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Effects of Alcohol on the Corpus Callosum
C H A P T E R
15 Effects of Alcohol on the Corpus Callosum Emilio Gonza´lez-Reimers1, Candelaria Martı´n-Gonza´lez1, Lucı´a Romero-Acevedo1, Geraldine Quintero-Platt1, Emilio Gonzalez-Arnay2 and Francisco Santolaria-Ferna´ndez1 1
Internal Medicine Service, University Hospital of the Canary Islands, University of La Laguna, Tenerife, Spain 2 Department of Anatomy and Pathology, University of La Laguna, Tenerife, Spain
LIST OF ABBREVIATIONS BBB DAMP DNA IL MCP MEOS NADPH NFκB NLR NOD NOX PAMP PDH RNA ROS TLR TNF-α
The corpus callosum is the largest white matter tract in the brain, connecting both hemispheres. We can distinguish several regions (Fig. 15.1), namely the rostrum, genu, corpus (body), and splenium. Fibers from prefrontal areas are predominantly transmitted through the genu; those from temporoparietal areas, through the splenium, whereas thick and highly myelinated fibers transmitting visual, auditory and somatosensorial stimuli are located in the body. Subsequent progress in neuroimaging has aided in the expansion of our knowledge about the alterations of the corpus callosum. In addition to measuring the corpus callosum area and/or thickness, white matter
blood brain barrier damage associated molecular patterns desoxyribonucleic acid interleukin monocyte chemoattractant protein microsomal ethanol oxidizing system reduced nicotine adenine dinucleotide phosphate nuclear factor κB NOD like receptors nucleotide oligomerization domain NADPH oxidase pathogen associated molecular patterns pyruvate dehydrogenase ribonucleic acid reactive oxygen species toll-like receptor tumor necrosis factor α
INTRODUCTION Ethanol affects neurons and, especially, white matter (de la Monte & Kril, 2014). The degree of atrophy is related to the amount of ethanol consumed, and the intensity of brain damage seems to be region-specific; for instance, the neurons of motor areas are not affected (Kril, Halliday, Svoboda, & Cartwright, 1997). Brain atrophy and degeneration may cause cognitive impairment (Harper & Matsumoto, 2005), although, sometimes, clinical expression is subtle (Pfefferbaum, Lim, Desmond, & Sullivan, 1996).
Neuroscience of Alcohol. DOI: https://doi.org/10.1016/B978-0-12-813125-1.00015-5
FIGURE 15.1 Corpus callosum. Regions of the corpus callosum (ro, rostrum; g, genu; c, corpus; sp, splenium).
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alterations can be evaluated. Diffusion-weighted highresolution magnetic resonance, coupled with fractional anisotropy analysis assess structural alterations of the white matter, including axonal diameter, fiber density and altered myelination. Axonal integrity can be estimated by longitudinal diffusivity, whereas axial diffusivity evaluates myelin integrity (Pfefferbaum et al., 2014). In alcoholics there is a progressive atrophy of the corpus callosum (Estruch et al., 1997), accompanied by microstructural fiber changes (Pfefferbaum, Adalsteinsson, & Sullivan, 2006), down-regulation of myelin-related genes (Mayfield et al., 2002), and altered protein expression (Kashem, James, Harper, Wilce, & Matsumoto, 2007). Direct effects of ethanol, protein-calorie malnutrition, alcohol-related liver disease and hepatic encephalopathy, associated drug use, and micronutrient deficiency, are all involved in its pathogenesis.
Corpus Callosum: Pathology In a classic study, Tarnowska-Dziduszko, Bertrand, and Szpak (1995) observed callosal lesions in 57 out of 66 alcoholics aged 24 78 years. Atrophy was diffuse in seven cases, involvement of the trunk was observed in 50 cases, and genu was affected in 32 cases. The most preserved area was the splenium. Focal alterations of the myelin sheaths, perivascular areas of demyelination, spongiform degeneration, and axonal alterations including axonal loss and spindle-shaped/ spherical dilatation of axons were also observed, findings that were later confirmed by Skuja, Groma, and Smane (2012). Fibrosis and/or hyalinization of small vessels with (38 cases) or without (23 cases) narrowing of their lumen were also present, with perivascular erythrocytic extravasation in 35 cases and perivascular gliosis in 25 cases. Authors also observed cortical and white matter atrophy affecting frontal, temporal, and parietal lobes, and suggest that changes in the corpus callosum were possibly derived from atrophy of brain lobes functionally connected to them. Oishi, Mochizuki, and Shikata (1999) measured regional cerebral blood flow in 15 alcoholics (without Marchiafava Bignami disease, Wernicke Korsakoff syndrome, or any other central nervous system diseases) and 15 controls and found a relationship between frontal cortex blood flow and the thickness of the genu (and other variables related to callosal atrophy), suggesting that callosal atrophy partly depends on cortical neuronal loss (especially of the prefrontal area) and oligodendrocyte alteration with impaired myelin synthesis.
