A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor
A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor
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DOI：
10.1523/jneurosci.2368-07.2007
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发表时间：
2007-09-19
影响因子：
5.3
通讯作者：
Nawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Mizuno, Makoto;Sotoyama, Hidekazu;Nawa, Hiroyuki
与神经炎症过程导致精神分裂症神经病理学的假设一致，精神分裂症患者表皮生长因子（EGF）及其受体ErbB 1的蛋白水平异常。为了评估这种异常的神经病理学意义，我们通过向纹状体给予EGF建立了行为缺陷的动物模型，并评估了环氧化酶-2（考克斯-2）抑制剂塞来昔布的作用。在几种精神分裂症模型中观察到，将EGF颅内输注到成年雄性大鼠的纹状体中激活了ErbB 1并诱导了神经行为障碍。单侧表皮生长因子输注到纹状体降低前脉冲抑制（PPI）的剂量依赖性方式和受损的潜伏期学习的主动休克避免，而不影响基础的学习能力。双侧EGF输注同样影响PPI。与此相反，EGF输注到脑桥核并没有引起行为缺陷。纹状体内EGF输注也增加了考克斯-2的表达，酪氨酸羟化酶活性升高，并上调多巴胺及其代谢产物的水平。塞来昔布亚慢性给药（10 mg/kg，p.o.）改善PPI和潜伏学习的异常以及正常的多巴胺代谢。我们的结论是，这种EGF触发的神经炎症过程介导的部分考克斯-2活性和干扰多巴胺代谢产生神经行为异常。
Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.