the lactic acidosis hypothesis of cerebral ischemia   postulates that lactic acid accumulates in the brain during an ischemic event and plays a major detrimental role in delayed neuronal damage postischemia . the findings of myers and yamaguchi   that glucose administration preischemia significantly aggravates the postischemic outcome have been reproduced numerous times , and have repeatedly been promoted as the validation of the lactic acidosis hypothesis of cerebral ischemia . the glucose paradox as proof of the validity of this hypothesis is based on the idea that preischemic hyperglycemia leads to elevated lactic acid levels , and thus to aggravation of post - ischemic brain damage . preventive measures are consequently being practiced in hospitals throughout the world , including the close monitoring and tight control of blood glucose levels . first , glucose is the only major aerobic and anaerobic energy substrate in the brain . second , during cerebral ischemia , glycolytic utilization of glucose is the only metabolic process capable of producing significant levels of atp until all glucose and glycogen levels are extinguished . third , during ischemia , lactate is the main product of glycolysis ; on reperfusion / reoxygenation , when brain glucose is all but gone , the abundant lactate can easily enter the tricarboxylic acid cycle to maintain atp production as efficiently as does glucose . thus , paradoxically , the only process that supplies atp to the ischemic tissue is viewed as the one responsible for the aggravation of the ischemic damage to this very tissue . both in vitro studies   and in vivo studies   have shown that preischemic glucose supply is not necessarily harmful , and that it could even be beneficial when provided preischemia . these in vivo findings are considered oddities , however , while in vitro data are not considered to necessarily represent the true in vivo situation . consequently , when dexa - methasone treatment in stroke patients was found to induce hyperglycemia , wass et al .   suggested that lactic acidosis , not the steroid itself , is responsible for the exacerbation of ischemic damage frequently observed with dexamethasone treatment . it is important to note , however , that steroids such as dexamethasone are regularly administered postischemia . in contrast , an association between a pronounced systemic stress response , an elevated level of cortisol in the plasma and increased mortality or morbidity has been reported . the steroid prednisone was shown to inhibit insulin secretion and to elevate blood glucose levels . ct , the rodent equivalent of human cortisol , was shown to depress the release of glucose - induced insulin , while other studies have concluded that hyperglycemia in acute stroke patients represents a stress response . glucocorticoids have been shown to inhibit glucose transport and glutamate uptake in hippocampal astrocytes , to accelerate atp loss following metabolic insults in neuronal culture , and thus to exacerbate insult - induced declines in energy metabolism . a recent in vitro study was able to demonstrate an aggravation of ischemic damage by ct in vitro . until recently , no studies had been conducted to determine whether glucose loading preischemia induces an elevation in blood glucocorticoids ( see below ) . in an unrelated study , harris et al .   found that glucose challenge in mice elevated ct blood levels sixfold 30 min after glucose injection , which returned to baseline levels 90 min later . wang et al .   demonstrated that a carbohydrate - rich diet boosted ct blood levels . in contrast , metyrapone ( 2-methyl-1,2-di-3-pyridyl-1-propanone ) , a glucocorticoid biosynthesis inhibitor , was shown to reduce ischemic brain injury , possibly by reducing blood ct levels . a recent study in rats is most revealing regarding the role that glucose plays in cerebral ischemia . when rats were made hyperglycemic by glucose loading ( 2 g / kg , intraperi - toneally ) 1560 min prior to a 7-min episode of cerebral ischemia , a significant increase in the degree of delayed neuronal damage postischemia was found in comparison with control , saline - injected rats ( fig . 1 ) . in contrast , rats loaded with glucose 120240 min preischemia , although also hyperglycemic at the onset of ischemia , showed a significantly lower degree of delayed neuronal damage postischemia in comparison with control rats . hippocampal levels of lactate were measured at the end of the ischemic period in rats administered with either saline or glucose preischemia . the lactate levels measured were significantly and equally higher in rats administered glucose either 15 or 120 min preischemia when compared with control , saline - administered rats . the effects of glucose administration ( 2 g / kg , intraperitoneally [ i.p . ] ) on three different parameters . blood glucose and corticosterone levels in samples taken from one group of rats at the time points indicated after glucose injection , and the degree of ischemic hippocampal damage ( as measured 7 days postischemia ) in another group of rats administered glucose at the same time points prior to induction of ischemia . also shown are the effects of either metyrapone ( 100 g / kg , i.p . ) or mifepristone ( ru486 ; 40 mg / kg , i.p . ) on the degree of ischemic damage in rats that were administered glucose 15 min preischemia . significantly different from control , normoglycemic rats ( p < 0.05 ) ; significantly different from hyperglycemic rats injected with glucose 15 min preischemia ( p < 0.05 ) using an unpaired t test . these results contradict , and thus refute , the hypothesis that delayed ischemic neuronal damage is directly correlated with brain lactate levels . our finding that inhibition of lactate utilization immediately postischemia is detrimental   further refutes the lactic acidosis hypothesis . thus , in those cases where high brain levels of lactate were detected 3090 min after the onset of reperfusion , lactate probably remained unused due to cell death . since neither glucose nor lactate appears to be the damaging factor during cerebral ischemia , we postulated that glucose loading evokes a short - lived ( 3060 min ) systemic response ( hormonal or other ) that , when occurring simultaneously with an ischemic episode , is capable of