Effects of Delayed Intraischemic and Postischemic Hypothermia on a Focal Model of Transient Cerebral Ischemia in Rats

Abstract

Background and Purpose-Intraischemic mild hypothermia has been shown to be neuroprotective in reducing cerebral infarction in transient focal ischemia. As a more clinical relevant issue, we investigated the effect of delayed intraischemic and postischemic hypothermia on cerebral infarction in a rat model of reversible focal ischemia. We also examined the effect of hypothermia on the inflammatory response after ischemia-reperfusion to assess the neuroprotective mechanism of brain hypothermia. Methods-Rats were subjected to 2 hours of middle cerebral artery occlusion followed by 22 hours of reperfusion under the following protocols: (1) rats were treated with normothermia (37.0°C, 4 hours) and then housed in room temperature (25°C, 18 hours) and (2) rats were treated with hypothermia (33.0°C, 4 hours, brain temperature modulation was started 30 minutes before the reperfusion) and then housed in cold temperature (5°C, 18 hours). Animals were killed 24 hours after the onset of ischemia. The infarct volume was examined with 2,3,5-triphenyl-tetrazolium chloride staining. The accumulation of polymorphonuclear leukocytes (PMNLs) and the expression of intercellular adhesion molecule-1 mRNA were evaluated in both groups. Results-A significant reduction (PϽ0.05) in infarct volume was found in the hypothermia group compared with the normothermia group. Compared with the normothermia group, hypothermic treatment also significantly reduced the accumulation of PMNLs (PϽ0.01) and inhibited the overexpression of intercellular adhesion molecule-1 mRNA at 22 hours of reperfusion after 2 hours of ischemia. Conclusions-Ischemic brain damage can be reduced with delayed intraischemic and prolonged postischemic hypothermia in a focal model of transient cerebral ischemia in rats. The neuroprotective mechanism of hypothermia may be mediated by suppression of PMNL-mediated inflammatory response after ischemia-reperfusion in this model. Key Words: cerebral ischemia, focal Ⅲ hypothermia Ⅲ intercellular adhesion molecule-1 Ⅲ neutrophils Ⅲ peroxidase I schemic stroke is a leading source of disability in elderly persons, and much emphasis in research is being placed on the early treatment of stroke. The advancement of intravascular techniques and thrombolytic agents, especially recombinant tissue plasminogen activator (rtPA), has been shown to reduce functional deficits within an optimal time window. 1,2 The acceleration of recanalization with thrombolytic agents can salvage brain tissue in an ischemic area from irreversible cell death. However, the time window for effective treatment is narrow because longer durations of ischemia and subsequent reperfusion increase the likelihood of brain edema formation and hemorrhagic transformation. 3 This phenomenon has been demonstrated in various tissues, especially in the heart and lung, and been termed "reperfusion injury." The understanding and treatment of reperfusion injury are important in the new era of reperfusion therapy for cerebral stroke. See Editorial Comment, page 1989There has been renewe...

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

“…Intraischemic hypothermia delays or attenuates both ATP depletion (Ibayashi et al, 2000;Sutton et al, 1991;Welsh et al, 1990) and anoxic depolarization (Bart et al, 1998;Nakashima and Todd, 1996;Takeda et al, 2003), it also blocks glutamate release (Busto et al, 1989b;Patel et al, 1994;Winfree et al, 1996), suppresses inflammation (Kawai et al, 2000;Wang et al, 2002), maintains the integrity of the BBB (Dietrich et al, 1990;Huang et al, 1999;Kawanishi, 2003), reduces free radical production , inhibits protein kinase C translocation (Cardell et al, 1991;Shimohata et al, 2007a, b;Tohyama et al, 1998), inhibits matrix metalloproteinase expression (Hamann et al, 2004), and blocks both necrosis and apoptosis. Intraischemic hypothermia also preserves the base-excision repair pathway, which repairs oxidative damage (Luo et al, 2007).…”

“…However, most reports suggest that mild to moderate hypothermia has no effect on the CBF level during ischemia in the penumbra (Kawai et al, 2000;Morikawa et al, 1992;Yanamoto et al, 2001). Nevertheless, one study reported that moderate hypothermia (301C) significantly reduced CBF using a diffusion-weighted imaging technique (Jiang et al, 1994).…”

“…Nevertheless, one study reported that moderate hypothermia (301C) significantly reduced CBF using a diffusion-weighted imaging technique (Jiang et al, 1994). Some studies suggest that hypothermia does not affect CBF after reperfusion in focal ischemia (Kawai et al, 2000;Morikawa et al, 1992), whereas others suggest that hypothermia blocks the postischemic hyperperfusion and the delayed, sustained hypoperfusion (Huang et al, 1998;Jiang et al, 1994;Karibe et al, 1994b).…”

Transient Cooling during Early Reperfusion Attenuates Delayed Edema and Infarct Progression in the Spontaneously Hypertensive Rat. Distribution and Time Course of Regional Brain Temperature Change in a Model of Postischemic Hypothermic Protection

“…This is the experimental approach used in most studies reporting benefits of modest (301C to 341C) postischemic cooling (Ding et al, 2004;Kollmar et al, 2002;Maier et al, 2001;Zhang et al, 1993aZhang et al, , 1993b. In one such study, 331C hypothermia was initiated before reperfusion and sustained at 351C by housing at 51C, but the control group reached hyperthermic brain temperatures in excess of 391C during the 24-h interval evaluated (Kawai et al, 2000). However, in no other report was temperature monitored during an extended recirculation interval after recovery from anesthesia.…”

Mild hypothermia reduces polymorphonuclear leukocytes infiltration in induced brain inflammation

“…PMNL accumulation is maximal at 48-72h. Attenuation of the inflammatory response may be one of the mechanisms by which hypothermia reduces ischemic neuronal injury 13,19,20 . Since it has been demonstrated that carr a g eenin is a highly reactive substance with inflammat o ry pro p e rt i e s 2 1 and brain inflammation can be induced with its subarachnoidal injection in brains of mice 2 2 , in this study we aimed to demonstrate that mild hypothermia can have neuroprotective e ffects in brains of rats submitted to inflammatory injury by means of the use of carrageenin.…”