Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
J Pharmacol Sci. 2019 Jul;140(3):263-272. doi: 10.1016/j.jphs.2019.07.015. Epub 2019 Aug 8.
Atypical antipsychotics improve positive and negative symptoms but are not effective for treating cognitive impairments in patients with schizophrenia. We previously reported that cognitive impairments in neonatal ventral hippocampus (NVH)-lesioned rats show resistance to atypical antipsychotics risperidone and are associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) signaling in memory-related regions. The cognitive enhancer ST101 (spiro[imi-dazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) stimulates CaMKII activity in the hippocampus and medial prefrontal cortex (mPFC). We thus tested ST101 on cognitive impairments in NVH-lesioned rats. Chronic ST101 administration (0.1 and/or 0.5 mg/kg, p.o.) significantly improved deficits in prepulse inhibition (PPI), social interaction, and cognitive function in NVH-lesioned rats. ST101 administration (0.5 mg/kg, p.o.) significantly restored the decreased CaMKII autophosphorylation (Thr-286) in the mPFC and hippocampal CA1 regions of NVH-lesioned rats when assessed by immunohistochemistry. Chronic ST101 administration (0.1 mg/kg, p.o.) improved the decline in phosphorylation levels of CaMKII (Thr-286), PKCα (Ser-657), α-amino-3-hydroxy-5-methyl-4-isoxazol- propionic acid (AMPA)-type glutamate receptor subunit 1 (GluA1: Ser-831), and N-methyl-d-aspartate (NMDA) receptor subunit 1 (GluN1: Ser-896) in the mPFC and hippocampal CA1 regions. Taken together, these results suggest that ST101 improves schizophrenia-like behaviors and cognitive impairment by enhancing CaMKII/PKCα signaling in the mPFC and hippocampus in NVH-lesioned rats.
非典型抗精神病药可改善阳性和阴性症状，但对治疗精神分裂症患者的认知障碍无效。我们之前报道过，新生大鼠腹侧海马（NVH）损伤模型的认知障碍对非典型抗精神病药利培酮具有抗性，并且与记忆相关区域中钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）和蛋白激酶 C（PKC）信号转导减少有关。认知增强剂 ST101（螺[咪唑并[1,2-a]吡啶-3,2-茚]-2(3H)-酮）可刺激海马体和内侧前额叶皮层（mPFC）中的 CaMKII 活性。因此，我们在 NVH 损伤大鼠中测试了 ST101 对认知障碍的影响。慢性 ST101 给药（0.1 和/或 0.5mg/kg，po）可显著改善 NVH 损伤大鼠的前脉冲抑制（PPI）、社会交往和认知功能缺陷。ST101 给药（0.5mg/kg，po）通过免疫组织化学法显著恢复了 NVH 损伤大鼠 mPFC 和海马 CA1 区 CaMKII 自磷酸化（Thr-286）的降低。慢性 ST101 给药（0.1mg/kg，po）可改善 mPFC 和海马 CA1 区 CaMKII（Thr-286）、PKCα（Ser-657）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体亚基 1（GluA1：Ser-831）和 N-甲基-D-天冬氨酸（NMDA）受体亚基 1（GluN1：Ser-896）磷酸化水平的下降。综上所述，这些结果表明 ST101 通过增强 NVH 损伤大鼠 mPFC 和海马体中的 CaMKII/PKCα 信号转导，改善了类似精神分裂症的行为和认知障碍。
