Role of bilirubin oxidation products in the pathophysiology of DIND following SAH.
Despite intensive research efforts, by our own team and many others, the molecules responsible for acute neurological damage following subarachnoid hemorrhage (SAH) and contributing to delayed ischemic neurological deficit (DIND) have not yet been elucidated. While there are a number of candidate mechanisms, including nitric oxide (NO) scavenging, endothelin-1, protein kinase C (PKC) activation, and rho kinase activation, to name but a few, that have been investigated using animal models and human trials, we are, it seems, no closer to discovering the true nature of this complex and enigmatic pathology. Efforts in our laboratory have focused on the chemical milieu present in hemorrhagic cerebrospinal fluid (CSF) following SAH and the interaction of the environment with the molecules generated by SAH and subsequent events, including NO scavenging, immune response, and clot breakdown. We have identified and characterized a group of molecules formed by the oxidative degradation of bilirubin (a clot breakdown product) and known as BOXes (bilirubin oxidation products). We present a synopsis of the characterization of BOXes as found in human SAH patients' CSF and the multiple signaling pathways by which BOXes act. In summary, BOXes are likely to play an essential role in the etiology of acute brain injury following SAH, as well as DIND.
Mayfield Clinic, Cincinnati, OH, USA. pynegj@ucmail.uc.edu
Gail J
GJ
Pyne-Geithman
Sunil G
SG
Nair
Danielle N Caudell
DN
Stamper
Joseph F
JF
Clark
D000818:Animals; D001663:Bilirubin / Q000134:cerebrospinal fluid*; D001930:Brain Injuries / Q000209:etiology*; D002545:Brain Ischemia / Q000134:cerebrospinal fluid / Q000150:complications / Q000209:etiology; D019332:Endothelin-1 / Q000134:cerebrospinal fluid; D006801:Humans; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009569:Nitric Oxide / Q000134:cerebrospinal fluid; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000134:cerebrospinal fluid; D015398:Signal Transduction / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000134:cerebrospinal fluid / Q000150:complications*; D054460:rho-Associated Kinases / Q000134:cerebrospinal fluid
D019332:Endothelin-1; D009569:Nitric Oxide; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D001663:Bilirubin