Novel therapeutic advances in the field of trauma management depend upon animal models that can accurately predict the clinical efficacy of interventions. In the battlefield, TBI injuries occur as a direct result of blast waves (primary blast injury), impact from objects put in motion by the blast (secondary blast injury), and by people being forcefully put in motion by the blast (tertiary blast injury). The brain is clearly vulnerable to both secondary and tertiary blast injury. The most common type of TBI in the battlefield is diffuse axonal injury. In this regard, we chose to use Marmarou’s acceleration impact model to induce head trauma in the present study. This model produces a pronounced diffuse cellular and axonal injury in forebrain structures such as sensorimotor cortex and hippocampus but limited brainstem damage (23
). Posttraumatic ventriculomegaly is observed in survivors at 4–6 wk after injury, which mirrors the experience in human head injury. In addition, TBI and hemorrhagic shock often occur concomitantly in the battlefield due to multiple injuries. In the current study, we determined the efficacy of ghrelin in a highly military relevant experimental rat model of TBI combined with uncontrolled hemorrhagic shock. To mimic the far-forward battlefield situation, the first dose of ghrelin was intravenously administered together with low volume crystalloid resuscitation (that is, field resuscitation) at 45 min after TBI and hemorrhage. To study the long-term effects of ghrelin after TBI and UH, ghrelin or vehicle was s.c. administered daily for 10 d after TBI and UH in additional groups of animals. The animals were observed for up to 28 d after TBI and UH. Our results demonstrate that administration of ghrelin attenuated brain injury, improved brain functions, and reduced mortality in a rat model of TBI and uncontrolled hemorrhagic shock.
Gastrointestinal dysfunction occurs frequently in patients with TBI (32
). More than 50% of patients with severe head injuries develop gastrointestinal dysfunction as manifested by vomiting, abdominal distention, delayed gastric emptying, esophageal reflux and decreased intestinal peristalsis. Failure to maintain gastrointestinal function is a significant cause of posttrauma morbidity and mortality. However, little is known about whether gastrointestinal hormones are involved in modulating neuronal integrity and function after TBI. Ghrelin is a novel gastrointestinal hormone, cleaved from a precursor, preproghrelin (33
). It is principally synthesized in endocrine cells of the stomach, termed X/A-like or ghrelin cells, and particularly found in the gastric fundus. About 2/3 to 3/4 of circulating ghrelin is of gastric origin. Lesser concentrations of ghrelin are found throughout the small intestine. The biological effects of ghrelin are mediated through the ghrelin receptor (that is, GHSR-1a), a 7 trans-membrane domain Gq protein coupled receptor (9
). Ghrelin is the only identified endogenous ligand for this receptor. The wide distribution of ghrelin receptors suggests multiple paracrine, autocrine and endocrine roles of ghrelin (35
). It has been linked to the regulation of pituitary hormone secretion, feeding, energy homeostasis, gastrointestinal function, and cardiovascular and immune system (16
). The results from the current study suggest that ghrelin, a gastrointestinal hormone, may be associated with neuronal damage and recovery after TBI. A recent study has shown that ghrelin levels decreased in a mouse model of TBI (40
). In this regard, the decreased level of ghrelin may contribute to the secondary brain injury under such conditions. In our future studies, we will define the contribution of ghrelin downregulation on brain injury after TBI and UH.
The protective effects of ghrelin after brain injury appear to be related to its an-tiinflammatory (16
) and anti-apoptosis (20
) properties. TBI initiates a cascade of inflammatory processes including the release of proinflammatory mediators (43
), which contributes to the acute pathologic processes and long-term neuronal damage following TBI (28
). In this article, we found that brain levels of TNF-α and IL-6 increased significantly at 4 h after TBI and UH and ghrelin treatment dose dependently decreased brain levels of TNF-α and IL-6 under such conditions. Therefore, the beneficial effects of ghrelin after TBI and UH appears to be partially related to the downregulation of inflammatory mediators under such conditions. Apoptosis is thought to play an important role in both acute and chronic brain injury. Both animal and human studies have shown substantial evidence of neuronal apoptosis after TBI (44
). Clearly, therapies that protect neurons from apoptosis are of great importance, because the loss of these cells contributes to the loss of neurological function and can greatly impact outcome. Ghrelin has been shown to inhibit apoptosis in neuronal cells during oxygen-glucose deprivation (19
), and protect cortical neuron against focal ischemia/reperfusion in rats (20
). In the current study, we found that ghrelin reduced cortical apoptosis at 4 h after TBI and UH in a dose-dependent manner. In this regard, the antiapoptosis property of ghrelin also contributes to its protection after TBI and hemorrhage.
Ghrelin is a hormone with multiple functions. Several other properties of ghrelin may indirectly contribute to its neuroprotective effects after TBI. Ghrelin stimulates growth hormone (GH) secretion. Chronic GH insufficiency is a common complication following TBI, and is associated with depression and diminished quality of life (48
). Therefore, ghrelin may benefit TBI patients through a GH-dependent mechanism. Moreover, ghrelin has been reported to impact insulin secretion and glucose metabolism (49
). Patients with brain injury are particularly vulnerable to high blood glucose concentrations (51
). Both hypo- and hyperglycemia affect prognosis in brain-injured patients, and there is an increasing belief that strict glucose control may benefit these patients (53
). In this regard, the impact of ghrelin on GH, insulin and glucose concentrations in this model also warrants further investigation.