Protection against hippocampal CA1 cell loss by post-ischemie hypothermia is dependent on delay of initiation and duration

Summary:To evaluate the mechanism of tolerance to ischemia, inductions of heat shock protein (HSP) 70 and heat shock cognate protein (HSC) 70 mRNAs in gerbil hippocampus were compared with in situ hybridization between cases of a single 3.5-min period of forebrain isch emia and a 3.5-min period of ischemia 2 days after 2-min pretreatment with ischemia. Immunohistochemistry for HSP70 protein and morphological studies were also per formed in the same brains up to 7 days after the reperfu sion. Following a single 3.5-min period of ischemia, HSP70 and HSC70 mRNAs were induced in all hippo campal cells. However, the hippocampal CAl cells pro duced only a minimum of HSP70 protein, and the cells were almost lost by 7 days. Following 3.5 min of ischemia after 2-min pretreatment, large populations of the CAl cells survived at 7 days. The peak time of the HSP70 and

Section: Discussionmentioning

confidence: 99%

Acceleration of HSP70 and HSC70 Heat Shock Gene Expression following Transient Ischemia in the Preconditioned Gerbil Hippocampus

Akiyama

Abe

Kawagoe

et al. 1993

“…Intraischemic hypothermia is most effective in transient ischemia or 'reperfusion' models (Busto et al, 1989a;Carroll and Beek, 1992;Colbourne and Corbett, 1995); the effects of intraischemic hypothermia in permanent ischemia models are far less uniform (Baker et al, 1991;Kader et al, 1992;Kozlowski et al, 1997;Lo et al, 1993;Morikawa et al, 1992;Moyer et al, 1992;Ridenour et al, 1992;Zhao et al, 2007) . In addition, it will be most meaningful clinically if hypothermia protects when applied postischemically; however, therapeutic time windows for postischemic hypothermia are limited.…”

Section: Hypothermia Does Not Always Attenuate Stroke Even In the Labmentioning

confidence: 99%

General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

Zhao

Steinberg

Sapolsky

2007

152

135

Mild or moderate hypothermia is generally thought to block all changes in signaling events that are detrimental to ischemic brain, including ATP depletion, glutamate release, Ca 2 + mobilization, anoxic depolarization, free radical generation, inflammation, blood-brain barrier permeability, necrotic, and apoptotic pathways. However, the effects and mechanisms of hypothermia are, in fact, variable. We emphasize that, even in the laboratory, hypothermic protection is limited. In certain models of permanent focal ischemia, hypothermia may not protect at all. In cases where hypothermia reduces infarct, some studies have overemphasized its ability to maintain cerebral blood flow and ATP levels, and to prevent anoxic depolarization, glutamate release during ischemia. Instead, hypothermia may protect against ischemia by regulating cascades that occur after reperfusion, including blood-brain barrier permeability and the changes in gene and protein expressions associated with necrotic and apoptotic pathways. Hypothermia not only blocks multiple damaging cascades after stroke, but also selectively upregulates some protective genes. However, most of these mechanisms are addressed in models with intraischemic hypothermia; much less information is available in models with postischemic hypothermia. Moreover, although it has been confirmed that mild hypothermia is clinically feasible for acute focal stroke treatment, no definite beneficial effect has been reported yet. This lack of clinical protection may result from suboptimal criteria for patient entrance into clinical trials. To facilitate clinical translation, future efforts in the laboratory should focus more on the protective mechanisms of postischemic hypothermia, as well as on the effects of sex, age and rewarming during reperfusion on hypothermic protection.

“…Early studies established that cooling during global or focal cerebral ischemia greatly diminishes cell death and promotes functional recovery (for comprehensive reviews, see Ginsberg et al, 1992;Maher and Hachinski, 1993;Thornhill and Corbett, 2001;Wagner and Zuccarello, 2005). Although initially controversial (Dietrich et al, 1993), delayed postischemic hypothermia also reduces cell death and improves functional recovery (Carroll and Beek, 1992;Colbourne and Corbett, 1995;Colbourne et al, 2000;Maier et al, 1998;Yanamoto et al, 1996); therefore, hypothermia has great potential as a clinical therapy. Indeed, recent studies show that systemic hypothermia improves survival and recovery in outof-hospital cardiac arrest victims (Bernard et al, 2002; The Hypothermia After Cardiac Arrest Study Group, 2002).…”

Section: Introductionmentioning

confidence: 99%

A Simple Method to Induce Focal Brain Hypothermia in Rats

Clark

Colbourne

2007

Hypothermia reduces cell death and promotes recovery in models of cerebral ischemia, intracerebral hemorrhage and trauma. Clinical studies report significant benefit for treating cardiac arrest and studies are investigating hypothermia for stroke and related conditions. Both local (head) and generalized hypothermia have been used. However, selective brain cooling has fewer side effects than systemic cooling. In this study, we developed a method to induce local (hemispheric) brain hypothermia in rats. The method involves using a small metal coil implanted between the Temporalis muscle and adjacent skull. This coil is then cooled by flushing it with cold water. In our first experiment, we tested whether this method induces focal brain hypothermia in anesthetized rats. Brain temperature was assessed in the ipsilateral cortex and striatum, and contralateral striatum, while body temperature was kept normothermic. Focal, ipsilateral cooling was successfully produced, while the other locations remained normothermic. In the second experiment, we implanted the coil, and brain and body temperature telemetry probes. The coil was connected via overhead swivel to a cold-water source. Brain hypothermia was produced for 24 h, while body temperature remained normothermic. A third experiment measured brain and body temperature along with heart rate and blood pressure. Brain cooling was produced for 24 h without significant alterations in pressure, heart rate or body temperature. In summary, our simple method allows for focal brain hypothermia to be safely induced in anesthetized or conscious rats, and is, therefore, ideally suited to stroke and trauma studies.