Effects Of Lactate And Carbon Monoxide Interactions On Neuroprotection And Neuropreservation Part 1

Abstract

Lactate, historically considered a waste product of anaerobic metabolism, is a metabolite in whole-body metabolism needed for normal central nervous system (CNS) functions and a potent signaling molecule and hormone in the CNS. 

The central nervous system is one of the most important nervous systems of human beings. It plays a vital role in our physical activities, consciousness, and memory. Memory, in particular, has a great impact on our life and work.

The central nervous system consists of two parts: the brain and the spinal cord. Their complexity enables us to think, perceive, and act in various ways. Among them, the brain is the core of the central nervous system, and it is one of the most amazing organs of human beings. It can coordinate our thinking and perception and control various movements of our body. At the same time, the brain is also our memory bank. All memories are stored in the brain, and our language, knowledge, and life experience come from the memory in the brain.

The relationship between the central nervous system and memory is very close. If there is a problem with our central nervous system, it will affect our memory. For example, when the central nervous system is affected by trauma, poisoning, infection, and other factors, it will lead to cognitive impairment and memory loss. When we encounter this situation, we can take some measures to improve it.

The first is brain exercise. Using your brain is the best way to improve memory. You can exercise your central nervous system by playing memory games, learning new knowledge, challenging difficult thinking problems, etc., to increase the energy and flexibility of the brain.

The second is physical exercise. Physical exercise can improve cardiovascular function, promote blood circulation in the brain, increase physical endurance, etc., all of which can help us improve the function of the central nervous system and thus improve our memory.

In addition, we should also keep a happy mood. Emotional stability helps the normal functioning of the central nervous system, especially positive emotions can help improve our memory.

In short, the relationship between the central nervous system and memory is very close. We should do our best to protect and enhance our central nervous system to maintain the health of our body and brain and improve our memory. It can be seen that we need to improve memory. Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc., which can promote brain health in many ways.

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Neuronal activity signals normally induce its formation primarily in astrocytes and production is dependent on anaerobic and aerobic metabolisms. Functions are dependent on normal dynamic, expansive, and evolving CNS functions. 

Levels can change under normal physiologic conditions and with CNS pathology. A readily combusted fuel that ishuttleded throughout the body, lactate is used as an energy source and is needed for CNS hemostasis, plasticity, memory, and excitability. 

Diffusion beyond the neuron active zone impacts the activity of neurons and astrocytes in other areas of the brain. Barriergenesis, the function of the blood-brain barrier, and buffering between oxidative metabolism and glycolysis and brain metabolism are affected by lactate. Important to neuroprotection, presence or absence is associated with L-lactate and heme oxygenase/carbon monoxide (a gasotransmitter) neuroprotective systems. 

Effects of carbon monoxide on L-lactate affect neuroprotection – interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article.

Keywords: astrocytes; biochemical interactions; CNS; gasotransmitters; microglia; neuropreservation; neuroprotection; oligodendrocytes.

INTRODUCTION

Lactate (discovered in 1780, considered a waste product of metabolism) is a requisite molecule fowhole-bodydy metabolism and normal central nervous system (CNS) development and functioning. It is the preferred substrate for energy purposes and a precursor of lipids in oligodendrocytes, astrocytes, and neurons during the perinatal period,1,2 but is preferentially associated with ischemia of the brain. 

Evidence now, however, indicates that lactate is found in the CNS under physiological conditions.3,4 Neuronal activity signals induce formation primarily in astrocytes. 

While it is used as an energy source, it is also needed for CNS hemostasis, plasticity, memory, and excitability and is now recognized as a necessary metabolite in the coordination of whole-body metabolism as a readily combusted fuel that is shuttled throughout the body, a potent signaling molecule, and a hormone.3-7 These functions are dependent on CNS requirements for normal dynamic, expansive, and evolving CNS physiological functions. 

Presence or absence is also important to CNS neuroprotection and is associated with L-lactate and heme oxygenase/ carbon monoxide (CO) (a gasotransmitter) neuroprotective systems.8 Effects of CO on L-lactate affect neuroprotection - interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article. 

