Importance of Posttraumatic Hypothermia and Hyperthermia on the Inflammatory Response after Fluid Percussion Brain Injury: Biochemical and Immunocytochemical Studies

Hypothermia reduces excitotoxic neuronal damage after seizures, cerebral ischemia and traumatic brain injury (TBI), while hyperthermia exacerbates damage from these insults. Presynaptic release of ionic zinc (Zn 2 þ ), translocation and accumulation of Zn 2 þ ions in postsynaptic neurons are important mechanisms of excitotoxic neuronal injury. We hypothesized that temperature-dependent modulation of excitotoxicity is mediated in part by temperature-dependent changes in the synaptic release and translocation of Zn 2 þ . In the present studies, we used autometallographic (AMG) and fluorescent imaging of N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining to quantify the influence of temperature on translocation of Zn 2 þ into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn 2 þ translocation is strongly influenced by brain temperature. Vesicular Zn 2 þ release was detected by AMG staining 1 h after TBI. At 301C, hippocampus showed almost no evidence of vesicular Zn 2 þ release from presynaptic terminals; at 36.51C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn 2 þ release; and at 391C vesicular Zn 2 þ release was significantly greater (40% to 60%) than at 36.51C. At 6 h after TBI, intracellular Zn 2 þ accumulation was detected by the TSQ staining method, which showed that Zn 2 þ translocation also paralleled the vesicular Zn 2 þ release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn 2 þ , being minimal at 301C and maximal at 391C. We conclude that pathological Zn 2 þ translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn 2 þ translocation.

Section: Discussionmentioning

confidence: 99%

Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

Suh

Frederickson

Danscher

2005

“…Neuroprotective strategies, including antibody treatments and therapeutic hypothermia, have been reported to decrease the acute inflammatory response and lead to histopathological protection (Carlos et al, 1997;Chatzipanteli et al, 2000). However, a recent review by Emerich and colleagues (2002) concluded that no study has successfully demonstrated that leukocytes satisfy any criteria for causing cell death or increased infarction due, in part, to a lack of sufficient controls.…”

Section: Inflammationmentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

Self Cite

553

358

Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

“…The mechanisms underlying the beneficial effects of posttraumatic hypothermia are multifactorial and include excitotoxicity, calciumdependent intercellular signaling, apoptosis, and edema formation (Dietrich and Bramlett, 2010;Yenari and Han, 2012). In addition, hypothermia has been reported to attenuate various inflammatory events including proinflammatory gene expression and protein levels when compared with normothermic TBI in some (Chatzipanteli et al, 2000;Goss et al, 1995;Kinoshita et al, 2002;Lotocki et al, 2006;Marion et al, 1997;Vitarbo et al, 2004;Whalen et al, 1997) but not all studies (Buttram et al, 2007;Truettner et al, 2005). Thus, a current area of research is directed to the continued investigation of the cellular and molecular events associated with the beneficial effects of hypothermia on posttraumatic inflammatory processes.…”

Section: Introductionmentioning

confidence: 99%

Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

Tomura

Vaccari

Keane

et al. 2012

Traumatic brain injury (TBI) activates the NALP1/NLRP1 inflammasome, which is an important component of the early innate inflammatory response to injury. We investigated the influence of therapeutic hypothermia on inflammasome activation after TBI. Adult male Sprague-Dawley rats were subjected to moderate fluid percussion brain injury. Temperature manipulation (331C or 371C) was initiated 30 minutes after TBI and maintained for 4 hours. At 4 or 24 hours after TBI, traumatized cortex and hippocampus were prepared for immunoblot or immunohistochemical analysis. In the normothermic groups, caspase-1, caspase-11 and expression of the purinergic receptor P2X7 increased at 24 hours after TBI. Posttraumatic hypothermia lead to decreased expression of these proteins at 24 hours compared with normothermic levels. Immunocytochemical studies showed that posttraumatic hypothermia also decreased caspase-1 staining in cerebral cortical neurons compared with normothermic TBI. Cultured cortical neurons subjected to stretch injury demonstrated significant secretion of caspase-1 into the culture medium and caspase-3 activation, both results reduced by hypothermic treatment. Posttraumatic hypothermia decreases inflammasome signaling in neurons and reduces the innate immune response to TBI at 24 hours after injury. Therapeutic hypothermia may protect the injured central nervous system by targeting the detrimental consequences of the innate immune response to injury.