The Neuroprotective Effect of Lactate Is Not Due to Improved Glutamate Uptake after Controlled Cortical Impact in Rats

Abstract

For many years lactate was considered to be a waste product of glycolysis. Data are accumulating that suggest that lactate is an important energy substrate for neurons during activation. In severe traumatic brain injury (TBI) glutamate release and ischemic cerebral blood flow (CBF) are major factors for a mismatch between energy demand and supply and for neuronal cell death. Although ATP and behavior could be improved by lactate treatment after TBI, no histological correlate nor any linkage to better astrocytic glutamate uptake or CBF as possible mechanisms have been described. We subjected male rats to a controlled cortical impact (CCI; 5 m/sec, 2.5 mm). To study the effects of lactate treatment on lesion volume, glutamate release, and CBF, animals were infused with either NaCl or 100 mM lactate for up to 3 h. The role of endogenous lactate was investigated by inhibiting transport with α-cyano-4-hydroxy-cinnamic acid (4-CIN; 90 mg/kg). Lactate treatment 15 min post-CCI reduced lesion volume from 21.1±2.8 mm³ to 12.1±1.9 mm³ at day 2 after CCI. Contusion produced a significant three- to fourfold increase of glutamate in microdialysates, but there was no significant difference between treatments that began 30 min before CCI. In this experiment lesion volume was significantly reduced by lactate at day 7 post-CCI (23.7±4 to 9.3±1-2 mm³). CBF increased immediately after CCI and dropped thereafter below baseline in all animals. Lactate infusion 15 min post-CCI elevated CBF for 20 min in 7 of 10 animals, whereas 7 of 8 NaCl-treated animals showed a further CBF decline. Neuroprotection was achieved by lactate treatment following contusion injury, whereas blocking of endogenous lactate transport exerted no adverse effects. Neuroprotection was not achieved by improved glutamate uptake into astrocytes, but was supported by augmented CBF following CCI. Due to its neuroprotective property, lactate might be a beneficial pharmacological treatment for TBI patients.

Temporal Dynamics of Cerebral Blood Flow, Cortical Damage, Apoptosis, Astrocyte–Vasculature Interaction and Astrogliosis in the Pericontusional Region after Traumatic Brain Injury

“…The structural and functional integrity of the brain depends on a continuous vascular supply of oxygen and glucose, and if CBF is interrupted or unable to meet an increased metabolic demand, neurons cease to function, and reduced thresholds for activation of pathways leading to delayed neuronal death (1, 8, 43). A phasic elevation in CBF after acute head injury is a necessary condition for achieving functional recovery (44).…”

“…Astrocytes are thought to play a crucial role in response to injury; they are important in neuronal antioxidant defense, secreting neuroprotective factors, and in maintaining the homeostasis of the extracellular environment after brain injury (8, 9). Astrocytes also provide neurons with energy from metabolic substrates and the precursors of neurotransmitters.…”

Lactate Storm Marks Cerebral Metabolism following Brain Trauma

“…Furthermore, the injured neurons early following severe TBI are unable to pick up and metabolize the increased lactate, resulting in a lactate storm in the failing metabolic environment. The findings have significant clinical implications because perhaps a mechanism to safely scavenge and/or chelate the excess lactate (31), buffer the pH effect (32), or inhibit glial metabolism (33, 34) may be of benefit to the dying brain as opposed to further administering lactate, as some of the contemporary research has been suggesting (5,6). Given that uncoupled metabolism occurs rapidly following trauma, such therapeutic measures would best be administered at the accident site, taking advantage of the known blood-brain barrier disruption and understanding of the neurovascular unit (35)(36)(37).…”

“…Increased lactate, alanine, GABA, and succinate following [2-13 C]acetate infusion further support ongoing glial metabolism, with the latter diverting to an activated malic enzyme pathway. High lactate levels, as seen in [3][4][5][6][7][8][9][10][11][12][13] C]lactate infusion animals, imply impaired neuronal metabolism that fails to utilize lactate that the glial cells continue to produce. In other words, it appears that following severe TBI, as early as minutes to an hour after injury, the neurons and glial metabolism become uncoupled (i.e.…”

“…Lactate serves as an alternative energy substrate to glucose for normal or injured neurons (2)(3)(4). Contemporary studies have also suggested its potential neuroprotective or therapeutic role in TBI (5,6). Indeed, although a recent international clinical trial is aimed at the study of the therapeutic benefit of lactate in TBI, 3 it is important to consider that the findings presented here suggest that this may not be the case.…”