Pathogenesis Two main mechanisms explain the decreased number of axons: damage to the neuronal bodies and secondary axonal degeneration, and disruption of myelin sheaths, rendering the axons more vulnerable to the damaging effects of ethanol (Samantaray et al., 2015). A very important factor obscuring the precise role of pure ethanol toxicity is the frequently (80%) associated thiamine deficiency. Thiamine depletion plays a critical role in decreased hippocampal-frontal cortical circuit plasticity and subsequent cognitive deficiency (Vedder, Hall, Jabrouin, & Savage, 2015). Without thiamine deficiency, the negative effect of ethanol on neurogenesis is less important than that exerted on the white matter ( Kril et al., 1997). Thiamine deficiency is due to ethanol toxicity, since ethanol alters thiamine intake, absorption, and transport into brain and damages apoenzymes involved in thiamine metabolism (Thomson, Guerrini, & Marshall, 2012). Ethanol and thiamine deficiency exert additive effects in the pathogenesis of brain alterations observed in alcoholics. He, Sullivan, Stankovic, Harper, and Pfefferbaum (2007) demonstrated that callosal atrophy was more intense among rats exposed to ethanol and thiamine deprivation. Thiamine deficiency seems to be more responsible than alcohol itself in the development of cerebellar atrophy (Mulholland et al., 2005). Thiamine acts as cofactor of branched chain alpha keto-acid dehydrogenase, transketolase, pyruvate dehydrogenase (PDH), and AKGDH. Transketolase is involved in the production of reduced nicotine adenine dinucleotide phosphate (NADPH), a molecule that is essential for the synthesis of glutathione, a main antioxidant compound (Kilanczyk, Saraswat Ohri, Whittemore, & Hetman, 2016). PDH transforms pyruvate into acetylcoenzyme A, so deficiency of this enzyme disturbs energy production and also affects acetylcholine synthesis and myelin synthesis (Potter, Rowitch, & Petryniak, 2011). Alpha ketoglutarate dehydrogenase deficiency interferes with glycolysis, reducing adenosine triphosphate production (Aikawa et al., 1984), and also alters the levels of important neurotransmitters, such as aspartate, glutamate, and gamma-aminobutyric acid (Abdou & Hazell, 2015). Indeed, glutamate excitoxicity, derived from altered synthesis and transport of glutamate is a major cause of neuronal death and apoptosis in vulnerable brain areas (thalamus) in thiamine deficiency (Hazell & Butterworth, 2009). Disturbed glycolysis and lactic acidosis may damage mitochondria (Abdou & Hazell, 2015), impairing oxidative metabolism and causing cell death. In damaged mitochondria there is an imbalance between reactive oxygen species (ROS) production and
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INTRODUCTION
ROS detoxification (Lin & Beal, 2006), aggravated by the aforementioned deficiency in glutathione function. Oxidative damage is a major mediator of brain injury in thiamine deficiency. Mitochondrial damage causes neuronal death and triggers an inflammatory process, activating microglia. These cells change their phenotype and secrete proinflammatory cytokines that act on neighboring cells (astrocytes and oligodendrocytes). Astrocyte activation alters blood brain barrier (BBB) permeability and normal astrocyte-neuronal metabolite trafficking (Fig. 15.2). Oligodendrocytes are essential for myelin synthesis. Myelin is formed by 70% 85% lipids (mainly cholesterol, glycolipids, phospholipids, especially galactosylceramide), and 15% 30% proteins (Potter et al., 2011) whose expression becomes altered in ethanol-mediated corpus callosum damage. Microglia activation leads to oligodendrocyte death and myelin and axonal damage (di Penta et al., 2013). Ethanol and Oxidative Damage Thiamine deficiency is ultimately involved in myelin alterations, but also causes neuronal damage and axonal loss. These effects add to other consequences of ethanol. Ethanol delays oligodendrocyte formation and maturation (Newville, Valenzuela, Li, Jantzie, & Cunningham, 2017) and impairs de novo myelin synthesis and the expression of several oligodendrocytederived myelin-related proteins (Gnaedinger, Noronha, & Druse, 1984). It also alters membrane phospholipid content, membrane fluidity, and decreases sphingolipid synthesis (Tong et al., 2015), both in mature and immature brains (Samantaray et al., 2015), and membrane receptors for insulin-like growth factors and
insulin (Soscia et al., 2006). Myelin alterations are more intense in adolescent brains (Pascual, Pla, Min˜arro, & Guerri, 2014). The main mechanism is oxidative damage which results from an imbalance between excessive ROS production and reduced antioxidant mechanisms. The latter include cellular enzymatic pathways (superoxide dismutases, catalase and glutathione peroxidase) that may be altered by ammonia (Cagnon & Braissant, 2008) and circulating molecules (thioredoxin, metallothioneins, uric acid, bilirubin, vitamin E, vitamin C, vitamin D, vitamin A, and homocysteine-related vitamins) that may be affected in alcoholics and were recently reviewed (Gonza´lez-Reimers, Quintero-Platt, Martı´n-Gonza´lez, Romero-Acevedo, & SantolariaFerna´ndez, 2017). Several mechanisms lead to excessive ROS production (Fig. 15.3). Cerebral Ethanol Metabolism and Reactive Oxygen Species Generation Ethanol is also metabolized in the brain (Hipo´lito, Sa´nchez, Polache, & Granero, 2007). Instead of alcohol dehydrogenase, the main pathway in liver, catalase, and microsomal ethanol oxidizing system (MEOS) are operative in microglia, astrocytes, and neurons (Zimatkin & Buben, 2007). The MEOS pathway is coupled with activation of NADPH oxidase (NOX), an important source of ROS (Qin and Crews, 2012). Although some studies suggest that microglia activation might play a protective role (Marshall et al., 2013), several experiments have shown that ethanol activates microglia and up-regulates NOX, an effect that is longlasting. Astrocytes of the cortex, dentate gyrus, and FIGURE 15.2 Main consequences of thiamine deficiency. Thiamine deficiency can lead to an imbalance between reactive oxygen species (ROS) production/detoxification.
Thiamine deficiency
Lactic acidosis
Disturbed glycolysis
ROS imbalance mitochodrial damage
Neuronal death
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Glial activation
– ↑BBB permeability – Altered glial-neuronal trafficking
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forceps minor of corpus callosum were also activated. In neurons and microglia, nuclear factor κB (NFκB) expression was enhanced and ROS production increased up to sevenfold in cortex and dentate gyrus (Qin & Crews, 2012). Postmortem studies also showed increased number of cells expressing NOX in neurons, astrocytes and microglia. The increase in NFκB expression enhances synthesis of proinflammatory cytokines. Ethanol also induces the synthesis of cyclooxygenase and inducible nitric oxide synthase (Blanco, Pascual, Valles, & Guerri, 2004). This
provokes increased prostaglandin synthesis and increased production of peroxynitrite, a highly reactive compound that aggravates oxidative stress (Valle´s, Blanco, Pascual, & Guerri, 2004). This increases BBB permeability (Haorah et al., 2007) and alters mitochondrial function (Reddy, Padmavathi, Kavitha, Saradamma, & Varadacharyulu, 2013) and causes lipid, protein and desoxyribonucleic acid (DNA) damage. Mitochondrial alteration affects ROS production (Fig. 15.4). The proinflammatory cytokines secreted exacerbate ROS production, inflammation, and cellular damage.
