The Effects of Age and Ketogenic Diet on Local Cerebral Metabolic Rates of Glucose After Controlled Cortical Impact Injury in Rats

Abstract

Previous studies from our laboratory have shown the neuroprotective potential of ketones after TBI in the juvenile brain. It is our premise that acutely after TBI, glucose may not be the optimum fuel and decreasing metabolism of glucose in the presence of an alternative substrate will improve cellular metabolism and recovery. The current study addresses whether TBI will induce age-related differences in the cerebral metabolic rates for glucose (CMRglc) after cortical controlled impact (CCI) and whether ketone metabolism will further decrease CMRglc after injury. Postnatal day 35 (PND35; n ¼ 48) and PND70 (n ¼ 42) rats were given either sham or CCI injury and placed on either a standard or a ketogenic (KG) diet. CMRglc studies using 14 C-2deoxy-d-glucose autoradiography were conducted on days 1, 3, or 7 post-injury. PND35 and PND70 standard-fed CCI-injured rats exhibited no significant neocortical differences in CMRglc magnitude or time course compared to controls. Measurement of contusion volume also indicated no age differences in response to TBI. However, PND35 subcortical structures showed earlier metabolic recovery compared to controls than PND70. Ketosis induced by the KG diet was shown to affect CMRglc in an age-dependent manner after TBI. The presence of ketones after injury further reduced CMRglc in PND35 and normalized CMRglc in PND70 rats at 7 days bilaterally after injury. The changes in CMRglc seen in PND35 TBI rats on the KG diet were associated with decreased contusion volume. These results suggest that conditions of reduced glucose utilization and increased alternative substrate metabolism may be preferable acutely after TBI in the younger rat.

Glucose administration after traumatic brain injury exerts some benefits and no adverse effects on behavioral and histological outcomes

“…Lactate or pyruvate treatments attenuate TBI-induced reductions in extracellular brain glucose (Chen et al, 2000; Fukushima et al, 2009) and increased concentrations of systemic glucose are also reported to increase interstitial levels of brain glucose after TBI (Diaz-Parejo et al, 2003; Stover et al, 2002). Provision of exogenous metabolic fuel early after TBI may thus improve outcomes, as found here for supplemental glucose and as previously reported for administration of lactate, pyruvate or ketone bodies (Alessandri et al, 2012; Appelberg et al, 2009; Chen et al, 2000; Davis et al, 2008; Deng-Bryant et al, 2011; Fukushima et al, 2009; Holloway et al, 2007; Moro and Sutton, 2010; Prins et al, 2005; Prins and Hovda, 2009; Rice et al, 2002; Shi et al, 2015; Su et al, 2011; Zlotnik et al, 2008; 2012). Although the mechanisms by which exogenous glucose improved outcomes are uncertain it is possible that increased blood levels of glucose, as well as increased lactate or pyruvate resulting from peripheral glucose metabolism, ensured that sufficient concentrations of these biofuels were available to meet the increased cerebral metabolic demands after TBI.…”

“…As the primary source for energy in brain cells is glucose, the prior findings suggest that endogenous fuel levels may be insufficient to meet the cerebral metabolic demands in the acute phase of TBI, resulting in an energy crisis (Vespa et al, 2003, 2005). Although changes in cerebral blood flow or mitochondrial functions may contribute to the metabolic dysfunctions and tissue damage after TBI (Harris et al, 2012; Jiang et al, 2000; Lifshitz et al, 2004; Sullivan et al, 2005), the “insufficient fuel” hypothesis is supported by multiple studies indicating that early administration of metabolic substrates after experimental TBI, including lactate (Alessandri et al, 2012; Chen et al 2000; Holloway et al, 2007; Rice et al, 2002), pyruvate (Fukushima et al, 2009; Moro and Sutton, 2010; Shi et al, 2015; Su et al, 2011; Zlotnik et al, 2008; 2012) and ketone bodies (Appelberg et al, 2009; Davis et al, 2008; Deng-Bryant et al, 2011; Prins et al, 2005; Prins and Hovda, 2009), can improve cerebral metabolic and behavioral outcomes and reduce histopathology.…”

Functional Neuroimaging in Traumatic Brain Injury: From Nodes to Networks

“…Following this period, glucose metabolism decreases from 5 to 14 days post-injury in animal models (31, 32) with greater and longer-lasting depression in the penumbra (33). In animal models, the magnitude and duration of glucose metabolism changes are greater in older rodents (33, 34), suggesting an energy-based mediator for cognitive decline following TBI. Indeed, focal glucose metabolism rates following TBI in the thalamus, brain stem, and cerebellum are positively correlated with consciousness measured by the Glasgow Coma Scale (35).…”

Metabolic Response of Pediatric Traumatic Brain Injury

“…70,71 Correspondingly, unlike adolescent rats in whom ketogenic diet administration decreased the size of the cortical contusion roughly to half, adult rats who similarly received the ketogenic diet following severe traumatic brain injury did not demonstrate a reduction in contusion volume compared to those fed a standard diet. 32,66, …”