RESUMEN
At present, thiamine deficiency (TD) is managed with administration of high doses of thiamine. Even so, severe and permanent neurological disorders can occur in recurrent episodes of TD. In this study, we used a murine model to assess the efficacy of TD recovery treatments using thiamine with or without additional administration of the antioxidant Trolox or the anti-inflammatory dimethyl sulfoxide (DMSO) after a single or recurrent episode of TD. TD was induced for 9 days with deficient chow and pyrithiamine, and the recovery period was 7 days with standard amounts of chow and thiamine, Trolox, and/or DMSO. After these periods, we evaluated behavior, histopathology, and ERK1/2 modulation in the brain. Deficient animals showed reductions in locomotor activity, motor coordination, and spatial memory. Morphologically, after a single episode of TD and recovery, deficient mice showed neuronal vacuolization in the dorsal thalamus and, after two episodes, a reduction in neuronal cell number. These effects were attenuated or reversed by the recovery treatments, mainly in the treatments with thiamine associated with Trolox or DMSO. Deficient animals showed a strong increase in ERK1/2 phosphorylation in the thalamus, hippocampus, and cerebral cortex after one deficiency episode and recovery. Interestingly, after recurrent TD and recovery, ERK1/2 phosphorylation remained high only in the deficient mice treated with thiamine and/or Trolox or thiamine with DMSO. Our data suggest that a protocol for TD treatment with thiamine in conjunction with Trolox or DMSO enhances the recovery of animals and possibly minimizes the late neurological sequelae.
Asunto(s)
Cromanos/farmacología , Dimetilsulfóxido/farmacología , Deficiencia de Tiamina/tratamiento farmacológico , Tiamina/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Cromanos/administración & dosificación , Dimetilsulfóxido/administración & dosificación , Modelos Animales de Enfermedad , Locomoción/efectos de los fármacos , Masculino , Ratones , Recurrencia , Memoria Espacial/efectos de los fármacosRESUMEN
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.