The following databases were systematically searched: MEDLINE, EMBASE, and Cochrane. Databases were searched from their inception to December 31, 2020.

SOURCES OF LACTATE IN THE CENTRAL NERVOUS SYSTEM

Considered a waste product of anaerobic metabolism, lactate has known beneficial roles in the CNS and its production is not limited to anaerobic metabolism. CNS concentration depends on serum lactate levels, oxygen availability, neuronal firing, degradation, and metabolic rate. 

Lactate serves as an important metabolic fuel and an intercellular messenger – its diffusion beyond the neuron active zone impacts the activity of neurons and astrocytes in other areas of the brain.9-11 

Contributing to neuronal metabolic support by transferring lactate through cytoplasmic myelinic channels and monocarboxylate transporters (MCTs), oligodendrocytes are active participants in this process – lactate is released by myelinating oligodendrocytes and then used by axons for generation of mitochondrial adenosine triphosphate.12,13 Oligodendrocytes are associated with the cell-to-cell lactate shuttle and the astrocyte-neuron lactate shuttle (lactate shuttling between cells producing lactate and cells consuming lactate is important to oligodendrocyte metabolism). 

These processes allow lactate to be used as a signaling molecule, energy source, and gluconeogenic precursor in the CNS.6,11 Lactate also affects barrier genesis and function of the blood-brain barrier (BBB),14 which is a buffer between oxidative metabolism and glycolysis,15 and maybe the preferred fuel for brain metabolism.16 

Lactate shuttles within and between cells and lactate uptake across the BBB suggests it is integral to CNS homeostasis although its transport across the BBB is rate-limited and lactate production within the brain reflects the needs of the CNS (metabolism and utilization is dynamic). 

Astrocyte-to-neuron lactate shuttling occurs during rest, but with excitation glycolysis of glucose to lactate (exceeding rate of mitochondrial fuel oxidation) in the neurons provides for increased energy needs.17,18 In the newborn mammalian brain, elevated blood lactate is utilized as a substrate, and, in the adult resting brain with baseline blood lactate levels, about 10% of the brain energy needs are met by oxidation of lactate (can oxidize more as plasma lactate levels increase.)19,20 CNS lactate topography suggests region-specific biology/metabolism and is similar between individuals.21-23 

Inherent to lactate homeostasis, elimination from the CNS is equally important – much of the lactate produced in the CNS during neuron activity is removed rather than being used as an energy source.

Uptake through the BBB

The highly vascularized BBB, a protective interface between the body and the CNS, selectively allows the passage of substances, including lactate, into the brain. Initially identified by Paul Ehrlich24 (who injected a dye into the bloodstream of mice and noticed that the dye did not enter the brain or spinal cord), the term BBB was introduced by Lewandowsky25 after studies showed that different substances injected into the ventricles of the brain resulted in neurologic symptoms that were not seen when injected intravenously. 

Electron microscopy showed that the brain endothelial cells construct a barrier between blood and CNS with a single layer of brain endothelial cells in contact with neurons, astrocytes, pericytes, and vascular smooth muscle cells. 

BBB function depends on the signaling and crosstalk of this neurovascular unit.26,27 Tight junctions (barrier to the passage of ions and molecules through the paracellular pathway and to the movement of proteins and lipids between the apical and the basolateral domains of the plasma membrane) and adherent junctions (allow epithelial cells to establish polarity with different proteins and lipids in the apical and basal plasma membranes) maintain the integrity of the BBB. 

Although it is best known for its barrier function of restricting the transport of toxic and/or harmful substances from the blood to the brain, the BBB also has a carrier function that is responsible for the removal of metabolites and the transport of nutrients to the brain. Its barrier function depends on the paracellular barrier, transcellular barrier, enzymatic barrier, and efflux transporters. 

Passive diffusion and specific transport proteins are necessary for its carrier function.28 Flow of blood affects BBB cell structure and function increases BBB tightness, and affects endothelial cell differentiation.29 

Clearance of substances from the CNS includes perivascular efflux, metabolism, and the BBB.30,31 L-lactate is considered a volume transmitter and can travel large distances from the site of production (i.e., muscle) to a site of consumption (i.e., CNS) with monocarboxylate transporters (MCTs) mediating diffusion of lactate between extracellular space and cells. 

