Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke's encephalopathy

Abstract

Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke’s encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls+glucose, n=6; pyrithiamine+saline, n=5; pyrithiamine+glucose, n=13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.

Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo

“…Further treatment (7 days of pyrithiamine + another EtOH exposure) caused a greater increase in volumes of lateral ventricles and CSF in the PE group. These findings in the PE group are consistent with enlargement of lateral ventricles observed with MRI in thiamine deficient rats (i.e., equivalent to the PS group in this study)(Dror et al 2010; Dror et al 2014; Zahr et al 2014a). In the previous studies, however, ventricular enlargement was more profound and appeared to persist (Dror et al 2010; Dror et al 2014), possibly because the length of thiamine deficiency was longer (14 days) and thiamine replacement was shorter (3 days)(Dror et al 2010; Dror et al 2014).…”

“…Similarly, as has previously been reported in the literature of MRS case studies of WE (Mascalchi et al 2002; Murata et al 2001) and models of thiamine deficiency in rats treated with pyrithiamine hydrochloride (Lee et al 2001; Lee et al 1995; Pfefferbaum et al 2007; Rose et al 1993; Zahr et al 2014a), lower levels of both NAA and Cho were observed in pyrithiamine-treated relative to control rats. In the combined thiamine deficiency + EtOH exposure group, however, levels of Cho were not as low as in the thiamine deficiency group only.…”

“…Lower levels of both NAA and Cho compared with controls are reported in MRS case studies of human WE (Mascalchi et al 2002; Murata et al 2001) and models of thiamine deficiency in rats treated with pyrithiamine hydrochloride (Lee et al 2001; Lee et al 1995; Pfefferbaum et al 2007; Rose et al 1993; Zahr et al 2014a). A reduction in Cho is also seen in patients with cirrhosis of the liver, along with reduced signal from myo-Inositol (mI) and an elevated signal from the combined resonance (Glx) of glutamate (Glu) and glutamine (Gln); typically no effect of liver cirrhosis is observed on NAA levels (Cordoba et al 2001; Geissler et al 1997; Kreis et al 1992; Laubenberger et al 1997; Lee et al 1999; Ross et al 1994).…”

Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF‐kB danger signaling in rat frontal cortex and depressive‐like behavior induced by ethanol binge administration

“…We observed that OEA reduces, not only IL‐1β and TNF‐α, but also MCP‐1 production. This finding may reveal unknown properties of OEA for the treatment of Wernicke's encephalopathy, a neuropsychiatric condition associated with alcoholism, because thiamine (vitamin B1) deficiency, a core element for the disorder, has been correlated with brain levels of MCP‐1 (Zahr et al ), which caused microglia recruitment/activation and exacerbated neurodegeneration (Yang et al ).…”

A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol‐Related Brain Damage

“…Experimental TD in rodents produces up‐regulation of cytokine genes and bioactive protein in vulnerable brain regions, including the thalamus and inferior colliculus (Karuppagounder et al., ; Vemuganti et al., ). Levels of chemokine/cytokine protein together with in vivo measures of pathology also had been determined in TD animal models to establish a relationship between neuroinflammatory and pathology markers (Zahr et al., ). After 12 days of PTD treatment, increased expression of chemokine/cytokine protein concentrations (MCP‐1, tumor necrosis factor‐α [TNF‐α], interleukin‐1β (IL‐1β), IL‐10, IL‐6) was observed in brain regions, such as inferior colliculi, thalamus, hypothalamus, anterior vermis, and hippocampus (Zahr et al., ).…”