Alcohol metabolism in the brain
Catalase pathway
MEOS pathway
Activation of NADPH-oxidase (NOX)
ROS generation
Acetaldehyde
FIGURE 15.3 Main consequences of brain ethanol metabolism. Ethanol is metabolized by the catalase and microsomal ethanol oxidizing system (MEOS) pathways in the brain. The MEOS pathway activates reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX), an important source of reactive oxygen species (ROS).
Ethanol
↑ROS production
Induction of COX and iNOS
↑Prostaglandins
↑ NFkB expression
↑Peroxynitrite
↑Proinflammatory cytokines
↑BBB permeability
Lipid damage
Protein damage
DNA damage
FIGURE 15.4 Ethanol and oxidative damage. Ethanol increases reactive oxygen species (ROS) production, and induces cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS). Mitochondrial damage perpetuates increased ROS production and inflammation.
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INTRODUCTION
tumor necrosis factor α (TNF-α) is a potent inductor of ROS generation, and, together with interferon gamma, it also increases the synthesis of ROS (Hukkanen et al., 1995). Increased ROS production activates NFκB (Gloire, Legrand-Poels, & Piette, 2006), closing a selfperpetuating positive feedback loop. Increased ROS and proinflammatory cytokines production by activated microglia negatively affect other neurons (Yang et al., 2014). Activation of Toll-Like Receptors In alcoholics, toll-like receptors (TLRs) located in microglia and other cells become activated. Proinflammatory cytokines, glutamate (high levels of which are found in thiamine deficiency) and other molecules such as the nonhistone DNA binding protein high mobility group (see Box 15.1), released from neurons and astrocytes during inflammation, may activate TLR-3 and aggravate the inflammatory response by secreting more TNF-α, IL-6, IL-1β, and monocyte chemoattractant protein 1 (MCP-1) (Qin & Crews, 2012). Ethanol activates receptors located within the cell, such as NOD like receptors (NLRs), that detect cytosolic DAMPs or pathogen associated molecular patterns (PAMPs). Activation of NLRs leads to the formation of inflammasomes, formed by several proteins (P) that activate caspases (proinflammatory or apoptotic).
Proinflammatory caspases, such as caspase-1 induce the secretion of IL-18 and IL-1β. Astrocyte NLR-P3 inflammasome (especially at the dentate gyrus and corpus callosum) become activated by ethanol, in relation to increased mitochondrial ROS generation. These cells produce more IL-1β and IL-18 and increase inflammatory response (Alfonso-Loeches, Uren˜a-Peralta, MorilloBargues, Oliver-De La Cruz, & Guerri, 2014). Moreover, direct activation of TLR-4 by ethanol leads to increased expression of NFκB (adding to the direct effect of ROS) and secretion of proinflammatory cytokines, such as IL-1β, MCP-1and IL-6 (Zhang & Ghosh, 2001). Interestingly, TLR-4 knock-out mice are protected from the ethanol induced activation of NLR-P3, so both sensor systems (TLRs and NLRs) are necessary to orchestrate an inflammatory response (Fig. 15.5). The Gut Brain Axis Acetaldehyde increases intestinal permeability (Elamin et al., 2012), allowing Gram bacteria to reach the portal blood. Endotoxemia may overwhelm the Kupffer system and reach the systemic circulation, especially in cirrhotics (Rao, 2009). Via TLR-4 receptors (mainly), portal germs activate astrocytes to increase secretion of proinflammatory cytokines. Ethanol aids in this production, potentiating the induction of NFkB, and its binding to DNA. This proinflammatory effect is accompanied by a reduction in binding to DNA of
Insult: ethanol
TLR-4
Insult: ethanol
ASC Procaspase I
Inflammasome
NLPR3
NFkB caspase I
Procytokines
Cytokines
FIGURE 15.5
Some pathways of the innate immune response affected by ethanol. Ethanol activates cell receptors, leading to proinflammatory cytokine secretion. Proinflammatory cytokines may activate toll-like receptors closing a positive feedback cycle.
