Trifluoroacetic Acid Induced a Cyclophilin D-Dependent Cognitive Impairment in Mice.

Abstract

Studies have linked inhalation anesthesia and surgery to increased cognitive impairment, particularly in the elderly. Our previous research showed that isoflurane, but not desflurane, affected cognitive function in mice by modulating cyclophilin D (CypD), a key regulator of the mitochondrial permeability transition pore (mPTP) and mitochondrial function. Both anesthetics metabolize into trifluoroacetic acid (TFA), which is associated with cognitive deficits. However, the specific role of CypD in the TFA-induced mitochondrial dysfunction and cognitive impairments is unclear. This study aims to explore the interaction between TFA, CypD, and cognitive function in neurons and mice. TFA was administered to 2-3-month-old wild-type (WT) and CypD knockout (KO) female and male mice at 120 μg/kg and to primary cultured neurons from these mice at 10 μM. Immunofluorescence staining and Western blot analyses assessed the impact of TFA on the levels of CypD, voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), reactive oxygen species (ROS), and caspase-3 activation in neurons, along with cognitive function assessments in mice. The data from the present study demonstrated cognitive impairments in mice following TFA treatment. Elevated CypD and ROS levels were observed post-TFA exposure, alongside the TFA-induced caspase-3 activation in WT neurons and mice. Notably, the absence of CypD significantly mitigated these effects. The findings suggest that TFA-induced mitochondrial dysfunction, caspase-3 activation, and subsequent cognitive impairments rely on CypD expression, particularly in the hippocampus of mice. This study illuminates the molecular pathways influenced by anesthesia-related compound TFA and its impact on cognitive function.