Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.

Abstract

We have demonstrated previously that mild intraischemic hypothermia confers a marked protective effect on the final histopathological outcome. The present study was carried out to evaluate whether this protective effect involves changes in the degree of local cerebral blood flow reductions, tissue accumulation of free fatty acids, or alterations in the extracellular release of glutamate and dopamine. Rats whose intraischemic brain temperature was maintained at 36° C, 33° C, or 30° C were subjected to 20 minutes of ischemia by four-vessel occlusion combined with systemic hypotension. Levels of local cerebral blood flow, as measured autoradiographically, were reduced uniformly in all experimental animals at the end of the ischemic period. Cortical and striatal free fatty acid levels were measured at the end of ischemia by gas chromatography after tissue extraction and separation by thin layer chromatography. A massive ischemia-induced accumulation of individual free fatty acids was observed in animal groups whose intraischemic brain temperature was maintained at either 36° C or 30° C. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. In rats whose intraischemic brain temperature was maintained at 36° C, dopamine and glutamate increased significantly during ischemia and the early period of recirculation (by 500-fold and sevenfold, respectively). In animals whose brain temperature was maintained at 33° C and 30° C, the release of glutamate was completely inhibited, and the release of dopamine was significantly attenuated (by 60%). These results suggest that mild intraischemic hypothermia does not affect the ischemia-induced local cerebral blood flow reduction or free fatty acid accumulation. Received December 27, 1988; accepted March 7, 1989. hypothermia has been attributed mainly to a decrease in brain energy demands, energy failure during the ischemic insult, or both. Recently, we have demonstrated that relatively modest decrements (2° C) in brain temperature during the ischemic insult markedly attenuate neuronal damage in vulnerable brain regions such as the hippocampus or striatum. 8 However, the degree of high-energy phosphate depletion and lactate accumulation at the end of the ischemic insult were not affected by these temperature variations. These results suggest that a moderate reduction in intraischemic brain temperature affects a different consequence of brain ischemia that is important for the development of neuronal damage in these selectively vulnerable brain regions.Neurotransmitter release has been implicated in the pathophysiology of brain damage within hippocampal and striatal areas after ischemia.

Hypothermia Attenuates the Loss of Hippocampal Microtubule-Associated Protein 2 (MAP2) following Traumatic Brain Injury

“…Hypothermia has been shown to decrease intracellular acidosis caused by ischemia (Norwood and Norwood, 1982), reduce the metabolic require ments of the brain (Siesjo, 1978), and significantly ameliorate trauma-induced edema (Clasen et aI., 1968). Of particular relevance to fluid percussion injury, however, Busto et al (1989) have demon strated that moderate cerebral hypothermia (30°C) dramatically attenuates the levels of excitotoxins (glutamate and aspartate) accumulating after isch emic injury. Fluid percussion injury in rats, of the type reported here, produces a significant increase in excitatory glutamate (Faden et al, 1989;Katayama et aI., 1990) and acetylcholine (Gorman et aI., 1989) levels.…”

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

“…It has been reported that mild hypothermia completely blocks (Busto et al, 1989b;Li et al, 1999;MartinezTica and Zornow, 2000;Patel et al, 1994), partially blocks Winfree et al, 1996;Yamamoto et al, 1999), merely delays (Asai et al, 2000(Asai et al, , 1998, or does not inhibit an increase in [Glu] e after cerebral ischemia (Berger et al, 1998;Zhao et al, 1997). Furthermore, the effect of hypothermia on [Glu] e depends on the brain area, ischemic severity, and animal age (Berger et al, 2002;Lo et al, 1993;Van Hemelrijck et al, 2003).…”

“…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).…”

Therapeutic Hypothermia for Acute Neurological Injuries

“…Excess glutamate triggers the excitotoxic cascade that can ultimately result in cell injury and death [39]. Even mild decreases in temperature have been shown to ameliorate these detrimental effects [40][41][42]. Brain injury activates the inflammatory/ immune response [43,44].…”