Paraquat Increases Interleukin-1β in Hippocampal Dentate Gyrus to Impair Hippocampal Neurogenesis in Adult Mice

Ecotoxicol Environ Saf. 2020 Sep 1;200:110733. doi: 10.1016/j.ecoenv.2020.110733. Epub 2020 May 22.

Abstract

Paraquat (1,1'-dimethyl-4,4'-bipyridium dichloride, PQ), a non-selective and efficient herbicide, causes neuroinflammation, neurodegeneration and memory dysfunction. However, adverse effects of PQ on the neuroimmune interactions have rarely been investigated. Female adult C57/BL6 mice were divided into 3 groups and treated with PQ (intraperitoneal injection, 1 mg/kg or 5 mg/kg) or the vehicle (an equivalent volume of 0.9% saline) every two days, at day 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, for a total of 14 doses. We evaluated blood-brain barrier (BBB) integrity and PQ concentrations during the course of PQ exposure and tested interleukin-1β (IL-1β) concentrations in dentate gyrus (DG) after 28 days PQ exposure. In addition, memory function, neural stem cells (NSCs) proliferation, neurogenesis and microglia polarization were analyzed after PQ exposure. Furthermore, mice were intraperitoneal injections of anti-IL-1β during 5 mg/kg PQ exposure to test the rule of IL-1β. Blood-brain barrier (BBB) permeability and PQ concentrations increased gradually during PQ exposure (n = 6). Moreover, memory function, NSCs proliferation and neurogenesis were impaired after 5 mg/kg PQ exposure (n = 6). Further analyses revealed that 'classically' activated (M1) microglia and IL-1β concentrations in DG were increased after 5 mg/kg PQ treatment (n = 6). Moreover, we found that neutralization of IL-1β partly restored PQ-induced NSCs impairments and memory dysfunction (n = 6). In conclusion, our results revealed that PQ induced NSCs impairments and memory dysfunction in adult mice, which was related to the release of IL-1β by M1-polarized microglia in DG. These findings may help understand the neurotoxic effect of PQ.

Keywords: Hippocampal dentate gynus; Interleukin-1β; Memory; Neural stem cells; Neurogenesis; Paraquat.