ERK1/2 modulation in the central nervous system of male and female thiamine-deficient mice with amprolium.

Thiamine deficiency experimental models focus on using the pyrithiamine analog in male rodents, making the thiamine deficiency effects in females and the use of other thiamine antagonists, such as amprolium, unknown. We investigated the impact of thiamine deficiency with amprolium in the cerebral cortex and thalamus of male and female mice by evaluating the modulation of ERK1/2 phosphorylation. The animals were exposed for 20 days to thiamine-deficient chow with different doses of amprolium (20, 40, 60 and 80 mg/kg) and at different treatment periods (five, 10, 15 or 20 days) at a dose of 60 mg/kg. After treatments, ERK1/2 phosphorylation was analyzed by western blot. In male mice, we observed a progressive increase in ERK1/2 phosphorylation in both the cerebral cortex and thalamus in response to the dose of amprolium. In females, ERK1/2 phosphorylation did not progressively increase in response to the amprolium dosage. However, an increase in phosphorylation at the higher doses of 60 and 80 mg/kg was observed. We observed a more intense increase in ERK1/2 phosphorylation in males' cerebral cortex and thalamus from 10 days onwards. In females, the ERK1/2 modulation profiles were similar. The results show that thiamine deficiency induction with amprolium is efficient, compatible with other recognized models that use pyrithiamine, showing changes in cell signaling in the nervous system. The study showed differences in response to thiamine deficiency with amprolium between male and female mice in relation to ERK1/2 phosphorylation and demonstrated that females respond positively to the method and can also be used as model animals.

Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes.

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.

Role of astrocytes in thiamine deficiency.

Thiamine deficiency (TD) is the underlying cause of Wernicke's encephalopathy (WE), an acute neurological disorder characterized by structural damage to key periventricular structures in the brain. Increasing evidence suggests these focal histological lesions may be representative of a gliopathy in which astrocyte-related changes are a major feature of the disorder. These changes include a loss of the glutamate transporters GLT-1 and GLAST concomitant with elevated interstitial glutamate levels, lowered brain pH associated with increased lactate production, decreased levels of GFAP, reduction in the levels of glutamine synthetase, swelling, alterations in levels of aquaporin-4, and disruption of the blood-brain barrier. This review focusses on how these manifestations contribute to the pathophysiology of TD and possibly WE.

Spatial memory deficits and thalamic serotonergic metabolite change in thiamine deficient rats.

The purposes of the present study were to verify the effects of a severe thiamine deficiency episode on spatial cognitive aspects and thalamic serotonergic parameters. The animals were submitted to a severe thiamine deficiency treatment that was interrupted after the onset of the last neurological signs. The results obtained confirm previous findings about TD deficiency effects on cognitive function and, further show that this vitamin increases the thalamic serotonine metabolite, 5-hidroxyindolacetic acid (5-HIAA), level. In addition, the present data shed light on the importance of this metabolite in spatial cognitive function.