a Department of Anesthesiology , The Third Hospital of HeBei Medical University , Shijiazhuang , HeBei Province , China.
b Department of Pharmacology , HeBei Medical University , Shijiazhuang , HeBei Province , China.
Pharm Biol. 2017 Dec;55(1):2188-2195. doi: 10.1080/13880209.2017.1392987.
The effects of the anticancer drug paclitaxel on learning and memory are rarely studied.
This study investigated changes in GABA receptor expression during paclitaxel-induced apoptosis of hippocampal neurons and the role of the p38MAPK/NF-κB pathway in this process.
Hippocampal neurons isolated from neonatal Sprague-Dawley rats were divided into six groups: Control (C), SB (10 µL of 10-µmol/L SB203580), SN (53 µg/mL SN50), N (1 µmol/L paclitaxel), SB + N (10 µmol/L SB203580 + 1 µmol/L paclitaxel) and SN + N (53 µg/mL SN50 + 1 µmol/L paclitaxel). Cells in different groups were treated with corresponding agents for 24 h at 37 °C. The apoptosis rate and protein levels of GABA receptors and NF-κB p65 were evaluated. Rat models of neuropathic pain was induced by paclitaxel and were divided into four groups such as N, B + N, SN + N and SN + B + N groups. Rats in the N group received intrathecal injections of normal saline solution. Rats in the B + N group received intrathecal injections of 10 μL baclofen (0.05 μg/μL). Rats in the SN + N and SN + B + N groups received intrathecal injections of SN50 and SN50 plus baclofen, respectively. Spatial learning and memory were evaluated in rat models based on the escape latency and the number of crossings over the platform and protein levels of GABA receptors, NF-κB, IL-1β and TNFα were measured by immunohistochemistry assay and western blot.
The neuronal apoptosis rate was significantly increased in N (49.16 ± 3.12)%, SB + N (31.18 ± 3.02)% and SN + N (28.47 ± 3.75)% groups, accompanied by increased levels of GABA receptors and NF-κB p65 (p < 0.05). The paclitaxel-treated rats demonstrated significantly increased latency (24.32 ± 2.94)s and decreased the crossings number (3.14 ± 0.63) after 15 d in the Morris water maze (p < 0.05). Immunohistochemistry assay showed that compared with the N group (GABA9.0 ± 1.6, NF-κB p65:29.6 ± 2.4, IL-1β: 30.4 ± 3.4, TNFα: 31.0 ± 3.4), B + N, SN + N and SN + B + N groups evidently increased levels of GABA receptor (B + N:SN + N:SN + B + N = 19.4 ± 2.1:20.8 ± 1.9:28.0 ± 1.9) but significantly decreased levels of NF-κB p65 (B + N:SN + N:SN + B + N = 21.2 ± 1.5:18.6 ± 2.1:12.6 ± 1.5), IL-1β (B + N:SN + N:SN + B + N = 22.0 ± 1.0:19.6 ± 1.8:14.6 ± 1.5) and TNF α (B + N:SN + N:SN + B + N = 23.0 ± 1.6:22.2 ± 0.8:16.6 ± 1.7). Similar findings were found in western blot analysis.
Paclitaxel may reduce cognitive function in rats through the p38MAPK/NF-κB pathway and GABA receptors.
紫杉醇对学习和记忆的影响很少被研究。
本研究探讨了紫杉醇诱导海马神经元凋亡过程中 GABA 受体表达的变化，以及 p38MAPK/NF-κB 通路在此过程中的作用。
将分离的新生 Sprague-Dawley 大鼠海马神经元分为六组：对照组（C）、SB（10μL 的 10-μmol/L SB203580）、SN（53μg/mL SN50）、N（1μmol/L 紫杉醇）、SB+N（10μmol/L SB203580+1μmol/L 紫杉醇）和 SN+N（53μg/mL SN50+1μmol/L 紫杉醇）。不同组的细胞在 37°C 下用相应的药物处理 24 小时。评估细胞凋亡率和 GABA 受体和 NF-κB p65 的蛋白水平。通过紫杉醇诱导大鼠神经病理性疼痛模型，并将其分为 N、B+N、SN+N 和 SN+B+N 组。N 组大鼠鞘内注射生理盐水。B+N 组大鼠鞘内注射 10μL 巴氯芬（0.05μg/μL）。SN+N 和 SN+B+N 组大鼠分别鞘内注射 SN50 和 SN50 加巴氯芬。通过逃避潜伏期和穿越平台的次数评估大鼠模型的空间学习和记忆，并通过免疫组织化学和 Western blot 测定 GABA 受体、NF-κB、IL-1β 和 TNFα 的蛋白水平。
N（49.16±3.12）%、SB+N（31.18±3.02）%和 SN+N（28.47±3.75）%组神经元凋亡率显著增加，同时 GABA 受体和 NF-κB p65 水平升高（p<0.05）。紫杉醇处理大鼠在 Morris 水迷宫中潜伏期（24.32±2.94）s 显著延长，穿越次数（3.14±0.63）减少，15 天后差异有统计学意义（p<0.05）。免疫组织化学检测显示，与 N 组（GABA9.0±1.6，NF-κB p65：29.6±2.4，IL-1β：30.4±3.4，TNFα：31.0±3.4）相比，B+N、SN+N 和 SN+B+N 组 GABA 受体水平显著升高（B+N：SN+N：SN+B+N=19.4±2.1：20.8±1.9：28.0±1.9），而 NF-κB p65 水平显著降低（B+N：SN+N：SN+B+N=21.2±1.5：18.6±2.1：12.6±1.5），IL-1β（B+N：SN+N：SN+B+N=22.0±1.0：19.6±1.8：14.6±1.5）和 TNFα（B+N：SN+N：SN+B+N=23.0±1.6：22.2±0.8：16.6±1.7）。Western blot 分析也得到了相似的结果。
紫杉醇可能通过 p38MAPK/NF-κB 通路和 GABA 受体降低大鼠的认知功能。
