Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice via activation of caspase-3.

Abstract

Cognitive and memory dysfunction, a common sequela of traumatic brain injury (TBI), places a heavy social and economic burden on individuals, families, communities, and countries. Although the potent anti-tumor effects of spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma, little is known regarding its efficacy on alleviation of cognitive and memory dysfunction. Here, we describe the effect of spautin-1 administration on cognitive and memory impairment post-TBI, and reveal its underlying mechanism of action. We first induced mild TBI in mice through Feeney's weight-drop model, then immediately administered spautin-1 (10mmol/μl, 2μl) into the left lateral ventricle. Behavioral and pathological changes were assessed at 24h, 7 and 30days after TBI by analyzing neurological severity scores (NSS), novel objective recognition (NOR), Morris water maze (MWM) test, recording of local field potential (LFP), as well as western blot, and immunofluorescence assays. Mild TBI not only reduced recognition index and times crossing platform, but also aggravated neuronal injury, including reduced MAP2, GAD2, VGlut2, and CHAT intensity. It also elevated activated microglia and CD86-occupied areas in TMEM119-positive cells, but suppressed θ, β, and γ oscillation power in the hippocampal CA1. However, spautin-1 administration significantly reversed these changes, whereas AC-DEVD-CHO an inhibitor of caspase-3 partially blocked the neuroprotective effects of spautin-1. Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice, potentially through activation of caspase-3.