Stimulating the Central Nervous System to Prevent Intestinal Dysfunction After Traumatic Brain Injury

Bansal, Vishal; Costantini, Todd W.; Ryu, Seok Yong; Peterson, Carrie Y.; Loomis, William; Putnam, James G.; Elicieri, Brian P.; Baird, Andrew; Coimbra, Raúl

doi:10.1097/ta.0b013e3181d87373

Cited by 71 publications

(71 citation statements)

References 26 publications

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“…Unlike other studies that examine TBI-induced intestinal and inflammatory changes at later time points, we studied the early effects of TBI on intestinal injury. For this reason, TNF-a is the ideal inflammatory cytokine, since it rises acutely following TBI and tends to plateau at 6 h (Bansal et al, 2010). This increased inflammatory milieu may manifest as the set of physiologic changes coined the systemic inflammatory response (SIRS), which can lead to micro-thrombosis, decreased tissue perfusion, tissue injury, and eventually sepsis and death (Swank and Deitch, 1996).…”

Section: Discussionmentioning

confidence: 99%

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The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

Bansal

Ryu

Blow

et al. 2010

Journal of Neurotrauma

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Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 mg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-a. Permeability increased in the TBI group compared to the sham group (109.7 AE 21.8 mg/mL vs. 32.2 AE 10.1 mg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 AE 4.2 mg/mL vs. 109.7 AE 21.8 mg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group ( p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-a increased following TBI compared to the sham group (46.2 AE 7.1 pg/mL vs. 24.4 AE 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-a to sham levels (29.2 AE 5.0 pg/mL; p ¼ NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-a. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities.

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Section: Discussionmentioning

confidence: 99%

“…TBI (Bansal et al, 2010 Tracey and colleagues (2007). Similarly, other investigators have demonstrated that exogenous glutamine and progesterone, administered following TBI, decrease IL-1, TNF-a, and IL-6 levels in both intestinal and brain tissue (Chen, Shi, Jin, et al, 2008;Chen, Shi, Qi, et al, 2008).…”

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confidence: 99%

The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

Bansal

Ryu

Blow

et al. 2010

Journal of Neurotrauma

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“…136 Acute VNS can also significantly reduce intestinal TNF levels and prevent intestinal permeability in mice following TBI. 137 Intestinal inflammation also reduced neuron proliferation from the dorsal motor nucleus of the vagus in rats which can also be attenuated by ghrelin. 138 Accumulating evidence strongly supports the idea that inflammation and the immune response play a critical role in the pathophysiology of epilepsy.…”

Section: Va Author Manuscriptmentioning

confidence: 99%

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

Chen

Flanagan

Samadani

2013

Neurological Research

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Objectives-Traumatic brain injury has a high morbidity and mortality in both civilian and military populations. Blast and other mechanisms of traumatic brain injury damage the brain by causing neurons to disconnect and atrophy. Such traumatic axonal injury can lead to persistently vegetative and minimally conscious states, for which limited treatment options exist, including physical, occupational, speech and cognitive therapies.More than 60,000 patients have received vagus nerve stimulation for epilepsy and depression. In addition to decreased seizure frequency and severity, patients report enhanced mood, reduced daytime sleepiness independent of seizure control, increased slow wave sleep, and improved cognition, memory, and quality of life.Early stimulation of the vagus nerve accelerates the rate and extent of behavioral and cognitive recovery after fluid percussion brain injury in rats.Methods-We recently obtained FDA approval for a pilot prospective randomized crossover trial to demonstrate objective improvement in clinical outcome by placement of a vagus nerve stimulator in patients who are recovering from severe traumatic brain injury. Our hypothesis is that stimulation of the vagus nerve results in increased cerebral blood flow and metabolism in the forebrain, thalamus and reticular formation, which promotes arousal and improved consciousness, thereby improving outcome after traumatic brain injury resulting in minimally conscious or persistent vegetative states.Discussion-If this study demonstrates that vagus nerve stimulation can safely and positively impact outcome, then a larger randomized prospective crossover trial will be proposed.

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“…This phenomenon may be explained by the role of nerves in controlling the gut barrier, and demonstrates the risks with conclusion from cell culture systems, lacking the nerve innervation. The vagus nerve has also been shown to affect the intestinal permeability 100,101 . Indeed, vagus nerve stimulation has been shown to attenuate disruption of tight junction in intestinal epithelium in endotoxemic mice, by a mechanism that seem to involve α7 nicotine acetylcholine receptor (α7 nAchRs) 102 .…”

Section: Paracellular Permeabilitymentioning

confidence: 99%

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response. An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease. Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response. Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease. In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease

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Stimulating the Central Nervous System to Prevent Intestinal Dysfunction After Traumatic Brain Injury

Cited by 71 publications

References 26 publications

The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

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