Effects of Combination Treatment with Dexamethasone and Mannitol on Neuronal Damage and Survival in Experimental Heat Stroke

Abstract

Unless immediately recognized and treated, heat stroke is often lethal, and victims who do survive may sustain permanent neurological damage.1) The clinical diagnosis of heat stroke is demonstrated when hyperthermia is accompanied with circulatory shock (arterial hypotension), intracranial hypertension, and cerebral ischemia and injury. 2,3) Meanwhile, the heat stroke-induced central nervous system dysfunction includes delirium, convulsion, or coma. 4) Hence, prolonging survival time in heat stroke victims may offer more sufficient time for urgent treatment, thereby ameliorating the heat stroke-induced damage.Several lines of evidence indicate that rodents share with humans almost the same heat stroke syndromes, such as arterial hypotension, activated inflammation, and multiorgan dysfunction (in particular, cerebral ischemia, injury, and dysfunction. [5][6][7] In the rodents heat stroke model, significant decrements in both mean arterial pressure (MAP) and cerebral blood flow (CBF), but increments of cerebral monoamines levels and free radical productions are obtained in urethane-anaesthetized rats after heat stroke. 8,9) These pathophysiological changes are known to aggravate the conditions of cerebral ischemia and neuronal damage during heat stroke in rats.10,11) Activated inflammation is evidenced by overproduction of pro-inflammatory cytokines (e.g., tumor necrosis factor-a (TNF-a)) in plasma of heat stroke rats.12,13) High levels of TNF-a in the peripheral blood stream, as well as excessive accumulation of glutamate, hydroxyl radicals, dopamome (DA) and serotonin (5-HT) in the central brain, correlate with the severity of circulatory shock, cerebral ischemia and neuronal damage during heat stroke in rats. 6,9,11,14,15) Various clinical and experimental investigations have shown that single doses of dexamethasone (DXM; exogenous glucocorticoids) or mannitol are extensively used in the treatment of cerebral ischemia and/or cerebral injury. [16][17][18] In the studies of heat stroke, pretreatment with DXM attenuated serum IL-1b levels and improved survival in heat stroke. 19) Additionally, pretreatment with mannitol before the onset of heat stroke caused significant reduction of the heat strokeinduced the increased free radical formation and intracranial hypertension. 20) Although, many therapeutic agent show potential promise in many animal models, the results of most single-agent clinical trials are sobering. Consequently, various authors advocate studies to estimate the efficacy of combined therapeutic approaches. 21,22) Hence, the mannitol that acts to decrease intracranial pressure and radical formation, and a potent inflammatory agent (such as DXM) might be combined to develop an improved fluid therapy for attenuation or amelioration of heat stroke-induced damage. Furthermore, there is less attention to evaluate immediate effects of both DXM and mannitol (the combined agent) on heat stroke-induced pathophysiological changes, let alone their neuroprotective underlying influences, especially in the aspects...

Dexamethasone Improves Heat Stroke-Induced Multiorgan Dysfunction and Damage in Rats

“…During heat stroke, rodents display hyperthermia, arterial hypotension, intracranial hypertension, cerebral ischaemia, neuronal damage and overproduction of inflammatory cytokines [ 6 , 11 , 12 ]. The present results, as well as our previous results [ 3 , 4 , 13 ] revealed that all heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased TNF-α, IL-1β, PT, aPTT, and D-D dimer, and decreased IL-10 and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of BUN, creatinine, SGOT, SGPT, and ALP, and striatal levels of glycerol, glutamate, and lactate/pyruvate ratio, were all elevated during heat stroke. In contrast, the values of mean arterial pressure and striatal levels of local blood flow were all significantly lower during heat stroke.…”

“…After onset of heat stroke, rats revealed ischemia and injury in several cerebral regions, especially in the corpus striatum. Both of our previous [ 3 , 13 ] and present results displayed that the local CBF of striatum decreased significantly, but the values of striatal neuronal ischemic and injury index were sharply increased in rats with heat stroke (as shown in Figure 1 ). However, acute immediate treatment with DXM revealed appreciable decrements of neuronal damage, ischemic and hypoxic indexes in rats of heat stroke.…”

“…A clinical diagnosis of heat stroke suggests that body hyperthermia (over 42 °C) associated with a systemic inflammatory response leads to multiple organ dysfunction, in particular, neurological abnormalities after exposure to high temperature [ 1 , 2 ]. Several lines of evidence indicate that animals share with humans almost the same heat stroke syndromes [ 3 , 4 ]. In rodents, heat stress leads to arterial hypotension, hyperpyrexia, and hypercoagulable state, and excessive activated inflammation may contribute to multiple organ failure (including cerebral, hepatic and renal ischemia, injury, and dysfunction) in heat stroke [ 3 , 4 , 5 , 6 ].…”

“…Several lines of evidence indicate that animals share with humans almost the same heat stroke syndromes [ 3 , 4 ]. In rodents, heat stress leads to arterial hypotension, hyperpyrexia, and hypercoagulable state, and excessive activated inflammation may contribute to multiple organ failure (including cerebral, hepatic and renal ischemia, injury, and dysfunction) in heat stroke [ 3 , 4 , 5 , 6 ].…”

Repeated Heat Exposure Impairs Nigrostriatal Dopaminergic Neurons in Mice

“…To avoid the influence of diurnal cycling, heat exposure was started at approximately the same time each day between 9 and 10 a.m. Heat exposure was achieved by transferring the mice in their cage into a chamber (Jeio Tech, Daejeon, Korea) at 43°C and 60± 10% humidity for 15 min once a day. The heat condition was slightly modified from Yang et al, 14) based on survival rate. In preliminary test, mice with up to 15 min heat exposure at 43°C easily recovered in 10 min without death at room temperature.…”