Pathophysiological significance of inducible histamine in the brain.

我们以前报道过，除了肥大细胞或神经元以外，大鼠脑内的细胞也能合成组胺，以响应脂多糖（LPS）或白细胞介素1β（IL 1β）。为了鉴定责任细胞，我们检测了GMI 6 -3小鼠小胶质细胞中组氨酸脱羧酶（HDC）活性和HDC mRNA的表达。LPS诱导GM 16 -3细胞HDC的活性和mRNA表达，并且这种诱导对钙调素依赖性激酶II抑制剂KN 62敏感。这些结果表明，小胶质细胞是脑内产生组胺的第三种细胞类型，在脑组织组胺的生理意义方面，我们新发现：（1）瘦素注射显著减少摄食，但在H1受体敲除小鼠中无此作用;（2）瘦素显著增加大鼠下丘脑前部组胺的释放，（3）瘦素对双侧鼓索神经切断大鼠组胺释放无影响。研究结果清楚地表明，瘦素，厌食激素激活组胺能系统的外周信号输入通过鼓索，导致抑制食物摄入通过组胺H1受体。虽然这一作用的主要负责细胞是组胺能神经元细胞，但小胶质细胞诱导的组胺可能通过上述途径在炎症过程中发挥一定的厌食作用。最后，我们研究了诱导组胺在血脑屏障牵张中的病理生理作用

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