Pathophysiological significance of inducible histamine in the brain.

我们以前报道过，除了肥大细胞和神经元外，大鼠脑中的其他细胞也可以合成组胺，以响应脂多糖（LPS）或白细胞介素1β。为了鉴定负责细胞，我们检测了GMI6-3小鼠小胶质细胞中组氨酸脱羧酶（HDC）的活性和HDC mRNA的表达。LPS可诱导GMI6-3细胞中HDC的活性和mRNA表达，且对钙调素依赖性激酶II抑制剂KN62敏感。这些发现表明，小胶质细胞是大脑中产生组胺的第三种细胞类型。关于脑组胺的生理意义，我们最近发现(1)瘦素注射能显著减少食物摄取量，但在h1受体敲除小鼠中没有作用；(2)瘦素能显著增加大鼠下丘脑前部的组胺释放；(3)在双侧横断鼓室索神经的大鼠中，瘦素对组胺释放没有影响。研究结果清楚地表明，瘦素是一种厌食激素，通过外周信号输入，通过鼓室索激活组胺能系统，从而通过组胺h1受体抑制食物摄入。虽然这种作用的主要负责细胞是组胺能神经元细胞，但在炎症过程中，小胶质诱导的组胺可能通过上述途径具有一定的厌食作用。最后，我们正在研究诱导组蛋白在血脑屏障分散中的病理生理作用

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