Excessive brain lactate, as may develop in cerebral ischemia, has been implicated as a major cause of irreversible cell damage. With an experimental model that produces cerebral ischemia by bilateral carotid ligation combined with systemic hypotension, previous studies have shown that treatment with 25 mg/kg sodium dichloroacetate (DCA) is effective in reducing brain lactate more quickly than no treatment at all. Because higher doses of DCA may be more effective, the main objective of our study was to examine the dose-response of brain tissue lactate to DCA. In addition, other metabolites that may be indirectly affected by this response (eg, glucose, glycogen, ATP, and phosphocreatine) also were measured. Adult male Wistar rats were assigned to experimental and treatment groups, and real or sham ischemia was induced as described in our previous article. After 30 minutes of reperfusion, rats were euthanized by in situ freezing of the brain. Cerebral cortex, hippocampus, and cerebellum were analyzed bilaterally. There was no effect of DCA dose on glucose or glycogen. When compared with hippocampus, lactate was higher in the cerebral cortex after ischemia, and DCA was more effective in reducing those levels. This is evidence of a lower metabolic rate in hippocampus than in cortex. Cerebellum did not exhibit an increase in lactate; therefore, it can serve as an in situ tissue control for that metabolite. Significantly different levels of metabolites in one hemisphere of some DCA-treated ischemic rats appeared to reflect a dose effect of DCA on lactate and a significant change in ATP and phosphocreatine at the higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

In shock, the presence of hyperlactatemia is prognostic of a failure to survive. An experimental model of stroke that combines bilateral carotid ligation and bleeding to a mean arterial pressure of 50 mm Hg induces hyperlactatemia like that associated with tissue hypoperfusion of hemorrhagic shock. In previous nonsurvival studies with this model, post-ischemic treatment of fed rats with 25 mg/kg of sodium dichloroacetate (DCA) was effective in lowering brain tissue lactate but did not significantly affect the ischemia-induced increase in serum lactate measured after 30 minutes of ischemia followed by 30 minutes of reperfusion. Investigators using other animal models treated hyperlactatemia associated with tissue hypoperfusion successfully with a DCA dose of more than 25 mg/kg. Our goal was to determine the effect of a higher dose of DCA on serum lactate in the model of cerebral ischemia with systemic hypotension that we had used in previous studies. The previously unstudied dose-response also was evaluated in our study. Rats that had been fed ad libitum were assigned randomly to either a real or sham (control) ischemic group. Immediately after 30 minutes of ischemia and subsequent reinfusion of blood or after 30 minutes of sham ischemia, rats received DCA (0, 25, 50, 100, 200, or 300 mg/kg). Comparisons were made of blood values measured at the end of equilibration before ischemia, after 30 minutes of ischemia, and after 30 minutes of reperfusion. All ischemic rats were hyperlactatemic. Serum lactate levels were not correlated to blood glucose elevation during ischemia. After treatment in both control and ischemic rats, the percentage decrease in serum lactate varied as a logarithmic function of the DCA dose administered. Glucose levels and pH were not affected by DCA treatment at any dose. Because acidemia decreases lactate uptake by the liver, values for acidotic rats were compared with those for nonacidotic rats. Whereas lactate in acidotic rats decreased significantly only when treated with DCA, nonacidotic rats evidenced this decrease regardless of whether they received DCA. We discuss the relationship of these findings to the peak levels of lactate achieved, the resolution of hyperlactatemia, and factors that affect the interpretation of data in therapeutic studies using DCA.

Serum lactic acidosis is characterized by a pH < 7.25 and lactate > 5 mEq. A Altough sodium bicarbonate (NaHCO3) is standard treatment for this condition, clinical and experimental studies suggest that high doses of NaHCO3 may be ineffectual or even detrimental to brain, cardiovascular, and respiratory function, as well as survival. For this reason, low dose therapy with NaHCO3 has been recommended. Sodium dichlorocaetate (NaDCA) has been used successfully to treat clinical and experimentally-induced lactic acidosis. The present study was designed to compare the effects of low dose NaHCO3 with NaDCA on blood pressure, blood chemistries and brain metabolites in rats with a low flow-induced (Type A, the most common type) lactic acidosis. Fasted male Wistar rats were subjected to cerebral ischemia and systemic hypotension for 30 min at which time, if the pH or HCO3− fell to 7.2 or 10, respectively, the rat was treated with NaHCO3, NaDCA, or an equal volume of sterile water. Over the 30 min of recirculation that followed ischemia, treatment had no effect on blood pressure or glucose or on brain glucose or glycogen. NaHCO3 had no effect on lactate but appeared to stabilize pH and increase HCO3− more than in sham- or NaDCA-treated rats. Although NaDCA caused a greater increase in HCO3− than sham treatment, pH continued to decline. However, lactate decreased more in NaDCA- than in sham- or NaHCO3− treated rats. These results suggest that low dose NaHCO3 is not detrimental in this model; however, although NaHCO3 stabilized pH, it did not rapidly correct the acidosis. NaDCA at this dose had no effect on the acidosis but was effective in decreasing lactate. Since serum lactate has previously correlated with survival and since higher doses of NaDCA have corrected lactic acidosis in other studies, future evaluation of postischemic treatment with higher doses of NaDCA is warranted.

Despite advances in cardiac resuscitation, ischemic brain injury remains generally untreatable. Animal studies of brain ischemia associate brain lactate levels of more than 18 mumol/g with irreversible neuronal injury. Lowering brain lactate therefore may prevent or minimize ischemic brain necrosis. Earlier studies in our laboratory using fasted rats demonstrated that sodium dichloroacetate (DCA) decreases ischemic brain lactate when given either before or immediately after partial global ischemia (PGI). Other investigators have shown that fed animals have more glucose and generate higher lactate levels by anaerobic metabolism during PGI. We evaluated the ability of DCA to lower brain lactate in fed male Wistar rats subjected to PGI. Four groups (n = 6 each) were studied--PGI and control rats with either placebo or DCA treatment. PGI was induced for 30 minutes by combining bilateral carotid artery occlusion with hemorrhagic hypotension. This was followed by release of carotid occlusion, reinfusion of shed blood, and immediate treatment with either DCA (25 mg/kg, IV) or placebo. Thirty minutes later brains were frozen in situ with liquid nitrogen for extraction and measurement of tissue glucose, glycogen, and lactate. Blood glucose and serum lactate were monitored throughout the experiment. No significant differences were found between the two PGI groups in brain glucose, brain glycogen, or ischemia-induced elevations in blood glucose and serum lactate. However, brain lactate was significantly lower in DCA-treated (12.5 mumol/g) than in untreated (22.8 mumol/g) PGI rats (P less than .001). In addition, all untreated PGI rats had levels of more than 18 mumol/g, and therefore were at high risk for neuronal necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Normal compensatory mechanisms protect the central nervous system (CNS) from moderate hypoxia and ischemia; however, after more severe ischemia progressive brain hypoperfusion ensues and irreversible damage occurs. Ischemic brain injury remains greatly significant clinically and elucidating the determinants of ischemic neuronal injury and death continues to challenge researchers. Although altered perfusion and decreased energy charge may contribute to the production of irreversible damage, the distribution of lesions seen after insult does not correspond with the degree of ischemic blood flow impairment, nor can neuronal energy deprivation explain the cell damage. Other factors, such as derangements in astrocyte function, calcium homeostasis, free radical metabolism, acid-base regulation and excitatory neurotransmitters also probably mediate ischemic neuronal death. Continued investigation to establish the cellular pathophysiology of cerebral ischemia can guide rational research and therapeutic strategies.