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an antiapoptotic transcription factor (the c-AMP responsive element-binding protein), especially in dentate gyrus (Bison & Crews, 2003). Cytokines produced in the liver are transported to brain and stimulate brain endothelial cells to produce additional cytokines (Erickson, Dohi, & Banks, 2012) that stimulate neuroinflammation and inhibit hippocampal neurogenesis. The global effect on neuroinflammation may be long-lasting: systemic lipopolysaccharide administration caused a marked increase in brain TNF-α levels, that remained high for 10 months, activating microglia and increasing expression of proinflammatory factors (Qin et al., 2007), an effect markedly enhanced by previous ethanol treatment (Qin et al., 2008) and in binge-drinking animal models. Free Iron Accumulation In the normal brain, iron accumulates in oligodendrocytes and serves for myelin synthesis (Rosato-Siri et al., 2017). Excessive iron disrupts white matter in patients with multiple sclerosis (Raz et al., 2015). Several mechanisms cause brain iron accumulation in alcoholics (Fig. 15.6). 1. Increased permeability of the BBB allows extravasation of red blood cells to the intersticial space, where they are destroyed, liberating heme and free iron. This causes an increase in ferritin, as a defensive mechanism against free iron. 2. Repeated microtrauma, related to the peculiar style of life of alcoholics also lead to iron deposition (Lu,
Cao, Wei, Li, & Li, 2015), that plays a major role in brain lesions after intracerebral hemorrhage, due to the marked ability of this element to generate ROS (Yang et al., 2017). Usually, hepcidin—widely distributed in brain—downregulates iron transport proteins and exerts a protective role on neuronal damage (Zhou et al., 2017). The importance of altered iron metabolism is so striking that the outcome of patients with brain bleeding can be predicted by a combination of serum iron, ferritin, and transferrin (Yang et al., 2016). Repetitive microtrauma also damage the brain leading to abnormal accumulation of a tau protein, that leads to progressive brain function impairment. (Morikawa et al., 1999). 3. Metabolism of ethanol by the MEOS system generates an increase in oxygen consumption, stimulating increased synthesis of hypoxia inducible factor 1 (Wang, Wu, Yang, Gan, & Cederbaum, 2013), that is, involved in the synthesis of TNF-α, and NO, in the induction of NOX (Yuan et al., 2011), and in iron cell accumulation by upregulation of transferrin receptor 1 (Ding et al., 2011). MicroRNA-Associated Oxidative Stress MicroRNAs may modulate the inflammatory response: an in vitro study described an inhibition of the expression of proinflammatory factors by microRNA-339-5p (Lippai, Bala, Csak, Kurt-Jones, & Szabo, 2013). Others have found that ethanol induces
FIGURE 15.6 Free iron and brain damage. Mechanisms involved in free iron deposition, that may increase oxidative damage.
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KEY FACTS
(microRNA-155) production in the cerebellum with increased TNF-α and MCP-1 secretion by cerebellar microglia (Zhang, Wei, Di, & Zhao, 2014). Toxic Lipids: The Liver Brain Axis In steatohepatitis, increased hepatocyte metabolism of lipids may lead to the formation of ceramide that provokes insulin resistance, activates proinflammatory cytokines, increases lipid peroxidation, and induces expression of ceramide genes in brain (de la Monte, Longato, Tong, DeNucci, & Wands, 2009), closing a deleterious feedback loop.
MINI-DICTIONARY OF TERMS Fractional anisotropy Measures the degree of anisotropy of water molecules. Without obstacles, water molecules diffuse freely in any direction, a pattern that may be changed by the presence of macromolecules, cell membranes, etc. If water molecules are conducted within a tube (or an axon), diffusion only occurs along the axis of this tube. Therefore, diffusion is not isotropic, but anisotropic. The degree of anisotropy can be measured, and allows to infer alterations in the axonal diameter, fiber density or myelin structure. Diffusion-weighted magnetic resonance imaging draws maps of the diffusion pattern of water molecules, allowing the detection of microstructural details of normal or altered anatomy of a given region. Apoptosis Noninflammatory programmed cell death in response to signals derived from the preapoptotic cell (intrinsic pathway) or from other cells (extrinsic pathways). Toll-like receptors Receptors that are an essential part of the innate immunity, they recognize foreign molecules mainly derived from bacteria. NOD receptors Receptors that recognize intracellular foreign molecules (viral particles or altered cytosolic proteins) DAMP damage associated molecular patterns or alarmins are molecules derived from the host cell that become altered after insults (i.e., nuclear membrane leakage, cell necrosis, heat shock, etc.). They may elicit an inflammatory reaction PAMP pathogen derived foreign molecules that generate an inflammatory response. MicroRNA small noncoding RNA molecules, located within or extracellularly. They may interfere with gene expression or promote inflammatory responses, apoptotic or antiapoptotic signals. Ceramide Membrane-bound molecules formed by fatty acids and sphingosine. They may promote lipid peroxidation, inflammation and apoptosis. Perivascular gliosis Reactive proliferation of astrocytes in response to an insult, frequently linked to inflammation-derived disturbances of the blood brain barrier. It resembles a neural equivalent of reactive fibrosis.
SUMMARY POINTS • In alcoholics, white matter atrophy is more severe than gray matter atrophy.
• Callosal atrophy depends on myelin alterations and axonal degeneration that may be secondary to neuronal damage. • Oligodendrocytes synthesize myelin, and ethanol impairs their development and function. • Ethanol alters thiamine intake, absorption, transport into brain and also damages apoenzymes involved in thiamine metabolism. • Thiamine deficiency plays an important role on white matter damage in alcoholics. • Oxidative damage is the main pathogenetic mechanism involved in white matter atrophy. It depends on an imbalance between excessive reactive oxygen species (ROS) production and altered antioxidant systems. • Main mechanisms leading to excessive ROS production include: metabolism of ethanol, activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR), excessive cytokine production, ethanol-mediated brain accumulation of free iron, microRNA, and toxic lipids derived from liver.
KEY FACTS Brain and Corpus Callosum Structure and Function • The central nervous system consists of gray matter (neuronal bodies) and white matter (nervous tracts). • Nervous tracts connect different areas of the nervous system and are formed by axons (prolongations of neuronal bodies) covered by myelin sheaths. • Myelin is formed by complex phospholipids. It is necessary for adequate transmission of nerve signals. • Corpus callosum, the largest white matter structure of the brain, connects both brain hemispheres. • Myelin sheaths are formed by specialized glial cells called oligodendrocytes
Effects of Ethanol on Corpus Callosum • Neuronal loss and/or myelin damage may alter white matter structure and function. • Ethanol can affect gray matter, although its main effect is observed in white matter. • Ethanol directly affects oligodendrocytes, impairing myelin synthesis. • Toxic compounds derived from ethanol metabolism, mainly the so called reactive oxygen species, damage myelin sheets.
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• Myelin may be also damaged by local and systemic inflammatory mediators directly or indirectly derived from ethanol metabolism.
CONCLUSION Many mechanisms observed in alcoholics are involved in brain damage, with catastrophic consequences on brain function. Corpus callosum becomes especially affected, as we show in this chapter. Alcohol abstinence markedly improves these alterations.
