Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8, Canada; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8, Canada.
Psychoneuroendocrinology. 2019 Jun;104:42-48. doi: 10.1016/j.psyneuen.2019.01.029. Epub 2019 Feb 1.
Second generation antipsychotic (AP)s remain the gold-standard treatment for schizophrenia and are widely used on- and off-label for other psychiatric illnesses. However, these agents cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for whole body energy regulation, and disruptions in energy sensing (e.g. insulin signaling) and inflammation in this brain region have been implicated in the development of insulin resistance and obesity. To elucidate mechanisms by which APs may be causing metabolic dysregulation, we explored whether these agents can directly impact energy sensing and inflammation in hypothalamic neurons.
The rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine (0.25-100 uM), clozapine (2.5-100 uM) or aripiprazole (5-20 uM). Western blots measured the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3β), and components of the MAPK pathway (ERK1/2, JNK, p38). Quantitative real-time PCR was performed to determine changes in the mRNA expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor (BDNF).
Olanzapine (100 uM) and clozapine (100, 20 uM) significantly increased pERK1/2 and pJNK protein expression, while aripiprazole (20 uM) only increased pJNK. Clozapine (100 uM) and aripiprazole (5 and 20 uM) significantly increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited insulin-induced phosphorylation of AKT. Olanzapine (100 uM) treatment caused a significant increase in IL-6 while aripiprazole (20 uM) significantly decreased IL-10. Olanzapine (100 uM) and aripiprazole (20 uM) increased BDNF expression.
We demonstrate that antipsychotics can directly regulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK activation by all antipsychotics, alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of pro-inflammatory pathways. Clozapine and aripiprazole inhibition of insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic energy sensor) suggests impaired insulin action and energy sensing. Conversely, olanzapine and aripiprazole increased BDNF, which would be expected to be metabolically beneficial. Overall, our findings suggest differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing.
第二代抗精神病药物（APs）仍然是精神分裂症的金标准治疗方法，并且广泛用于其他精神疾病的标签外和标签内治疗。然而，这些药物会导致严重的代谢副作用。下丘脑是负责全身能量调节的主要脑区，该脑区的能量感应（例如胰岛素信号）和炎症的破坏与胰岛素抵抗和肥胖的发展有关。为了阐明 APs 可能引起代谢失调的机制，我们探讨了这些药物是否可以直接影响下丘脑神经元的能量感应和炎症。
用奥氮平（0.25-100μM）、氯氮平（2.5-100μM）或阿立哌唑（5-20μM）处理大鼠下丘脑神经元细胞系 rHypoE-19。Western blot 测定能量感应蛋白 AMPK、胰岛素信号通路的组成部分（AKT、GSK3β）和 MAPK 通路的组成部分（ERK1/2、JNK、p38）。实时定量 PCR 用于确定白细胞介素（IL）-6、IL-10 和脑源性神经营养因子（BDNF）的 mRNA 表达变化。
奥氮平（100μM）和氯氮平（100、20μM）显著增加了 pERK1/2 和 pJNK 蛋白表达，而阿立哌唑（20μM）仅增加了 pJNK。氯氮平（100μM）和阿立哌唑（5 和 20μM）显著增加了 AMPK 磷酸化（一种食欲促进的能量传感器），并抑制了胰岛素诱导的 AKT 磷酸化。奥氮平（100μM）处理导致 IL-6 显著增加，而阿立哌唑（20μM）显著降低了 IL-10。奥氮平（100μM）和阿立哌唑（20μM）增加了 BDNF 的表达。
我们证明抗精神病药可以直接调节下丘脑神经元中的胰岛素、能量感应和炎症途径。所有抗精神病药都会增加 MAPK 激活，奥氮平相关的 IL-6 增加，阿立哌唑相关的 IL-10 减少，提示促炎途径的诱导。氯氮平和阿立哌唑抑制胰岛素刺激的 pAKT 和 AMPK 磷酸化（一种食欲促进的能量传感器）增加，表明胰岛素作用和能量感应受损。相反，奥氮平与阿立哌唑增加了 BDNF，这有望在代谢上带来益处。总体而言，我们的发现表明抗精神病药对下丘脑神经炎症和能量感应有不同的影响。
