Effects Of Lactate And Carbon Monoxide Interactions On Neuroprotection And Neuropreservation Part 3

Molecular

Regulation of pH

Normal functioning of the CNS is affected by pH as changes affect the tightly regulated micro-circuits. 

There is a close relationship between the nervous system and memory. The nervous system is one of the most important systems in the human body. It is responsible for receiving, transmitting, and processing external information, internal information, and activity instructions. At the same time, memory is one of the cores of human cognitive ability, and it is inseparable from the normal operation of the nervous system.

Neurons in the nervous system are extremely important cells in the human brain. They have extremely high plasticity and connectivity and can transmit and process information through chemical and electrical signal exchanges between neurons. Through the self-organization and feedback control between plastic neurons, we can establish and maintain various neural networks, and then realize our cognitive abilities, including learning, memory, thinking, etc.

Memory refers to people's ability to preserve and reproduce experiences, knowledge, and information. In the nervous system, the formation and storage of memory are completed through the exchange of chemical and electrical signals between neurons. Deep learning from Huangpu Education shows that "neural plasticity" is one of the important mechanisms for the formation and storage of human memory. Neuroplasticity refers to the ability of neurons to adapt and store new information through changes in morphology, structure, and function after receiving information and stimulation.

Further research on neuroplasticity has found that through continuous exercise and training, neuronal activity in the nervous system can be stimulated, thereby promoting memory formation and enhancement. For example, reading more books and newspapers not only expands people's knowledge but also helps promote neuroplasticity, thereby improving memory. At the same time, physical exercise and a healthy lifestyle are also important ways to promote neuroplasticity and memory enhancement.

In short, there is a close relationship between the nervous system and memory. Through proper exercise and training, neuroplasticity and memory enhancement can be improved, thereby better exerting human cognitive abilities. Therefore, we should pay attention to a healthy lifestyle, conduct more knowledge and physical training, stimulate the activities of the nervous system, and continuously improve our own cognitive level and quality of life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory, because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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Several processes regulate H+ in the CNS – intracellular H+ sequestering, CO2 diffusion, H+ buffering, membrane transport of acid/base equivalents across cell membranes, carbonic anhydrase activity, monocarboxylic acid transporters, vacuolar-type proton ATPase, etc. 

Acid extrusion as well as Na+/H+ exchange, Na+-HCO3 – cotransport, and Na+-dependent Cl– /HCO– exchange mediate pH levels.143-146 In the spinal cord, cells have two types of molecules in the cell membrane that detect pH levels with one reacting to acidic pH (acid-sensing ion channel subunit 3) and the other to alkaline pH levels (PKD2L 1.) With neuronal activity, lactate is released and pH becomes more acidic. 

Lower pH and higher pH are inhibitory on motor activity via the secretion of somatostatin from nerve terminals of the pH-sensing central canal cells.147 Ion channel gating/ conductances, metabolite exchange and neuronal excitability, synaptic transmission, and intercellular communication via gap junctions are dependent on pH and subsequent information processing. 

CNS lactate and CO can result in changes in pH. Normalization of pH can occur at multiple levels as noted above and both lactate and CO affect several of these processes. Studies to evaluate the interaction of lactate and CO on CNS pH have not been done.

Water transport and homeostasis

Water transport and homeostasis in the CNS are partly dependent on cotransporters – active and passive modes have been suggested. Numbers and types of cotransporters per cell and unit water permeability vary. 

Water channel proteins, AQPs, are from a large family of major intrinsic proteins that are integral to water transport and homeostasis in the human brain and mediate water flux between the four water compartments in the CNS. Eight AQPs are expressed in the brain – AQP1, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, and AQP11 with AQP1 and AQP4 expressed in the highest concentrations. 

Orthodox AQPs only conduct water while aquaglyceroporins also can conduct other small molecules. AQP9 is involved in water flux through plasma membranes and is also permeable to monocarboxylates (i.e., lactate). AQP4, the most abundant AQP in the brain, is concentrated in the astrocytic foot processes, is important to BBB defense, neuroplasticity, removal of waste, and homeostasis of water (transports water into the brain but also moves water out of the brain in times of edema).148-150 AQPs also conduct gas molecules. 

