Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury

ABSTRACT Traumatic brain injury (TBI) produces a state of vulnerability that reduces the brain capacity to cope with secondary insults. The silent information regulator 2 (Sir2) has been implicated with maintaining genomic stability and cellular homeostasis under challenging situation. Here we explore the possibility that the action of Sir2␣ (mammalian Sir2) in the brain can extend to serve neuronal plasticity. We provide novel evidence showing that mild TBI reduces the expression of Sir2␣ in the hippocampus, in proportion to increased levels of protein oxidation. In addition, we show that dietary supplementation of omega-3 fatty acids that ameliorates protein oxidation was effective to reverse the reduction of Sir2␣ level in injured rats. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) and phosphorylated-AMPK (p-AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after TBI and levels were normalized by omega-3 fatty acts supplements. Further, we found that TBI reduced ubiquitous mitochondrial creatine kinase (uMtCK), an enzyme implicated in the energetic regulation of Ca 2؉ -pumps and in the maintenance of Ca 2؉ -homeostasis. Omega-3 fatty acids supplements normalized the levels of uMtCK after lesion. Furthermore, we found that the correlation between Sir2␣ and AMPK or p-AMPK was disrupted by TBI, but restored by omega-3 fatty acids supplements. Our results suggest that TBI may compromise neuronal protective mechanisms by involving the action of Sir2␣. In addition, results show the capacity of omega-3 fatty acids to counteract some of the effects of TBI by normalizing levels of molecular systems associated with energy homeostasis