Role of GABAB receptors and p38MAPK/NF-κB pathway in paclitaxel-induced apoptosis of hippocampal neurons

Abstract

Context: The effects of the anticancer drug paclitaxel on learning and memory are rarely studied. Objective: This study investigated changes in GABAB receptor expression during paclitaxel-induced apoptosis of hippocampal neurons and the role of the p38MAPK/NF-κB pathway in this process. Materials and methods: 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 GABAB1 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 GABAB1 receptors, NF-κB, IL-1β and TNFα were measured by immunohistochemistry assay and western blot. Results: 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 GABAB1 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 (GABAB1:9.0 ± 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 GABAB1 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. Discussions and conclusions: Paclitaxel may reduce cognitive function in rats through the p38MAPK/NF-κB pathway and GABAB1 receptors.