AQP1 has been associated with nitric oxide permeation when reconstituted in lipid vesicles and in vivo. Nitric oxide is produced by both neuronal nitric oxide synthase and endothelial nitric oxide synthase – AQP4 is found in the proximity of both neuronal nitric oxide synthase and endothelial nitric oxide synthase (exists in plasma membranes of end-feet of astrocytes which surround endothelial cells of capillaries). 

AQP4 is more adapted for gas conduction when compared to AQP1.151-154 Whether AQPs can conduct gas molecules (and which gases) and whether AQP-mediated gas conduction is clinically important are not clear. Initial studies suggest that lactate and CO are probably affected by AQP's. Further studies are needed to determine the effects of AQPs on lactate and CO and the interactions between lactate, CO, and AQPs.

Neurotransmitter homeostasis

There are more than 40 neurotransmitters in the human CNS – excitatory (glutamate, acetylcholine, histamine, dopamine, norepinephrine, epinephrine), inhibitory (GABA, serotonin, dopamine), neuromodulators (dopamine, serotonin, acetylcholine, histamine, norepinephrine), and neurohormones (releasing hormones, oxytocin, vasopressin). 

Their homeostasis, the ability of a cell/system of cells in the brain to identify a change and to respond with a compensatory response that restores baseline function, results as an interaction of several mechanisms including regulation of release of neurotransmitters by autoreceptors, non-synaptic production of the neurotransmitters, neurotransmitter vesicular release from the presynapse, uptake by transporters, and diffusion of the neurotransmitters. Neurotransmitter gradients exist and their maintenance is crucial for neurological processes – glia surrounding the synapse are a major effector of outcomes. 

Computational models have shown that specific glial configurations may be necessary, non-synaptic sources are needed to maintain extracellular concentrations of neurotransmitters, transporter, and non-synaptic source densities can co-vary to provide tone on presynaptic autoreceptors, and synaptic glial configuration can be suggested for a given neurotransmitter and a given extracellular neurotransmitter concentration.155-157 CO (and nitric oxide) is a neurotransmitter as well. 

Not stored in synaptic vesicles, the release of CO with depolarization results in the activation of biosynthetic enzymes – heme-oxygenase 2 is activated by phosphorylation by casein kinase 2.158,159 The effects of lactate and CO on the homeostasis of the CNS neurotransmitters continue to be studied. Lactate serves as a signal to neurons to release more noradrenaline and COmediated facilitation of CNS cell interactions affects neural circuits.160-162 The interaction between lactate and CO in affecting these responses is unknown and needs to be studied.

Ion homeostasis

Ca2+

CO affects Ca2+ signaling (necessary for synaptic transmission, gene transcription, CNS excitation, and memory storage) and may control the switch between glucose and lactate utilization during CNS activation, synaptic activity, and neuropathology. 

Maintenance of normal CNS function requires regulation of calcium homeostasis – CO regulation of calcium channels (calcium-activated K+ – distributed in both excitable and non-excitable cells, highly sensitive to intracellular calcium concentrations and voltage, and able to decrease voltage-dependent Ca2+ entry through membrane hyperpolarization and serve as negative feedback regulators – and Ca2+ channel families) is necessary to normal CNS function. The mechanisms by which CO regulates the calcium channels are unclear, remain controversial, and require further study. 

Telezhkin et al.163 found that cysteine residue 911 in the C terminal tail of the human BKCaα subunit is important for activation by CO. Bak et al.164 proposed a compartmentalized Ca2+-induced limitation of the malate-aspartate shuttle that defines pre- and post-synaptic compartments metabolizing glucose and glucose plus lactate in which the latter displays a positive correlation between oxidative metabolism of glucose and Ca2+ signaling. Lactate is essential to calcium homeostasis as well. 