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15 Effects of Alcohol on the Corpus Callosum Emilio Gonza´lez-Reimers1, Candelaria Martı´n-Gonza´lez1, Lucı´a Romero-Acevedo1, Geraldine Quintero-Platt1, Emilio Gonzalez-Arnay2 and Francisco Santolaria-Ferna´ndez1 1
Internal Medicine Service, University Hospital of the Canary Islands, University of La Laguna, Tenerife, Spain 2 Department of Anatomy and Pathology, University of La Laguna, Tenerife, Spain
LIST OF ABBREVIATIONS BBB DAMP DNA IL MCP MEOS NADPH NFκB NLR NOD NOX PAMP PDH RNA ROS TLR TNF-α
The corpus callosum is the largest white matter tract in the brain, connecting both hemispheres. We can distinguish several regions (Fig. 15.1), namely the rostrum, genu, corpus (body), and splenium. Fibers from prefrontal areas are predominantly transmitted through the genu; those from temporoparietal areas, through the splenium, whereas thick and highly myelinated fibers transmitting visual, auditory and somatosensorial stimuli are located in the body. Subsequent progress in neuroimaging has aided in the expansion of our knowledge about the alterations of the corpus callosum. In addition to measuring the corpus callosum area and/or thickness, white matter
blood brain barrier damage associated molecular patterns desoxyribonucleic acid interleukin monocyte chemoattractant protein microsomal ethanol oxidizing system reduced nicotine adenine dinucleotide phosphate nuclear factor κB NOD like receptors nucleotide oligomerization domain NADPH oxidase pathogen associated molecular patterns pyruvate dehydrogenase ribonucleic acid reactive oxygen species toll-like receptor tumor necrosis factor α
INTRODUCTION Ethanol affects neurons and, especially, white matter (de la Monte & Kril, 2014). The degree of atrophy is related to the amount of ethanol consumed, and the intensity of brain damage seems to be region-specific; for instance, the neurons of motor areas are not affected (Kril, Halliday, Svoboda, & Cartwright, 1997). Brain atrophy and degeneration may cause cognitive impairment (Harper & Matsumoto, 2005), although, sometimes, clinical expression is subtle (Pfefferbaum, Lim, Desmond, & Sullivan, 1996).
Neuroscience of Alcohol. DOI: https://doi.org/10.1016/B978-0-12-813125-1.00015-5
FIGURE 15.1 Corpus callosum. Regions of the corpus callosum (ro, rostrum; g, genu; c, corpus; sp, splenium).
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alterations can be evaluated. Diffusion-weighted highresolution magnetic resonance, coupled with fractional anisotropy analysis assess structural alterations of the white matter, including axonal diameter, fiber density and altered myelination. Axonal integrity can be estimated by longitudinal diffusivity, whereas axial diffusivity evaluates myelin integrity (Pfefferbaum et al., 2014). In alcoholics there is a progressive atrophy of the corpus callosum (Estruch et al., 1997), accompanied by microstructural fiber changes (Pfefferbaum, Adalsteinsson, & Sullivan, 2006), down-regulation of myelin-related genes (Mayfield et al., 2002), and altered protein expression (Kashem, James, Harper, Wilce, & Matsumoto, 2007). Direct effects of ethanol, protein-calorie malnutrition, alcohol-related liver disease and hepatic encephalopathy, associated drug use, and micronutrient deficiency, are all involved in its pathogenesis.
Corpus Callosum: Pathology In a classic study, Tarnowska-Dziduszko, Bertrand, and Szpak (1995) observed callosal lesions in 57 out of 66 alcoholics aged 24 78 years. Atrophy was diffuse in seven cases, involvement of the trunk was observed in 50 cases, and genu was affected in 32 cases. The most preserved area was the splenium. Focal alterations of the myelin sheaths, perivascular areas of demyelination, spongiform degeneration, and axonal alterations including axonal loss and spindle-shaped/ spherical dilatation of axons were also observed, findings that were later confirmed by Skuja, Groma, and Smane (2012). Fibrosis and/or hyalinization of small vessels with (38 cases) or without (23 cases) narrowing of their lumen were also present, with perivascular erythrocytic extravasation in 35 cases and perivascular gliosis in 25 cases. Authors also observed cortical and white matter atrophy affecting frontal, temporal, and parietal lobes, and suggest that changes in the corpus callosum were possibly derived from atrophy of brain lobes functionally connected to them. Oishi, Mochizuki, and Shikata (1999) measured regional cerebral blood flow in 15 alcoholics (without Marchiafava Bignami disease, Wernicke Korsakoff syndrome, or any other central nervous system diseases) and 15 controls and found a relationship between frontal cortex blood flow and the thickness of the genu (and other variables related to callosal atrophy), suggesting that callosal atrophy partly depends on cortical neuronal loss (especially of the prefrontal area) and oligodendrocyte alteration with impaired myelin synthesis.
