Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Abstract

The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate͞ pyruvate ratio, which is in near equilibrium with the NADH͞NAD ؉ ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38 -53% in regions of the visual cortex but had no effect on the resting CBF or the wholebrain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate͞pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH͞NAD ؉ ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.T he nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate. Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism (1) have been contradicted by brain imaging studies with positron-emission tomography (PET) (2, 3) and functional MRI (4). Fox and his colleagues (2, 3) demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF (3, 5). Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia (6) or hypoxia (7). These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates. Ido et al. (8) recently reported that CBF in activated rat brain is modified by changes in the plasma lactate͞pyruvate ratio: CBF was augmented when lactate͞pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled. Based on the near equilibrium between the ratios of lactate͞pyruvate and cytosolic free NADH͞NAD ϩ (which reflects the local environment redox state) (9), they suggested that cytosolic free NADH is an important trigger or sensor of blood flow. The reoxidation of NADH to NAD ϩ is a step of vital importance for brain cells, especially in the acti...

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

“…As this mismatch occurs in the presence of normal or augmented oxygen levels, it has been termed aerobic glycolysis, paralleling the signal detected by functional magnetic resonance imaging (2). Aerobic glycolysis and its associated lactate surge are causally linked to diverse functions of the brain in health and disease (3)(4)(5)(6)(7)(8)(9)(10). Two signals are known to trigger aerobic glycolysis in brain tissue: glutamate and K + , which are released by active neurons and stimulate glycolysis in astrocytes (11,12).…”

Effects of lactate on the early visual cortex of non-human primates, investigated by pharmaco-MRI and neurochemical analysis

“…However these CBF changes apparently depend to a certain degree on lactate dose and application modality (bolus vs. slow infusion). For example, a bolus injection that increases systemic lactate to 9.8 ± 2.4 mM has induced a change in CBF in the range of 38-53% in human visual cortex (Mintun et al, 2004). This finding contrasts with the results of a subtle and continuous application of lactate (2 mmol/kg) in rats (reaching plasma concentrations of 3.5 ± 0.4 mM), which did not yield CBF changes greater than 4% (Ido et al, 2004).…”

“…The apparent use of the glycolytic pathway was demonstrated by an increase in cerebral blood flow (CBF), and the metabolic rate of glucose which was accompanied by only a slight increase in the metabolic rate of oxygen (Fox and Raichle, 1986;Fox et al, 1988). The coupling of the CBF response to the NADH/NAD + ratio which is in near equilibrium with the lactate/ pyruvate ratio was then shown by Mintun et al (2004;Vlassenko et al, 2006). Given the importance of lactate in the context of physiological brain metabolism, changes in lactate levels are to be expected under pathological circumstances.…”

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease

“…However, subtle changes in cellular NAD/NADH ratio, as well as in the lactate/pyruvate ratio appear to serve as sensitive "energy sensors", with potential relevance to CBF (Mintun et al, 2004;Ido et al, 2001) . Moreover, astrocytes are spatially linked with the vascular walls of arterioles and capillaries and can regulate the diameter and resistance of these vessels via perivascular release of vasoactive factors, among which are adenosine, K+, nitric oxide (NO) and prostaglandins (Harder et al, 2002;Paulson and Newman, 1987).…”