduce apoptosis. In conclusions, crocetin can minimize the cellular damage as evidenced by apoptosis and increased the survival of rats.
authors.affiliation: Department of Veterans Affairs Medical Center, Kansas City, MO 64128-2226, USA. animesh.dhar@med.va.gov
authors.forename: Animesh
authors.initials: A
authors.lastname: Dhar
authors.forename: George
authors.initials: G
authors.lastname: Cherian
authors.forename: Gopal
authors.initials: G
authors.lastname: Dhar
authors.forename: Gibanananda
authors.initials: G
authors.lastname: Ray
authors.forename: Ram
authors.initials: R
authors.lastname: Sharma
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014801:Vitamin A / Q000031:analogs & derivatives
chemical_list: D000227:Adenine Nucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D000255:Adenosine Triphosphate; D045304:Cytochromes c