Pathogenesis Two main mechanisms explain the decreased number of axons: damage to the neuronal bodies and secondary axonal degeneration, and disruption of myelin sheaths, rendering the axons more vulnerable to the damaging effects of ethanol (Samantaray et al., 2015). A very important factor obscuring the precise role of pure ethanol toxicity is the frequently (80%) associated thiamine deficiency. Thiamine depletion plays a critical role in decreased hippocampal-frontal cortical circuit plasticity and subsequent cognitive deficiency (Vedder, Hall, Jabrouin, & Savage, 2015). Without thiamine deficiency, the negative effect of ethanol on neurogenesis is less important than that exerted on the white matter ( Kril et al., 1997). Thiamine deficiency is due to ethanol toxicity, since ethanol alters thiamine intake, absorption, and transport into brain and damages apoenzymes involved in thiamine metabolism (Thomson, Guerrini, & Marshall, 2012). Ethanol and thiamine deficiency exert additive effects in the pathogenesis of brain alterations observed in alcoholics. He, Sullivan, Stankovic, Harper, and Pfefferbaum (2007) demonstrated that callosal atrophy was more intense among rats exposed to ethanol and thiamine deprivation. Thiamine deficiency seems to be more responsible than alcohol itself in the development of cerebellar atrophy (Mulholland et al., 2005). Thiamine acts as cofactor of branched chain alpha keto-acid dehydrogenase, transketolase, pyruvate dehydrogenase (PDH), and AKGDH. Transketolase is involved in the production of reduced nicotine adenine dinucleotide phosphate (NADPH), a molecule that is essential for the synthesis of glutathione, a main antioxidant compound (Kilanczyk, Saraswat Ohri, Whittemore, & Hetman, 2016). PDH transforms pyruvate into acetylcoenzyme A, so deficiency of this enzyme disturbs energy production and also affects acetylcholine synthesis and myelin synthesis (Potter, Rowitch, & Petryniak, 2011). Alpha ketoglutarate dehydrogenase deficiency interferes with glycolysis, reducing adenosine triphosphate production (Aikawa et al., 1984), and also alters the levels of important neurotransmitters, such as aspartate, glutamate, and gamma-aminobutyric acid (Abdou & Hazell, 2015). Indeed, glutamate excitoxicity, derived from altered synthesis and transport of glutamate is a major cause of neuronal death and apoptosis in vulnerable brain areas (thalamus) in thiamine deficiency (Hazell & Butterworth, 2009). Disturbed glycolysis and lactic acidosis may damage mitochondria (Abdou & Hazell, 2015), impairing oxidative metabolism and causing cell death. In damaged mitochondria there is an imbalance between reactive oxygen species (ROS) production and
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INTRODUCTION
ROS detoxification (Lin & Beal, 2006), aggravated by the aforementioned deficiency in glutathione function. Oxidative damage is a major mediator of brain injury in thiamine deficiency. Mitochondrial damage causes neuronal death and triggers an inflammatory process, activating microglia. These cells change their phenotype and secrete proinflammatory cytokines that act on neighboring cells (astrocytes and oligodendrocytes). Astrocyte activation alters blood brain barrier (BBB) permeability and normal astrocyte-neuronal metabolite trafficking (Fig. 15.2). Oligodendrocytes are essential for myelin synthesis. Myelin is formed by 70% 85% lipids (mainly cholesterol, glycolipids, phospholipids, especially galactosylceramide), and 15% 30% proteins (Potter et al., 2011) whose expression becomes altered in ethanol-mediated corpus callosum damage. Microglia activation leads to oligodendrocyte death and myelin and axonal damage (di Penta et al., 2013). Ethanol and Oxidative Damage Thiamine deficiency is ultimately involved in myelin alterations, but also causes neuronal damage and axonal loss. These effects add to other consequences of ethanol. Ethanol delays oligodendrocyte formation and maturation (Newville, Valenzuela, Li, Jantzie, & Cunningham, 2017) and impairs de novo myelin synthesis and the expression of several oligodendrocytederived myelin-related proteins (Gnaedinger, Noronha, & Druse, 1984). It also alters membrane phospholipid content, membrane fluidity, and decreases sphingolipid synthesis (Tong et al., 2015), both in mature and immature brains (Samantaray et al., 2015), and membrane receptors for insulin-like growth factors and
insulin (Soscia et al., 2006). Myelin alterations are more intense in adolescent brains (Pascual, Pla, Min˜arro, & Guerri, 2014). The main mechanism is oxidative damage which results from an imbalance between excessive ROS production and reduced antioxidant mechanisms. The latter include cellular enzymatic pathways (superoxide dismutases, catalase and glutathione peroxidase) that may be altered by ammonia (Cagnon & Braissant, 2008) and circulating molecules (thioredoxin, metallothioneins, uric acid, bilirubin, vitamin E, vitamin C, vitamin D, vitamin A, and homocysteine-related vitamins) that may be affected in alcoholics and were recently reviewed (Gonza´lez-Reimers, Quintero-Platt, Martı´n-Gonza´lez, Romero-Acevedo, & SantolariaFerna´ndez, 2017). Several mechanisms lead to excessive ROS production (Fig. 15.3). Cerebral Ethanol Metabolism and Reactive Oxygen Species Generation Ethanol is also metabolized in the brain (Hipo´lito, Sa´nchez, Polache, & Granero, 2007). Instead of alcohol dehydrogenase, the main pathway in liver, catalase, and microsomal ethanol oxidizing system (MEOS) are operative in microglia, astrocytes, and neurons (Zimatkin & Buben, 2007). The MEOS pathway is coupled with activation of NADPH oxidase (NOX), an important source of ROS (Qin and Crews, 2012). Although some studies suggest that microglia activation might play a protective role (Marshall et al., 2013), several experiments have shown that ethanol activates microglia and up-regulates NOX, an effect that is longlasting. Astrocytes of the cortex, dentate gyrus, and FIGURE 15.2 Main consequences of thiamine deficiency. Thiamine deficiency can lead to an imbalance between reactive oxygen species (ROS) production/detoxification.
Thiamine deficiency
Lactic acidosis
Disturbed glycolysis
ROS imbalance mitochodrial damage
Neuronal death
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Glial activation
– ↑BBB permeability – Altered glial-neuronal trafficking
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forceps minor of corpus callosum were also activated. In neurons and microglia, nuclear factor κB (NFκB) expression was enhanced and ROS production increased up to sevenfold in cortex and dentate gyrus (Qin & Crews, 2012). Postmortem studies also showed increased number of cells expressing NOX in neurons, astrocytes and microglia. The increase in NFκB expression enhances synthesis of proinflammatory cytokines. Ethanol also induces the synthesis of cyclooxygenase and inducible nitric oxide synthase (Blanco, Pascual, Valles, & Guerri, 2004). This
provokes increased prostaglandin synthesis and increased production of peroxynitrite, a highly reactive compound that aggravates oxidative stress (Valle´s, Blanco, Pascual, & Guerri, 2004). This increases BBB permeability (Haorah et al., 2007) and alters mitochondrial function (Reddy, Padmavathi, Kavitha, Saradamma, & Varadacharyulu, 2013) and causes lipid, protein and desoxyribonucleic acid (DNA) damage. Mitochondrial alteration affects ROS production (Fig. 15.4). The proinflammatory cytokines secreted exacerbate ROS production, inflammation, and cellular damage.