Takata and colleagues165 determined that support of synaptic function by lactate utilization is associated with activation of NMDA and L-type calcium channels. Studies to determine the relationship between lactate and CO on calcium homeostasis are needed.

Cl–

Chloride (Cl– ) homeostasis involves multiple complex interactions and is critical for synaptic inhibition, and volume regulation, and determines effects of glycine-mediated and GABA neurotransmission.166 Absence/presence and function of chloride transporters and channels (differ in brain cell types) affect the direction of Cl– fluxes and cell physiology. GABA, an excitatory neurotransmitter during CNS development is inhibitory in the adult. The switching of GABA from excitatory to inhibitory has been correlated with the intracellular concentration of Cl– – in early development intracellular Cl– is higher than extracellular concentrations, but in adults intracellular Cl– is lower than extracellular Cl–. 

When GABA binds to GABAA receptors, the Cl– ion channel opens, Cl– influxes, and the postsynaptic membrane hyperpolarizes with inhibition of the Ca2+ influx of the postsynaptic neuron.167 The role switch is related to the expression of cation/chloride cotransporters NKCC1 and KCC2 and parallels the maturation of the CNS. Inhibition by GABA depends on Cl– influx and its continuation on Cl– extrusion from the cell (electrochemical Cl– gradient does not get depleted) – in the adult CNS, KCC2 is crucial for the inhibitory effects of GABA (and glycine) in synaptic circuits.168 Cation/chloride cotransporters have fundamental roles in differentiation, disease, neuronal proliferation, damage, recovery, and functions associated with plasmalemma receptor- and channel-mediated effects (i.e., synaptic plasticity). 

These ion transporters depend on the electrochemical force of Na+ and K+ ions which interact with the Na+ -K+ ATPase and its modulators – regulation of NKCC1 and KCC2 is by insulin-like growth factor, brain-derived neurotrophic factor, and cystic fibrosis transmembrane conductance regulator, and by phosphorylation of enzymes.169 The Structure and mechanism of these two cation/chloride cotransporters determine the electroneutral transport of sodium, chloride, and/or potassium across membranes and, thereby, impact ion absorption and secretion, maintenance of ion homeostasis, and regulation of cell volume – ion-translocation pathways, key residues for transport activity, and ion-binding sites have been defined.170,171 These ion transporters determine GABA actions – lactate has been associated with GABA release and CO (as an excitatory molecule) effects in the hypothalamic supraoptic nucleus are dependent on GABA.172,173 These relationships require further studies defining interactions between Cl–, GABA, CO, and lactate on the health and disease of the CNS.

K+

Four main ions fluctuate with rhythmic firing in the CNS. These include Ca2+, Na+ , Cl– , and K+ . The synergy between these ions results in oscillatory activity. Astrocytes regulate neuronal firing by affecting extracellular concentrations.

Extracellular K+ levels in the CNS are low relative to intracellular levels and the gradient is important for synaptic communication and electrical signaling (with neuronal activity, a transient rise in extracellular levels is seen). If homeostasis is not maintained, wide-spread depolarization of CNS cells can occur and compromise normal synapses, neuronal firing, and uptake of neurotransmitters.174-177 Neuronal discharge results in the activation of the voltage-gated potassium channels with K+ moving to the extracellular space. 

The accumulating K+ is taken up by neighboring astrocytes and redistributed through the syncytium via the activation of gap junctions.178,179 In astrocytes, glycogenolysis is needed for the uptake of increased extracellular K+. 180,181 Kir channels (seven subfamilies with each having multiple members) and the Na+ -K+ pump are required for regulation of the extracellular K+. 174 Kir channels establish and regulate the resting membrane potential of excitable cells and, in astrocytes, affect potassium buffering (and, therefore, neuronal excitability.)182 In the CNS, Kir4.1 is a modulator of brain-derived neurotrophic factor. 

