Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats

Abstract

IntroductionThe 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.MethodsRats 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.ResultsWe 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.ConclusionsOur 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.

Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury

“…Supplement with hydrocortisone post trauma also improves neurological recovery and leads to beneficial outcomes [35]. Moreover, progesterone, an indirect precursor of cortisol, has shown promise to be a neuroprotective agent, and it is currently under clinical trials for the treatment of TBI [36, 37].…”

miR-21, a potential therapeutic target of alleviating blood-brain barrier damage after traumatic brain injury

“…However, a clinical trail (MRC CRSAH) involved 10008 patients conducted in more than 40 countries demonstrated that corticosteroids does not have any therapeutic effect on TBI patients in spite of the time of administration post-injury [7] . Our previous research also proved that high-dose methylprednisolone can aggravate cellular apoptosis and BBB damage in hypothalamus, which can exacerbate the acute critical illness-related corticosteroid insufficiency associated with TBI [8][9] . Molecular therapy for TBI has become the research hotspot in recent years.…”

Opposing effects of traumatic brain injury on excitatory synaptic function in the lateral amygdala in the absence and presence of preinjury stress

“…Nevertheless, the pathophysiology of TBI is a complex process, and we recognize that it is highly susceptible to several extrinsic factors, including those that are aversive or rehabilitative in nature (Griesbach et al, ; M.F. Chen et al, ; Klemenhagen et al, ). Although future studies examining physiology in the absence of behavioral testing would be informative, it is important to note that our findings may be more clinically relevant given that the majority of TBI patients undergo cognitive behavioral testing following injury.…”