aggravating the degree of delayed neuronal damage postischemia . allowing this short - lived systemic response to subside ( 120 min ) prior to the onset of the ischemic episode would make apparent the protective effect of glucose on the ischemic brain ( fig . this glucose - induced protection stems from both hyperglycemic supplies of the sugar to sustain anaerobic glycolysis and from the ample supplies of lactate available for oxidation on reperfusion / reoxygenation . preliminary experiments to test the effects of glucose loading on plasma ct levels revealed a sharp increase in the level of this stress hormone 1530 min after glucose administration , followed by a return to baseline level 120 min after glucose administration . these changes appear to correlate with the aggravation of neuronal damage by hyperglycemia when induced 15 min preischemia , and by the lack of such aggravation when glucose is administered 120 min preischemia . these preliminary results support the postulate by which the glucose paradox is an outcome of glucose - induced increase in ct levels that lasts for approximately 60 min ( see also ) . while the observed changes in plasma ct levels in response to glucose loading do correlate with the post - ischemic outcome , such correlation by itself does not provide the proof that ct is the culprit of the glucose paradox phenomenon . hence , either blockade of ct biosynthesis , on the one hand , or antagonism of its receptor , on the other , or both , would provide stronger supportive evidence if and when these approaches could abolish the aggravating effect of preischemic hyperglycemia . preliminary experiments with metyrapone   support the notion that glucose - induced ct release is the culprit behind the glucose paradox . as can be seen from figure 1 , rats pretreated with metyrapone suffered no aggravation of neuronal damage when administered glucose 15 min preischemia . these rats actually exhibited a degree of ischemic damage that was significantly lower than the damage measured in control , normoglycemic rats . this indicates that , once the aggravating factor ( i.e. ct ) is removed , glucose can be beneficial even when loaded shortly preischemia . the blood glucose levels of metyrapone - treated , glucose - loaded rats just prior to the ischemic episode were as high as those of untreated rats loaded with glucose . the second approach , antagonizing ct action at its receptor , was also tested . for that purpose , the glucocorticoid receptor antagonist mifepristone ( ru486 )   was used . glucose - loaded rats ( 15 min preischemia ) treated with the antagonist ( 40 mg / kg , intraperitoneally ) 45 min preischemia exhibited a significantly lower degree of postischemic damage than glucose - loaded rats untreated with ru486 . the damage was indistinguishable from that measured in control , normo - glycemic rats ( unpublished data ) . when the findings of the glucose - induced , short - lived increase in ct release and of the abilities of both metyrapone and ru486 to abolish the preischemic hyperglycemia - aggravated postischemic damage are taken together , they unequivocally point at ct as the culprit behind the glucose paradox of cerebral ischemia . the ct hypothesis is consequently being offered to explain this paradox instead of the lactic acidosis hypothesis . the glucose paradox of cerebral ischemia , the phenomenon of preischemic hyperglycemia - aggravated postischemic outcome , has been blamed on the accumulation of lactate and the intensification of acidosis . data have shown that lactate is an excellent aerobic energy substrate in the brain , and a crucial one during recovery from ischemia . glucose , the only readily available energy substrate in the brain under normoxic conditions , has been shown as the only substrate that could sustain ion homeostasis , at least for a while , during an ischemic episode . yet , when administered shortly ( 1560 min ) preischemia , an aggravation of the ischemic outcome is observed . when administered 23 hours preischemia , however , despite the presence of hyperglycemic conditions , no aggravation of the outcome was observed . it has been shown that glucose loading induces a short - lived ( ~60 min ) , several - fold increase in ct plasma levels , a stress hormone known to aggravate the outcome of metabolic insults . it has also been shown , however , that pretreatment of rats with metyrapone , an inhibitor of ct biosynthesis , abolished the postischemic aggravating effect of glucose when loaded shortly preischemia . finally , ru486 ( an antagonist of the ct receptor ) was also shown to abolish the aggravating effect of glucose loading shortly preischemia . it is hypothesized that glucose - induced ct release , when occurring shortly preischemia , is the event responsible for the phenomenon known as the glucose paradox of cerebral ischemia . both investigators and clinicians are encouraged to re - examine their notions and clinical practices regarding the roles of glucose in cerebral ischemia ( stroke ) .
the glucose paradox of cerebral ischemia ( namely , the aggravation of delayed ischemic neuronal damage by preischemic hyperglycemia ) has been promoted as proof that lactic acidosis is a detrimental factor in this brain disorder . 
 recent studies , both in vitro and in vivo , have demonstrated lactate as an excellent aerobic energy substrate in the brain , and possibly a crucial one immediately postischemia . 
 moreover , evidence has been presented that refutes the lactic acidosis hypothesis of cerebral ischemia and thus has questioned the traditional explanation given for the glucose paradox . 
 an alternative explanation for the aggravating effect of preischemic hyperglycemia on the postischemic outcome has consequently been offered , according to which glucose loading induces a short - lived elevation in the release of glucocorticoids . when an episode of cerebral ischemia in the rat coincided with glucose - induced elevated levels of corticosterone ( ct ) , the main rodent glucocorticoid , an aggravation of the ischemic outcome was observed . 
 both the blockade of ct elevation by chemical adrenalectomy with metyrapone or the blockade of ct receptors in the brain with mifepristone ( ru486 ) negated the aggravating effect of preischemic hyperglycemia on the postischemic outcome .