Dysfunction of astrocytic Kir4.1 channels facilitates its expression in astrocytes (activating the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway) and may be linked to psychiatric disorders.183,184 The relationship of CO and lactate to Kir channels and possibly brain-derived neurotrophic factors in the CNS has not been defined. CO, however, inhibits Kir channels in cardiomyocytes as does H2 S.185,186 The effects of gasotransmitters on Kir channels in the CNS have not been studied. Studies are needed to evaluate CO effects on Kir channels and brain-derived neurotrophic factors in the brain and the role of lactate in these metabolic processes (glycogenolysis is important).

Organ

Effects on the lymphatic system

CNS immune privilege and drainage are affected by the relationship between the CNS glymphatic system (a system that allows CNS perfusion by the CSF and ISF) and meningeal lymphatics (major role in drainage of ISF, CSF, CNS-derived molecules, and immune cells from CNS and meninges to peripheral lymph nodes). 

Meningeal lymphatic vessels, also important in the exchange of soluble contents between the CSF and ISF, are keys to removing cellular waste, solutes, and immune traffic from the CNS.97,187,188 The Connection between the two systems allows a continuous flow of CSF that perfuses the brain to be drained to peripheral nodes.96 Lactate is partially cleared from the CNS by these two systems. 

While heme oxygenase is involved in subarachnoid hemorrhage and its clearance through meningeal lymphatics,189 interactions between lactate clearance, CO, and the CNS lymphatic systems have not been defined and require study.

Effects on the BBB

BBB integrity is a prerequisite of normal CNS health. Its disruption, as with stroke, is associated with cerebral edema and neurologic deficiency.190,191 This disruption is alleviated by CO-releasing molecule-3, which reduces Evans blue leakage and brain edema, increases the expression of platelet-derived growth factor receptor β, Zonula occludens-1, and laminin, decreases the expression of matrix metallopeptidase-9, thus protecting pericytes, tight junction proteins, and matrix proteins.192 The heme oxygenase-1 pathways are also important to the migration and differentiation of endothelial progenitor cells important to BBB integrity.193,194 Lactate also affects barrier genesis and the functioning of BBB.14 Interactions between CO and lactate on the BBB have not been defined and need to be studied.

Cellular and network

Synaptic plasticity

Synaptic plasticity is important for maintaining homeostasis in the body, for sharing essential information among neurons, and for regulating synaptic transmission or electrical signal transduction to neuronal networks. Upregulation or downregulation of CO affects this plasticity and, therefore, neuropathologies.195,196 Lactate is also a signaling molecule in synaptic plasticity – L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade extracellular signal-regulated kinase 1/2.129,197,198 Inhibition of the latter increases synaptic vesicle exocytosis by increasing calcium influx through L-type calcium channels.199 Downregulation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling pathways by CO has been suggested as a possible mechanism.200,201 The interactions between CO and lactate and their impact on synaptic plasticity require further study.

Synaptogenesis/maintenance/elimination

Changes in brain structure and organization as we experience, learn, and adapt are neuroplasticity (continues throughout life). Connections within the brain are constantly becoming stronger or weaker. 

This intricately regulated and multi-step process is defined by neuronal synapse formation/maturation and depends on key regulators, occurs simultaneously in different brain regions and between different types of neurons (a single neuron receives thousands of synaptic inputs), and is affected by extrinsic input, neuronal activity, intrinsic signaling pathways, and sensory experience. Changes in synaptic or neuroplasticity are associated with multiple neuropsychiatric conditions. 

CO is important to restoring neuroplasticity in the CNS and in structuring synaptic plasticity and is being evaluated as a neurotherapeutic.194,195 The biochemical changes that occur with CO are not well defined and are being further evaluated. Lactate is a regulator of synaptic genes and affects synaptogenesis, maintenance, and elimination.70,194,202 The relationship between CO and lactate on synaptogenesis/maintenance/elimination has not been defined.

Neurogenesis

The process by which new neurons are formed in the brain, neurogenesis, is crucial when an embryo is developing and continues in certain brain regions after birth and throughout our lifespan. 

