ABSTRACT
Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.
Subject(s)
Brain/metabolism , Heme Oxygenase-1/metabolism , Membrane Proteins/metabolism , Thiamine Deficiency/physiopathology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Behavior, Animal/physiology , Body Weight/physiology , Brain/pathology , Cell Survival/physiology , Chromans/pharmacology , Dimethyl Sulfoxide/pharmacology , Eating/physiology , Inflammation/etiology , Inflammation/physiopathology , Male , Mice , Neuroprotective Agents/pharmacology , Oxidative Stress/physiology , Pyrithiamine , Thiamine Deficiency/chemically induced , Thiamine Deficiency/complications , Thiamine Deficiency/pathologyABSTRACT
BACKGROUND: Thiamine deficiency (TD) models have been developed, mainly using the thiamine analog pyrithiamine. Other analogs have not been used in rodents. We aimed to evaluate the effects and mechanisms of intraperitoneal (ip) amprolium-induced TD in mice. We also evaluated the associated pathogenesis using antioxidant and anti-inflammatory compounds (Trolox, dimethyl sulfoxide). METHODS: Male mice were separated into two groups, one receiving a standard diet (control animals), and the other a TD diet (deficient groups) for 20 days. Control mice were further subdivided into three groups receiving daily ip injections of saline (NaCl 0.9%; Cont group), Tolox (Tr group) or dimethyl sulfoxide (DMSO; Dmso group). The three TD groups received amprolium (Amp group), amprolium and Trolox (Amp+Tr group), or amprolium and DMSO (Amp+Dmso group). The animals were subjected to behavioral tests and then euthanized. The brain and viscera were analyzed. RESULTS: Amprolium exposure induced weight loss with hyporexia, reduced the behavioral parameters (locomotion, exploratory activity, and motor coordination), and induced changes in the brain (lower cortical cell viability) and liver (steatosis). Trolox co-treatment partially improved these conditions, but to a lesser extent than DMSO. CONCLUSIONS: Amprolium-induced TD may be an interesting model, allowing the deficiency to develop more slowly and to a lesser extent. Amprolium exposure also seems to involve oxidative stress and inflammation, suggested as the main mechanisms of cell dysfunction in TD.
