Breakdown of the blood brain barrier and the subsequent accumulation of
free radicals,
lactate, and
glutamate appear to be the immediate causes of
thiamine deficiency (TD)-induced damage to thalamus. The mechanisms triggering these events are unknown but recent evidence suggests an important role of
histamine. We therefore studied the effects of
histamine depletion on thalamic lesions in the
pyrithiamine-induced
thiamine deficient (PTD) rat. Chronic intracerebroventricular (i.c.v., 7 days) infusion of
alpha-fluoromethylhistidine (FMH), combined with bilateral ibotenate destruction of the
histamine-containing neurons in the tuberomammillary (TM) nucleus and bolus i.c.v. infusion of 48/80, a potent mast cell degranulating agent, was used to deplete brain
histamine levels. PTD rats receiving combined FMH + 48/80 + TM lesions developed acute neurological symptoms, including spontaneous
seizures, approximately 1 day earlier than PTD rats treated with i.c.v. infusion of vehicle and
sham lesions of the TM. When examined 1 week after restoration of
thiamine, the PTD vehicle +
sham lesion animals contained severe neuronal loss and
gliosis in midline, intralaminar, ventral, lateral, and posterior nuclei. PTD animals treated with FMH + 48/80 + TM lesions had little evidence of neuronal loss or microglial proliferation in thalamus except in the gelatinosus and anteroventral nuclei, in which there was complete neuronal loss. These data demonstrate a significant and regionally selective role of
histamine in the development of thalamic lesions in a rat model of
Wernicke's encephalopathy. Furthermore, these data suggest either a dissociation between
seizures and thalamic lesions or a significant role of
histamine in seizure-related damage to the thalamus.