Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats

Abstract

IntroductionMild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction.MethodsIn this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex.ResultsWe found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI.DiscussionThe decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.

TET1 displays catalytic and non-catalytic functions in the adult mouse cortex

“…Excess LPC has been shown to induce lipotoxicity in neuronal cells either by compromising cell membrane integrity or oxidative stress [ 117–120 ]. Furthermore, injection of LPC with long fatty acid side chain (16:0, 18:0) induced lipotoxicity that correlated with brain injury [ 113 , 120 , 121 ]. Excess LPC also induced neuronal cone collapse and neuronal death through excessive calcium influx in neurons [ 122 , 123 ].…”

Repeat traumatic brain injury exacerbates acute thalamic hyperconnectivity in humans

“…These have aimed to better understand increased cerebral vulnerability post-injury that can lead to greater adverse effects and neuropathological cascades than a single injury. Such cumulative effects include neurometabolic and lipidomic dysregulation associated with decreased sensorimotor performance, 19 persistent neuroinflammation associated with cognitive impairment and depression 14 and thalamic calcium influx. 11 In one of the few studies to evaluate this in humans, Vagnozzi et al 20 quantified cerebral N -acetylaspartate (NAA) using proton magnetic resonance spectroscopy as an established biochemical marker of brain metabolic imbalance.…”

Modulation of beta-hydroxybutyrate in traumatic brain injury

“…After about 6 h of enhanced glucose metabolism in the brain following TBI, a prolonged period of reduced metabolic activity follows, which could last for days after the injury. So, it is essential to replace substrates that can sustain oxidative metabolism in the brain during these vital periods [31]. There are several methods to modulate ketone bodies, including ketone supplements, ketogenic diets, and intermittent fasting regimens [32].…”