title: Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats.
abstract: BACKGROUND
  The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury.
  
  
  METHODS
  Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury.
  
  
  RESULTS
  We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood-brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus.
  
  
  CONCLUSIONS
  Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Zilong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Chai
authors.forename: Lanlan
authors.initials: L
authors.lastname: Luo
authors.forename: Rongcai
authors.initials: R
authors.lastname: Jiang
authors.forename: Jingfei
authors.initials: J
authors.lastname: Dong
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier; D001930:Brain Injuries / Q000188:drug therapy*; D016638:Critical Illness; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000187:drug effects; D006854:Hydrocortisone / Q000008:administration & dosage / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000293:injuries; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones; D006854:Hydrocortisone; D008775:Methylprednisolone