Alcohol metabolism in the brain
Catalase pathway
MEOS pathway
Activation of NADPH-oxidase (NOX)
ROS generation
Acetaldehyde
FIGURE 15.3 Main consequences of brain ethanol metabolism. Ethanol is metabolized by the catalase and microsomal ethanol oxidizing system (MEOS) pathways in the brain. The MEOS pathway activates reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX), an important source of reactive oxygen species (ROS).
Ethanol
↑ROS production
Induction of COX and iNOS
↑Prostaglandins
↑ NFkB expression
↑Peroxynitrite
↑Proinflammatory cytokines
↑BBB permeability
Lipid damage
Protein damage
DNA damage
FIGURE 15.4 Ethanol and oxidative damage. Ethanol increases reactive oxygen species (ROS) production, and induces cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS). Mitochondrial damage perpetuates increased ROS production and inflammation.
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INTRODUCTION
tumor necrosis factor α (TNF-α) is a potent inductor of ROS generation, and, together with interferon gamma, it also increases the synthesis of ROS (Hukkanen et al., 1995). Increased ROS production activates NFκB (Gloire, Legrand-Poels, & Piette, 2006), closing a selfperpetuating positive feedback loop. Increased ROS and proinflammatory cytokines production by activated microglia negatively affect other neurons (Yang et al., 2014). Activation of Toll-Like Receptors In alcoholics, toll-like receptors (TLRs) located in microglia and other cells become activated. Proinflammatory cytokines, glutamate (high levels of which are found in thiamine deficiency) and other molecules such as the nonhistone DNA binding protein high mobility group (see Box 15.1), released from neurons and astrocytes during inflammation, may activate TLR-3 and aggravate the inflammatory response by secreting more TNF-α, IL-6, IL-1β, and monocyte chemoattractant protein 1 (MCP-1) (Qin & Crews, 2012). Ethanol activates receptors located within the cell, such as NOD like receptors (NLRs), that detect cytosolic DAMPs or pathogen associated molecular patterns (PAMPs). Activation of NLRs leads to the formation of inflammasomes, formed by several proteins (P) that activate caspases (proinflammatory or apoptotic).
Proinflammatory caspases, such as caspase-1 induce the secretion of IL-18 and IL-1β. Astrocyte NLR-P3 inflammasome (especially at the dentate gyrus and corpus callosum) become activated by ethanol, in relation to increased mitochondrial ROS generation. These cells produce more IL-1β and IL-18 and increase inflammatory response (Alfonso-Loeches, Uren˜a-Peralta, MorilloBargues, Oliver-De La Cruz, & Guerri, 2014). Moreover, direct activation of TLR-4 by ethanol leads to increased expression of NFκB (adding to the direct effect of ROS) and secretion of proinflammatory cytokines, such as IL-1β, MCP-1and IL-6 (Zhang & Ghosh, 2001). Interestingly, TLR-4 knock-out mice are protected from the ethanol induced activation of NLR-P3, so both sensor systems (TLRs and NLRs) are necessary to orchestrate an inflammatory response (Fig. 15.5). The Gut Brain Axis Acetaldehyde increases intestinal permeability (Elamin et al., 2012), allowing Gram bacteria to reach the portal blood. Endotoxemia may overwhelm the Kupffer system and reach the systemic circulation, especially in cirrhotics (Rao, 2009). Via TLR-4 receptors (mainly), portal germs activate astrocytes to increase secretion of proinflammatory cytokines. Ethanol aids in this production, potentiating the induction of NFkB, and its binding to DNA. This proinflammatory effect is accompanied by a reduction in binding to DNA of
Insult: ethanol
TLR-4
Insult: ethanol
ASC Procaspase I
Inflammasome
NLPR3
NFkB caspase I
Procytokines
Cytokines
FIGURE 15.5
Some pathways of the innate immune response affected by ethanol. Ethanol activates cell receptors, leading to proinflammatory cytokine secretion. Proinflammatory cytokines may activate toll-like receptors closing a positive feedback cycle.
