First results on the effect of vincristine on brain glucose and energy metabolism in rats

Abstract

Animal models in experimental medicine should be closely related to human diseases. In gerontopsychiatry the major disease is dementia mostly due to primary degenerative brain process mainly characterized by neurofibrillary tangles. Since animals do not habitually develop such neurofibrillary tangles in an aging process, it would be necessary to produce such morphological variations artificially. Vincristine, the alkaloid from Vinca rosea, may be able to produce neurofibrillary tangles in neurons of animals. It also inhibits the synthesis of RNA in the brain. Since protein biosynthesis is a process consuming large amounts of energy and since in brain energy mainly derives from the oxidation of glucose, the hypothesis was tested as to whether glucose and energy metabolism of the brain might be affected by vincristine and as to whether similarities to pathophysiological variations in dementia patients could be found. The intermediates of glycolysis and the citric acid cycle as well as high-energy phosphates were investigated in the brain cortex of rats after vincristine application for two days and three weeks, respectively. It could be shown that after a two-day application of vincristine the concentration of fructose 1,6-bis(phosphate) was significantly decreased. After a three-week application of vincristine the decrease of fructose 1,6-bis(phosphate) was more pronounced than in the acute experiments and glucose concentration was significantly increased, indicating an inhibition of the enzyme phosphofructokinase controlling flux. Morphologically, a moderate degranulation and disruption of the rough endoplasmic reticulum and a detachment of ribosomes could be found in several parts of the central nervous system. The morphological and biochemical changes in brain cortex after a three-week application of vincristine were associated with behavioral and neurological disturbances. Similarities to changes in cerebral glucose metabolism in patients with primary degenerative dementia could be demonstrated. It is concluded that the vincristine model would be suitable for use in gerontopsychiatric ( i.e. dementia) research.