Lactate passage across the BBB by nonsaturable diffusion or via MCTs in the plasma membrane – equilibration between lactate concentration in the blood and brain results (lactate then equilibrates with pyruvate via lactate dehydrogenase) – can be restricted.32 

With normal plasma lactate levels, non-saturable diffusion can be as high as 50% of lactate transport from the blood to the CNS, and, with high plasma lactate levels, near-instantaneous equilibration occurs. MCTs carry L-lactate (the most abundant monocarboxylate in the brain) across different cell membranes including the BBB – cotransport of monocarboxylate anion and proton occurs. Four carriers (MCTs 1–4) account for the bidirectional, electroneutral 1:1 co-transport of protons and monocarboxylic acids (i.e., lactate). 

MCT2 has the highest affinity for lactate – regionalization of MCTs 1–4 has been suggested to indicate involvement in different aspects of lactate metabolism and their production varies under different conditions. 

Accessory proteins (i.e., embigin, basigin, neuroplastin) are necessary for their activity.4,32-36 Efflux is by passive transport which is mediated by MCT1 which is present in both the abluminal and luminal membranes.30,37

Production of lactate in the brain

Important major metabolic pathways, catabolic and anabolic, necessary for CNS life/growth/division include gluconeogenesis/glycolysis, fatty acid β-oxidation, urea cycle, pentose phosphate pathway, oxidative phosphorylation, and the citric acid cycle. 

Glucose, the obligatory CNS energy substrate in mature humans, depends on glucose transport/metabolism, is mostly consumed by oligodendrocytes and astrocytes, and metabolites produced and released by astrocytes and oligodendrocytes are used by neurons as energy sources. 

The preferred energy substrate of the brain, lactate, is an important energy substrate for axons, is important in the CNS heart is an important source earlier in, life, and is now thought to be an important metabolite needed in the adult brain. 

Present in astrocytes, microglia, neurons, and oligodendrocytes, lactate production is via multiple pathways and its timely metabolism and elimination promotes CNS health and well-being – metabolic switching to lactate in the CNS has been linked to resistance to disease, stress, and injury. 

Metabolic processes in the CNS, dependent on the presence of multiple cell types and level of development/maturity, result in a pyruvate/lactate ratio that decreases with maturation and differs in regions of the brain. 

Astrocyte-neuron interactions, important to lactate metabolism, reflect dynamic needs and its production – glycol, lysis, and glycogen metabolism are necessary for normal brain function, growth, and healing and can result in the production of lactate. 

CNS lactate production includes the following pathways: gluconeogenesis/glycolysis pathway, fatty acid β-oxidation, urea cycle, pentose phosphate pathway, oxidative phosphorylation, and citric acid cycle.4,7,38,39

Gluconeogenesis/glycolysis pathway

CNS generation of glucose from non-carbohydrate precursors (gluconeogenesis) is a multistep process – enzymes used in glycolysis may catalyze reversible reactions. There are, however, three irreversible reactions:

1) Conversion of pyruvate to phosphoenolpyruvate: Pyruvate carboxylase: Pyruvate (cytosol) -> pyruvate (mitochondria) -> -> -> oxaloacetate (mitochondria) -> oxaloacetate (cytoplasm);

Phosphoenolpyruvate carboxykinase: Oxaloacetate (cytoplasm) ->->-> phosphoenolpyruvate;

2) Dephosphorylation of fructose-1,6 biphosphate: Fructose 1,6-biphosphate (cytoplasm) ->->-> fructose-6 phosphate (cytoplasm);

3) Dephosphorylation of glucose 6-phosphate: Glucose-6 phosphate (cytoplasm) ->->-> glucose (cytoplasm).

Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate to pyruvate. 

Pyruvate can then be converted to lactate via lactate dehydrogenase availability ability of enzymes varies between cells. For example, astrocytes exhibit significant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis through synthesis or hydrolysis of fructose-2,6-bisphosphate. 

Preferential production of lactate via the gluconeogenesis/ glycolysis pathway is dynamic and determined by the needs, metabolism, and health of the CNS.40-45

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