Neurological diseases are quite varied and have a great economic impact on
livestock. Central nervous system (CNS) disorders may be caused by various
etiologic agents, such as biological agents and by metabolic disorders. In this case,
we highlight the polioencephalomalacia (PEM) triggered by thiamine deficiency
(vitamin B1). PEM has been described in several regions of Brazil, involving cattle,
sheep and goats. However, thiamine deficiency is important also for carnivores
(Chastek's palsy) and humans (Wernicke disease and Wernicke-Korsakoff
syndrome). The CNS regions involved in PEM are varied and contradictory, but are
affected from cortical areas to deep regions such as the midbrain and thalamus. At
these sites, there is typically neuronal degeneration and necrosis, with adjacent
involvement of astrocytic and inflammatory changes. Little is known about the
molecular and cellular mechanisms of degeneration and death of neurons. However,
it is considered that the process related to thiamine deficiency is initiated by
metabolic defects in the mitochondria with consequent establishment of oxidative
stress. In the present work, we aimed to determine different parameters related to
thiamine deficiency in the CNS in an in vivo model to evaluate the occurrence of cell
death and the molecular mechanisms involved, association of behavioral changes
and the design of efficient neuroprotective strategies, characterizing the CNS areas
involved in thiamine deficiency-induced degeneration. The model of dietary
deficiency in combination with injections of the thiamine antagonist, amprolium, was
used in the present study. The animals were treated for 15 or 20 days and divided
into 6 treatment groups: control (cont), amprolium (Amp), amprolium and Trolox®
(Amp+Tr), amprolium and DMSO (Amp+Dmso), Trolox®
(Tr) and DMSO (Dmso).
Mice subjected to the thiamine deficiency model (Amp) exhibited a significant
reduction in body weight gain after 15 and 20 days of treatment. The
histopathological analysis revealed in the Amp group, centrolobular hepatic steatosis
at 15-day and diffuse hepatic steatosis when treated for 20 days, in addition to
moderate proteinuria. Trolox®
and DMSO markedly attenuated steatosis (Amp+Tr
and Amp+Dmso groups). No histological changes were observed in the CNS within
15 or 20 days of treatment. However, the cellular viability of the cerebral cortex
significantly reduced in the Amp group after 20 days of treatment; which effect was
reversed in the Amp+Tr and Amp+Dmso groups. In addition, deficient animals (Amp)
presented behavioral changes such as reduction in ambulation and exploratory
activities and in motor coordination and, interestingly, Trolox®
and DMSO attenuated
these effects. These data suggest that in the model of thiamine deficiency with
amprolium the animals develop neurological and metabolic alterations, associated
with oxidative stress and possibly inflammation. In addition, the model proves
feasible for the study of vitamin deficiency with the establishment of a gradual
progressive process, without being markedly aggressive, as in the classic model of
pyrithiamine.
|
