Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

Abstract

Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2a]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2a phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility.

Salubrinal reduces oxidative stress, neuroinflammation and impulsive-like behavior in a rodent model of traumatic brain injury

“…ER stress can also lead to cognitive dysfunction following TBI as we previously demonstrated (Dash et al, 2015; Lucke-Wold et al, 2015a). In this paper, we show ER stress markers CHOP and pJNK fluorescence to be increased following single injury, and co-localized with iNOS following repeat injury.…”

The integrated stress response

“…Recent studies report the beneficial effects of enhancers of ISR in models of degenerative diseases, particularly where protein misfolding plays a role in disease pathogenesis. For example, guanabenz produces the beneficial effects in a rodent model of traumatic brain injury , in mouse models of multiple sclerosis , and in amyotrophic lateral sclerosis (ALS) . Similarly, Sephin1, a guanabenz derivative, has been shown to prevent several molecular defects in mouse models of Charcot–Marie–Tooth syndrome (CMT) and ALS .…”

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

“…Following TBI, misfolded and unfolded proteins in the endoplasmic reticulum will aggregate, which can cause ER stress (Harvey et al 2015). PERK activation is the first indicator of ER stress and aggravates inflammation and apoptosis following TBI (Dash et al 2015;Nakka et al 2014). Therefore, PERK, which is particularly enriched at the MAMs and is essential for MAM integrity, builds the bridge between MAMs and TBI.…”