title: Caspase-dependent cell death involved in brain damage after acute subdural hematoma in rats.
abstract: Traumatic brain injury is associated with acute subdural hematoma (ASDH) that worsens outcome. Although early removal of blood can reduce mortality, patients still die or remain disabled after surgery and additional treatments are needed. The blood mass and extravasated blood induce pathomechanisms such as high intracranial pressure (ICP), ischemia, apoptosis and inflammation which lead to acute as well as delayed cell death. Only little is known about the basis of delayed cell death in this type of injury. Thus, the purpose of the study was to investigate to which extent caspase-dependent intracellular processes are involved in the lesion development after ASDH in rats. A volume of 300microL blood was infused into the subdural space under monitoring of ICP and tissue oxygen concentration. To asses delayed cell death mechanisms, DNA fragmentation was measured 1, 2, 4 and 7 days after ASDH by TUNEL staining, and the effect of the pan-caspase inhibitor zVADfmk on lesion volume was assessed 7 days post-ASDH. A peak of TUNEL-positive cells was found in the injured cortex at day 2 after blood infusion (53.4+/-11.6 cells/mm(2)). zVADfmk (160ng), applied by intracerebroventricular injection before ASDH, reduced lesion volume significantly by more than 50% (vehicle: 23.79+/-7.62mm(3); zVADfmk: 9.06+/-4.08). The data show for the first time that apoptotic processes are evident following ASDH and that caspase-dependent mechanisms play a crucial role in the lesion development caused by the blood effect on brain tissue.
authors.affiliation: Institute for Neurosurgical Pathophysiology, University of Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany. beat.alessandri@uni-mainz.de
authors.forename: B
authors.initials: B
authors.lastname: Alessandri
authors.forename: T
authors.initials: T
authors.lastname: Nishioka
authors.forename: A
authors.initials: A
authors.lastname: Heimann
authors.forename: R M
authors.initials: RM
authors.lastname: Bullock
authors.forename: O
authors.initials: O
authors.lastname: Kempski
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001769:Blood / Q000378:metabolism*; D020520:Brain Infarction / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology; D002545:Brain Ischemia / Q000209:etiology / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020199:Hematoma, Subdural, Acute / Q000150:complications* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D019586:Intracranial Hypertension / Q000209:etiology / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases