Pathophysiological significance of inducible histamine in the brain.

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We previously reported that cells other than mast cells or neurons could synthesize histamine in response to lipopolysaccharide (LPS) or interleukin 1β in the rat brain. To identify the responsible cells, we examined histidine decarboxylase (HDC) activity and the expression of HDC mRNA in GMI6-3 mouse microglial cells. Both the activity and mRNA for HDC in GMI6-3 cells were induced by LPS treatment, and the induction was sensitive to calmodulin-dependent kinase II inhibitor, KN62. These findings indicate that microglia is a third cell type producing histamine in the brain.On the physiological significance of the brain histamine, we newly fond that (1) leptin injection significantly reduced food intake but not in H1-receptor knock out mice, (2) histamine release from the rat anterior hypothalamus was significantly increased by leptin, (3) leptin had no effect on histamine release in rats whose chorda tympani nerves were transected bilaterally. The findings clearly indicate that leptin, an anorectic hormone activates the histaminergic system by the peripheral signal inputs via the chorda tympani resulting in the suppression of food intake through histamine H1-receptors. Although the primary responsible cell on this effect is histaminergic neuronal cell, the microglial inducible histamine might have some anorectic effects through the above mentioned pathway in the course of inflammation.Finally, we are investigating the pathophysiological roles of the inducible histaine on blood-brain-barrier distraction