Journal of neurotrauma
-
Journal of neurotrauma · Jul 2012
Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury.
Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. ⋯ Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post-traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans.
-
Journal of neurotrauma · Jul 2012
Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice.
Among other deficits, traumatic brain injury (TBI) causes impaired arousal and cognitive dysfunction. Hypothalamic orexin neuropeptides (also called hypocretins) regulate levels of arousal, and cerebrospinal fluid orexin levels are reportedly low in TBI patients. We hypothesized that TBI acutely impairs the dynamics of orexin release into brain interstitial fluid, and that these extracellular orexin levels correlate with wakefulness and motor activity. ⋯ Following CCI but not sham surgery, the mice exhibited reduced wakefulness and motor activity, and correlations between orexin and these measures were diminished. These abnormal orexin dynamics were associated with hypothalamic astrogliosis, but not acute loss of orexin neurons, as assessed by immunohistochemistry 3 days after injury. Future studies involving experimental manipulations of the orexin system will be required to determine its contribution to neurological outcomes following injury.
-
Journal of neurotrauma · Jul 2012
Comparative StudyThe relationship between localized subarachnoid inflammation and parenchymal pathophysiology after spinal cord injury.
Subarachnoid inflammation following spinal cord injury (SCI) can lead to the formation of localized subarachnoid scarring and the development of post-traumatic syringomyelia (PTS). While PTS is a devastating complication of SCI, its relative rarity (occurring symptomatically in about 5% of clinical cases), and lack of fundamental physiological insights, have led us to examine an animal model of traumatic SCI with induced arachnoiditis. We hypothesized that arachnoiditis associated with SCI would potentiate early parenchymal pathophysiology. ⋯ This was demonstrated by significant increases in cytokine (IL-1α and IL-1β) and chemokine (MCP-1, GRO/KC, and MIP-1α) production, MPO activity, blood-spinal cord barrier (BSCB) permeability, and MMP-9 activity. However, parenchymal inflammatory mediator production (acute IL-1α and IL-1β, subacute chemokines), BSCB permeability, and fibrous scarring in the PTS group were larger than the sum of the SCI group and arachnoiditis group combined, suggesting that arachnoiditis does indeed potentiate parenchymal pathophysiology. Accordingly, these findings suggest that the development of arachnoiditis associated with SCI can lead to an exacerbation of the parenchymal injury, potentially impacting the outcome of this devastating condition.
-
Journal of neurotrauma · Jul 2012
Evaluation of a combined treatment paradigm consisting of environmental enrichment and the 5-HT1A receptor agonist buspirone after experimental traumatic brain injury.
Environmental enrichment (EE) and serotonin(1A) (5-HT(1A))-receptor agonists provide significant benefit after experimental traumatic brain injury (TBI). The aim of this study was to test the hypothesis that combining these therapies would produce an effect that is more robust than either therapy alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to EE or standard (STD) housing where they received either buspirone (0.3 mg/kg) or vehicle (1.0 mL/kg) once daily for 3 weeks. ⋯ These data show that EE and buspirone benefit functional outcome after TBI, but their combination is not more robust than either alone, which does not support the hypothesis. The lack of an additive effect may be due to the early-and-continuous EE paradigm on its own producing marked benefits, resulting in a ceiling effect. The evaluation of buspirone in a delayed-and-abbreviated EE paradigm is ongoing in our laboratory.
-
Journal of neurotrauma · Jul 2012
Exogenous administration of PACAP alleviates traumatic brain injury in rats through a mechanism involving the TLR4/MyD88/NF-κB pathway.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is effective in reducing axonal damage associated with traumatic brain injury (TBI), and has immunomodulatory properties. Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation induced by brain injury. ⋯ Pretreatment with PACAP inhibited upregulation of TLR4 and its downstream signaling molecules MyD88, p-IκB, and NF-κB, and suppressed increases in the levels of the downstream inflammatory agents interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the brain tissue around the injured cortex and in the hippocampus. Administration of PACAP both in vitro and in vivo attenuated the ability of the TLR4 agonist lipopolysaccharide (LPS) to increase TLR4 protein levels. Therefore, PACAP exerts a neuroprotective effect in this rat model of TBI, by inhibiting a secondary inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway in microglia and neurons, thereby reducing neuronal death and improving the outcome following TBI.