Diversity of neurons results from regulated neurogenesis during embryonic development – neural stem cells (complex identity/functions ranging between quiescence/ activation/intermediary subtypes) differentiate and become a specialized cell type at specific times and regions in the CNS and are affected by external factors. Mitochondrial dynamics are now known to be important during this process and neural stem cell fate decisions – mitochondria-regulated energetics is linked to neuronal development. Integral to this process, mitochondria are central to determining the replication and differentiation of these precursor cells in the CNS. 

Transition to a more differentiated cell type is accompanied by the downregulation of glycolysis and fatty acid oxidation pathways and mitochondrial biogenesis.203-206 Lactate levels affect neurogenesis as does the presence of CO.116,207-211 Studies are needed to further evaluate the interactions of lactate and CO on neurogenesis (and effects on neuropathologies).

Neuronal development and guidance

The human brain contains more than 1 × 1011 neurons and each neuron connects to other neurons – axons and dendrites grow out, interact with other cells, and selectively protrude to create a functional, integrated, coordinated, working network. Initiated from the late embryonic stage and defining neural progenitor differentiation, neuronal development is determined by axon targeting/growth, dendrite maturation, synapse formation requiring integration of intrinsic genetic programs and the extrinsic factors, and chemoaffinity. 

Synaptic connections, continuously formed and eliminated, determine neural circuit plasticity.212-215 Pruning of dendrites and axons to mature neural circuitry is necessary for normal CNS health. Within the first 2 years of life (in humans), more than half of the connections formed in utero are eliminated. Pruned neurites are important for remodeling networks, and may serve as pioneering neurons that can guide other neurons, eliminate initially formed extensive connections made in the earlier wiring process, eliminate excessive branches, and simplify developmental programs.216-219 Microglia (constitute up to 10–15% of all cells in mammalian CNS) are associated with synapse elimination and influence synaptic strength – neuronal activity can directly activate microglia (detect the functional state of the neuron.) As the CNS matures, microglia localize in different regions throughout the brain. 

This is thought to be due to the microenvironment and functional differences – classical activation and alternative activation related to anti-inflammatory reactions and tissue remodeling. Microglia monitor CNS parenchyma and affect the clearance of cells in the healthy brain, neuronal excitability, neurogenesis, and synaptic activity. 

Phenotypes can change from surveillant to pro- or anti-inflammatory in response to conditions. Upregulation of specific pathways based on stimuli can alter mitochondrial metabolism – changes in metabolism are seen with the activation of microglia. CO affects microglia respiration and depends on the concentration.220,221 A CO-releasing molecule 3 affects microglia activation.222 Microglial metabolism (including lactate metabolism) is affected by neuroinflammation.222,223 Interaction between these two systems with pruning and neurodegenerative diseases has not been defined.

Defining the architecture of the CNS

Brain architecture continues to develop over time and is an ongoing process that begins before birth and continues into adulthood. It is comprised of billions of connections between individual neurons across different areas of the brain – simpler neural connections and skills form first followed by more complex circuits and skills – and is dependent on the interaction of genes and experiences. 

Whole brain volume changes throughout life – growth occurs during childhood and into adolescence, a gradual volume decrease is then seen, and possibly more growth or no tissue loss between around 18 and 35 years of age, followed by volume loss which increases with age. Brain reference atlases to identify the complex anatomical architecture of the brain help to link structure to function.224,225 After birth, connections continue to be modulated based on environment and experiences with genes affecting the building of the different cellular membranes and defining the molecules and ions that are used for the functioning CNS. 

Synapses and microcircuits, as well as neurons, local circuits, and systems/ pathways, are affected. Experiences are crucial to the development of brain architecture and affect genes – genes can be turned on or off.226-228 Ability to change the architecture of the brain in response to experiences decreases over time. Anatomical architecture and structural/functional networks affect functional interactions in the brain – changes in structural connectivity are paralleled by changes in functional connectivity and characterize brain changes in aging.228 A Rise in brain lactate is seen with the aging of the brain - the mechanism varies with different brain regions (LDH status is important.)229,230 The changing architecture of the aging brain is under oxidative stress – heme oxygenase genes are induced. CO (products of reaction catalyzed by heme oxygenase) has profound effects on the CNS.231,232 The roles and interactions of lactate and CO in changing CNS architecture need further study.

