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

Abstract

Background Alcohol‐related brain damage (ARBD) is associated with neurotoxic effects of heavy alcohol use and nutritional deficiency, in particular thiamine deficiency (TD), both of which induce inflammatory responses in brain. Although neuroinflammation is a critical factor in the induction of ARBD, few studies have addressed the specific contribution(s) of ethanol (EtOH) versus TD. Methods Adult rats were randomly divided into 6 conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH for 6 months; CET with injections of thiamine (CET + T); severe pyrithiamine‐induced TD (PTD); moderate PTD; moderate PTD during CET; and pair‐fed controls. After the treatments, the rats were split into 3 recovery phase time points: the last day of treatment (time point 1), acute recovery (time point 2: 24 hours posttreatment), and delayed recovery (time point 3: 3 weeks posttreatment). At these time points, vulnerable brain regions (thalamus, hippocampus, frontal cortex) were collected and changes in neuroimmune markers were assessed using a combination of reverse transcription polymerase chain reaction and protein analysis. Results CET led to minor fluctuations in neuroimmune genes, regardless of the structure being examined. In contrast, PTD treatment led to a profound increase in neuroimmune genes and proteins within the thalamus. Cytokine changes in the thalamus ranged in magnitude from moderate (3‐fold and 4‐fold increase in interleukin‐1β [IL‐1β] and IκBα) to severe (8‐fold and 26‐fold increase in tumor necrosis factor‐α and IL‐6, respectively). Though a similar pattern was observed in the hippocampus and frontal cortex, overall fold increases were moderate relative to the thalamus. Importantly, neuroimmune gene induction varied significantly as a function of severity of TD, and most genes displayed a gradual recovery across time. Conclusions These data suggest an overt brain inflammatory response by TD and a subtle change by CET alone. Also, the prominent role of TD in the immune‐related signaling pathways leads to unique regional and temporal profiles of induction of neuroimmune genes.

The Effect of Chronic Ethanol Exposure and Thiamine Deficiency on Myelin‐related Genes in the Cortex and the Cerebellum

“…In Experiment 2 ( n = 145), as previously described (Toledo Nunes et al, 2019), the rats were randomly divided into 3 recovery phase time points after which they were euthanized: T1 during the final treatment day, T2 during acute recovery (24 h posttreatment), and T3 during delayed recovery (3 weeks posttreatment). Levels of gene expression recorded at T1 reflect alterations during the active treatment or intoxication condition, whereas levels of gene expression recorded at T2 reflect how acute withdrawal contributes to alterations in gene expression.…”

“…KS is caused by severe thiamine deficiency, most often associated with chronic alcohol abuse, and can lead to both unrecoverable brain damage and behavioral dysfunction (Arts et al, 2017; Kopelman et al, 2009; Kril and Harper, 2012; Phillips et al, 1990). KS has been replicated using animal models through a variety of treatments, including chronic EtOH treatment (CET), a thiamine‐deficient diet alone or combined with CET, a thiamine‐deficient diet combined with injections of pyrithiamine, called pyrithiamine‐induced thiamine deficiency (PTD), and a combination of CET and PTD (Pires et al, 2005; Toledo Nunes et al, 2019; Vedder et al, 2015).…”

“…The effects of prolonged EtOH consumption and thiamine deficiency on the brain are complex (Alfonso‐Loeches et al, 2012; Fernandez‐Lizarbe et al, 2013; Toledo Nunes et al, 2019; Vedder et al, 2015). Several preclinical studies have revealed that exposure to severe EtOH alone or combined with thiamine deficiency leads to white matter damage in the cortex and the cerebellum.…”

“…Several preclinical studies have revealed that exposure to severe EtOH alone or combined with thiamine deficiency leads to white matter damage in the cortex and the cerebellum. Neuroinflammation is a critical mechanism associated with alcohol‐related brain damage and has been suggested to participate in the myelin and white matter disruptions observed after prolonged heavy alcohol consumption (Alfonso‐Loeches et al, 2012; Toledo Nunes et al, 2019).…”

Thiamine Alleviates Cognitive Impairment and Epileptogenesis by Relieving Brain Inflammation in PTZ-induced Kindling Rat Model

“…Remarkably, thiamine de ciency led to increased concentrations of cytokines such as TNF-α and IL-1β in brain regions including the cortex and hippocampus (Zahr et al 2014;Toledo Nunes et al 2019). This suggests that there may be an interaction between thiamine de ciency and seizure formation in an epileptic brain.…”