Glymphatic clearance controls state-dependent changes in brain lactate concentration

Lundgaard, Iben; Lu, Minh Lon; Yang, Ezra; Peng, Weiguo; Mestre, Humberto; Hitomi, Emi; Deane, Rashid

doi:10.1177/0271678x16661202

Cited by 237 publications

(242 citation statements)

References 77 publications

(154 reference statements)

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“…Bosoi et al suggested that increased lactate contributes to the pathogenesis of brain edema (cytotoxic) and may imply that the observed increase in total brain lactate is due to its intracellular accumulation. If the rate of lactate production and glymphatic clearance (38) are not affected, intracellular retention of lactate would explain higher concentration of this metabolite as measured by NMR spectroscopy (39) and would be in full agreement with our data showing impairment of hemichannel-mediated release in HE.…”

Section: Discussionsupporting

confidence: 90%

Ammonia Mediates Cortical Hemichannel Dysfunction in Rodent Models of Chronic Liver Disease

Hadjihambi

Chiara

Hosford

et al. 2017

Journal of Clinical and Experimental Hepatology

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The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte-neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia-induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel-mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (HEPATOLOGY 2017;65:1306-1318 H epatic encephalopathy (HE) is a serious neuropsychiatric complication that is associated with liver dysfunction and is diagnosed when other known brain disorders are excluded.(1) HE comprises a range of symptoms, including sleep disturbances and alterations in cognitive, behavioral, fine motor, and psychomotor functions, with coma and death occurring at the late stages.(2) Several hypotheses regarding the pathogenesis of HE have been proposed, and numerous factors have been suggested as key players in HE, including inflammation, (3) oxidative stress,impaired brain energy metabolism, (5) and-most commonly-the neurotoxic effects of ammonia. (6) Recent evidence has demonstrated that astroglial lactate production and release in cortical cultures and in the somatosensory cortex of anesthetized rats is Abbreviations: 4-CIN, a-cyano-4-hydroxycinnamic acid; aCSF, artificial cerebrospinal fluid; ALF, acute liver failure; ANOVA, analysis of variance; BDL, bile duct

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Section: Discussionsupporting

confidence: 90%

Ammonia Mediates Cortical Hemichannel Dysfunction in Rodent Models of Chronic Liver Disease

Hadjihambi

Chiara

Hosford

et al. 2017

Journal of Clinical and Experimental Hepatology

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“…Tissue samples of MTS have been shown to present a striking lack of peri‐vascular AQP4 water channels that mediates the glymphatic water clearance (Eid et al., 2005). The absence of AQP4 channels in MTS areas could lead to altered extracellular electrolyte concentrations that sensitizes neuronal tissue to seizures (Eid et al., 2005; Lundgaard et al., 2017; Marchi et al., 2007). …”

Section: Discussionmentioning

confidence: 99%

Altered physiological brain variation in drug‐resistant epilepsy

et al. 2018

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IntroductionFunctional magnetic resonance imaging (fMRI) combined with simultaneous electroencephalography (EEG‐fMRI) has become a major tool in mapping epilepsy sources. In the absence of detectable epileptiform activity, the resting state fMRI may still detect changes in the blood oxygen level‐dependent signal, suggesting intrinsic alterations in the underlying brain physiology.MethodsIn this study, we used coefficient of variation (CV) of critically sampled 10 Hz ultra‐fast fMRI (magnetoencephalography, MREG) signal to compare physiological variance between healthy controls (n = 10) and patients (n = 10) with drug‐resistant epilepsy (DRE).ResultsWe showed highly significant voxel‐level (p < 0.01, TFCE‐corrected) increase in the physiological variance in DRE patients. At individual level, the elevations range over three standard deviations (σ) above the control mean (μ) CVMREG values solely in DRE patients, enabling patient‐specific mapping of elevated physiological variance. The most apparent differences in group‐level analysis are found on white matter, brainstem, and cerebellum. Respiratory (0.12–0.4 Hz) and very‐low‐frequency (VLF = 0.009–0.1 Hz) signal variances were most affected.ConclusionsThe CVMREG increase was not explained by head motion or physiological cardiorespiratory activity, that is, it seems to be linked to intrinsic physiological pulsations. We suggest that intrinsic brain pulsations play a role in DRE and that critically sampled fMRI may provide a powerful tool for their identification.

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“…knockout, CSF volume reduction, or alteration of posture all led to increased brain and reduced cervical lymph node lactate levels (21), even in the clearance-promoting anesthetized state (20). The importance of glymphatic clearance of interstitial solute is perhaps best demonstrated by the fact that its failure contributes to the pathophysiology of various CNS diseases.…”

Section: The Glymphatic System: Anatomy and Function In Health And DImentioning

confidence: 99%

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

Louveau

Plog

Antila

et al. 2017

Journal of Clinical Investigation

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Glymphatic clearance controls state-dependent changes in brain lactate concentration

Cited by 237 publications

References 77 publications

Ammonia Mediates Cortical Hemichannel Dysfunction in Rodent Models of Chronic Liver Disease

Ammonia Mediates Cortical Hemichannel Dysfunction in Rodent Models of Chronic Liver Disease

Altered physiological brain variation in drug‐resistant epilepsy

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

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