Janumpalli S, Butler L S, MacMillan L B, Limbird L E, McNamara J O
Epilepsy Research Laboratory, Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710-3676, USA.
J Neurosci. 1998 Mar 15;18(6):2004-8. doi: 10.1523/JNEUROSCI.18-06-02004.1998.
Norepinephrine serves as a neurotransmitter for a population of neurons the cell bodies of which reside in a brainstem nucleus and the axons of which project widely to discrete subsets of forebrain neurons. Norepinephrine powerfully inhibits epileptogenesis in the kindling model. Pharmacological methods have demonstrated that the antiepileptogenic actions of norepinephrine are exerted via alpha2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three alpha2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual alpha2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the alpha2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the alpha2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the alpha2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the alpha2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.
去甲肾上腺素作为一群神经元的神经递质，这些神经元的细胞体位于脑干核内，其轴突广泛投射到前脑神经元的离散亚群。在点燃模型中，去甲肾上腺素能强烈抑制癫痫发生。药理学方法已证明，去甲肾上腺素的抗癫痫发生作用是通过位于去甲肾上腺素能神经元靶标的α2肾上腺素能受体发挥的。三种α2肾上腺素能受体亚型的存在以及缺乏亚型特异性配体，使得人们难以理解单个α2肾上腺素能受体亚型在去甲肾上腺素抗癫痫发生作用中的作用。基因靶向技术被用于在小鼠基因组中引入α2A肾上腺素能亚型的点突变。该突变显著增强了癫痫发生，并消除了α2肾上腺素能受体拮抗剂咪唑克生的促癫痫发生作用。这些研究揭示了α2A受体亚型在抑制癫痫发生中的关键作用。开发促进α2A受体亚型选择性激活的药物可能为癫痫预防提供新的治疗策略。