Systemic level

Effects on sleep

Lactate is a biomarker of sleeping – lactate concentrations remain higher during waking relative to sleep and with forced sleep deprivation, increase with waking, and decrease within minutes of sleep.84,233,234 During sleep, there is decreased ISF concentration, decreased production, and increased perivascular clearance of lactate.37 Activation of the glymphatic system with change-of-state is associated with lowering CNS lactate during sleep.82 This changes the lactate/pyruvate ratio (and, therefore, the NADH/NAD redox potential).83 

In those patients with obstructive sleep apnea, exhaled CO correlates with hypoxia during sleep,235 postsleep circulating CO level is increased initially,236 and venous lactate is increased (improved with continuous positive airway pressure).237,238 The proinflammatory transcription factor nuclear factor kappa B (affected by lactate and CO) is also increased.239 Interactions between CO, lactate, and nuclear factor kappaB during sleep and in obstructive sleep apnea need further studies.

Regulation of energy balance

The brain is integral to maintaining energy balance – the hypothalamic nuclei and the brainstem, the main brain areas for energy balance regulation, are affected by nonhomeostatic and homeostatic circuits (interrelated and integrated). 

Neural circuits in the CNS process information regarding food consumption, food, food-related cues, and feeding and energy balance are associated with higher brain functions and degenerative processes.240-242 5′ adenosine monophosphate-activated protein kinase (AMPK), metabolic regulator of the entire organism, senses AMP: ATP and/or adenosine diphosphate/ATP ratios and maintains energy balance by promoting ATP production by increasing the activity/expression of proteins involved in catabolism and conserving ATP by switching off biosynthetic pathways. 

Selective activation of hypothalamic AMPK negates hypothalamic glucose/lactate-sensing mechanisms.243 Activated AMPK also stimulates heme oxygenase-1 gene expression and elevates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling axis.244,245 Further studies are needed to define the relationships between AMPK, lactate, and CO associated with the regulation of energy balance.

Chemosensing

Chemosensing (generation of a response to the presence of a chemical stimulus) is a fundamental sensory function and depends on a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. 

Some are mediated by somatosensory nerve endings of the trigeminal, glossopharyngeal, and vagus nerves – chemicals activate chemosensory receptors via mechanisms distinct from other sensory systems and the nerve endings can trigger a range of sensations and reflexes. Overlapping the sensitivity of individual ion channels to chemical agonists can result in the combinatorial activation of different classes of nerve endings by a single chemical. The complex interplay between chemical agonists and chemosensory receptors allows for chemosensory mimicry by chemically distinct agents. 

Multiple areas of the CNS are involved in eliciting a response to a particular chemical stimulus. Chemosensory mechanisms may be an important causative factor in some neurologic diseases, but studies to evaluate the roles of lactate and/or CO in chemosensing are lacking. However, lactate infusion is a provocative challenge for panic disorder and is thought to be related to chemosensory mechanisms.246-248 CO effects on this are unknown. Studies to evaluate lactate and CO interactions on chemosensing are needed.

SUMMARY

Lactate is no longer considered "just a waste product of metabolism." Overall CNS health is affected by its presence or absence and its biochemical properties. CO is now known to be critical to the production of lactate and its roles (as a fuel, hormone, and/or signaling molecule) in the CNS. The neuroprotective ability of L-lactate partially depends on the integrity of the heme-oxygenase system and, in particular, CO. Further evaluation is needed of the L-lactate/heme-oxygenase/ CO interactions to better understand the effects on its application in CNS health and neuropathologies.

References

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6. Brooks GA. The science and translation of lactate shuttle theory. Cell Metab. 2018;27:757-785. 

7. Dienel GA. The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression. Neurosci Lett. 2017;637:18-25. 

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