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an antiapoptotic transcription factor (the c-AMP responsive element-binding protein), especially in dentate gyrus (Bison & Crews, 2003). Cytokines produced in the liver are transported to brain and stimulate brain endothelial cells to produce additional cytokines (Erickson, Dohi, & Banks, 2012) that stimulate neuroinflammation and inhibit hippocampal neurogenesis. The global effect on neuroinflammation may be long-lasting: systemic lipopolysaccharide administration caused a marked increase in brain TNF-α levels, that remained high for 10 months, activating microglia and increasing expression of proinflammatory factors (Qin et al., 2007), an effect markedly enhanced by previous ethanol treatment (Qin et al., 2008) and in binge-drinking animal models. Free Iron Accumulation In the normal brain, iron accumulates in oligodendrocytes and serves for myelin synthesis (Rosato-Siri et al., 2017). Excessive iron disrupts white matter in patients with multiple sclerosis (Raz et al., 2015). Several mechanisms cause brain iron accumulation in alcoholics (Fig. 15.6). 1. Increased permeability of the BBB allows extravasation of red blood cells to the intersticial space, where they are destroyed, liberating heme and free iron. This causes an increase in ferritin, as a defensive mechanism against free iron. 2. Repeated microtrauma, related to the peculiar style of life of alcoholics also lead to iron deposition (Lu,
Cao, Wei, Li, & Li, 2015), that plays a major role in brain lesions after intracerebral hemorrhage, due to the marked ability of this element to generate ROS (Yang et al., 2017). Usually, hepcidin—widely distributed in brain—downregulates iron transport proteins and exerts a protective role on neuronal damage (Zhou et al., 2017). The importance of altered iron metabolism is so striking that the outcome of patients with brain bleeding can be predicted by a combination of serum iron, ferritin, and transferrin (Yang et al., 2016). Repetitive microtrauma also damage the brain leading to abnormal accumulation of a tau protein, that leads to progressive brain function impairment. (Morikawa et al., 1999). 3. Metabolism of ethanol by the MEOS system generates an increase in oxygen consumption, stimulating increased synthesis of hypoxia inducible factor 1 (Wang, Wu, Yang, Gan, & Cederbaum, 2013), that is, involved in the synthesis of TNF-α, and NO, in the induction of NOX (Yuan et al., 2011), and in iron cell accumulation by upregulation of transferrin receptor 1 (Ding et al., 2011). MicroRNA-Associated Oxidative Stress MicroRNAs may modulate the inflammatory response: an in vitro study described an inhibition of the expression of proinflammatory factors by microRNA-339-5p (Lippai, Bala, Csak, Kurt-Jones, & Szabo, 2013). Others have found that ethanol induces
FIGURE 15.6 Free iron and brain damage. Mechanisms involved in free iron deposition, that may increase oxidative damage.
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KEY FACTS
(microRNA-155) production in the cerebellum with increased TNF-α and MCP-1 secretion by cerebellar microglia (Zhang, Wei, Di, & Zhao, 2014). Toxic Lipids: The Liver Brain Axis In steatohepatitis, increased hepatocyte metabolism of lipids may lead to the formation of ceramide that provokes insulin resistance, activates proinflammatory cytokines, increases lipid peroxidation, and induces expression of ceramide genes in brain (de la Monte, Longato, Tong, DeNucci, & Wands, 2009), closing a deleterious feedback loop.
MINI-DICTIONARY OF TERMS Fractional anisotropy Measures the degree of anisotropy of water molecules. Without obstacles, water molecules diffuse freely in any direction, a pattern that may be changed by the presence of macromolecules, cell membranes, etc. If water molecules are conducted within a tube (or an axon), diffusion only occurs along the axis of this tube. Therefore, diffusion is not isotropic, but anisotropic. The degree of anisotropy can be measured, and allows to infer alterations in the axonal diameter, fiber density or myelin structure. Diffusion-weighted magnetic resonance imaging draws maps of the diffusion pattern of water molecules, allowing the detection of microstructural details of normal or altered anatomy of a given region. Apoptosis Noninflammatory programmed cell death in response to signals derived from the preapoptotic cell (intrinsic pathway) or from other cells (extrinsic pathways). Toll-like receptors Receptors that are an essential part of the innate immunity, they recognize foreign molecules mainly derived from bacteria. NOD receptors Receptors that recognize intracellular foreign molecules (viral particles or altered cytosolic proteins) DAMP damage associated molecular patterns or alarmins are molecules derived from the host cell that become altered after insults (i.e., nuclear membrane leakage, cell necrosis, heat shock, etc.). They may elicit an inflammatory reaction PAMP pathogen derived foreign molecules that generate an inflammatory response. MicroRNA small noncoding RNA molecules, located within or extracellularly. They may interfere with gene expression or promote inflammatory responses, apoptotic or antiapoptotic signals. Ceramide Membrane-bound molecules formed by fatty acids and sphingosine. They may promote lipid peroxidation, inflammation and apoptosis. Perivascular gliosis Reactive proliferation of astrocytes in response to an insult, frequently linked to inflammation-derived disturbances of the blood brain barrier. It resembles a neural equivalent of reactive fibrosis.
SUMMARY POINTS • In alcoholics, white matter atrophy is more severe than gray matter atrophy.
• Callosal atrophy depends on myelin alterations and axonal degeneration that may be secondary to neuronal damage. • Oligodendrocytes synthesize myelin, and ethanol impairs their development and function. • Ethanol alters thiamine intake, absorption, transport into brain and also damages apoenzymes involved in thiamine metabolism. • Thiamine deficiency plays an important role on white matter damage in alcoholics. • Oxidative damage is the main pathogenetic mechanism involved in white matter atrophy. It depends on an imbalance between excessive reactive oxygen species (ROS) production and altered antioxidant systems. • Main mechanisms leading to excessive ROS production include: metabolism of ethanol, activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR), excessive cytokine production, ethanol-mediated brain accumulation of free iron, microRNA, and toxic lipids derived from liver.
KEY FACTS Brain and Corpus Callosum Structure and Function • The central nervous system consists of gray matter (neuronal bodies) and white matter (nervous tracts). • Nervous tracts connect different areas of the nervous system and are formed by axons (prolongations of neuronal bodies) covered by myelin sheaths. • Myelin is formed by complex phospholipids. It is necessary for adequate transmission of nerve signals. • Corpus callosum, the largest white matter structure of the brain, connects both brain hemispheres. • Myelin sheaths are formed by specialized glial cells called oligodendrocytes
Effects of Ethanol on Corpus Callosum • Neuronal loss and/or myelin damage may alter white matter structure and function. • Ethanol can affect gray matter, although its main effect is observed in white matter. • Ethanol directly affects oligodendrocytes, impairing myelin synthesis. • Toxic compounds derived from ethanol metabolism, mainly the so called reactive oxygen species, damage myelin sheets.
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• Myelin may be also damaged by local and systemic inflammatory mediators directly or indirectly derived from ethanol metabolism.
CONCLUSION Many mechanisms observed in alcoholics are involved in brain damage, with catastrophic consequences on brain function. Corpus callosum becomes especially affected, as we show in this chapter. Alcohol abstinence markedly improves these alterations.
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