Regional Susceptibility to ER Stress and Protection by Salubrinal Following a Single Exposure to Deltamethrin.

Endoplasmic reticulum (ER) stress is a significant contributor to neurodegeneration and cognitive dysfunction. Recently, we reported that repeated exposure to the pyrethroid insecticide deltamethrin caused ER stress in the hippocampus of adult mice, which was accompanied by deficits in learning (Hossain et al., 2015). Here, we investigated regional susceptibility to ER stress and the ability of salubrinal, an inhibitor of ER stress, to reduce apoptosis following a single oral administration of deltamethrin (6 mg/kg). Deltamethrin significantly increased the ER stress marker C/EBP-homologous protein (CHOP) in the hippocampus by 148% at 24 and 48 h compared with age-matched controls. In contrast, CHOP was increased by 146% in the frontal cortex only at 48 h after deltamethrin exposure. Similarly, the level of GRP-78 was increased by 314% and 262% in the hippocampus at 24 and 48 h, whereas the same factors were increased by 178% at 24 h and 139% at 48 h in the frontal cortex. These changes were accompanied by increased levels of activated caspase-12, caspase-3, and TUNEL-positive cells in both brain regions, with the hippocampus showing a more robust response. Pre-treatment of mice with the eIf2α inhibitor salubrinal prevented deltamethrin-induced caspase-3 activation and attenuated the number of TUNEL-positive cells. These data demonstrate that the hippocampus appears to be particularly vulnerable to deltamethrin exposure in adult animals, which may contribute to observed effects of deltamethrin on cognitive function.