Effects of DHA on Hippocampal Autophagy and Lysosome Function After Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) triggers endoplasmic reticulum (ER) stress and impairs autophagic clearance of damaged organelles and toxic macromolecules. In this study, we investigated the effects of the post-TBI administration of docosahexaenoic acid (DHA) on improving hippocampal autophagy flux and cognitive functions of rats. TBI was induced by cortical contusion injury in Sprague-Dawley rats, which received DHA (16 mg/kg in DMSO, intraperitoneal administration) or vehicle DMSO (1 ml/kg) with an initial dose within 15 min after the injury, followed by a daily dose for 3 or 7 days. First, RT-qPCR reveals that TBI induced a significant elevation in expression of autophagy-related genes in the hippocampus, including SQSTM1/p62 (sequestosome 1), lysosomal-associated membrane proteins 1 and 2 (Lamp1 and Lamp2), and cathepsin D (Ctsd). Upregulation of the corresponding autophagy-related proteins was detected by immunoblotting and immunostaining. In contrast, the DHA-treated rats did not exhibit the TBI-induced autophagy biogenesis and showed restored CTSD protein expression and activity. T-weighted images and diffusion tensor imaging (DTI) of ex vivo brains showed that DHA reduced both gray matter and white matter damages in cortical and hippocampal tissues. DHA-treated animals performed better than the vehicle control group on the Morris water maze test. Taken together, these findings suggest that TBI triggers sustained stimulation of autophagy biogenesis, autophagy flux, and lysosomal functions in the hippocampus. Swift post-injury DHA administration restores hippocampal lysosomal biogenesis and function, demonstrating its therapeutic potential.

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

“…Given the above experimental model, we cannot exactly differentiate the effects of noise from electric stroke stressor on autophagy reflux. In different animal disease models and pathophysiological settings, the autophagic reflux occurred from 24 h to several weeks [51,52]. In our present study, we found that after the 7th day, the tail artery SBP of the SIH rats kept rising gradually around the 15th day.…”

Autophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

“…DHA has been shown to provide neuroprotection by improving neurological deficits, decreasing infarct volume and reducing proapoptotic proteins (Belayev et al, 2009 ; Mayurasakorn et al, 2011 ). Furthermore, Yin et al ( 2018 ) found that TBI significantly elevated the ATG preteins such as sequestosome 1 (SQSTM1/p62), lysosomal-associated membrane proteins 1 (Lamp1), Lamp2 and cathepsin D (Ctsd) in the rat hippocampusm, which led to decreased cognitive functions as well as both gray matter and white matter damages in rats. However, DHA treatment suppressed TBI-induced autophagy and reversed the hippocampal lysosomal biogenesis and function, suggesting that autophagy was detrimental for TBI and suppression of autophagy exhibited neuroprotective effects after TBI.…”

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury

“…IGF-1 has shown to increase the mitophagy via activating AMPK signal [11]. We have shown mitophagy is impaired in the chronic stage of TBI [12,13], and accordingly we predict that this might be due to the lower IGF-1 status after TBI, as tau phosphorylation can disrupt the mitophagy [14]. We also nd astrocytes have a supporting role for neurons and protect against excitotoxic injury with IGF-1 dependent [15,16].…”