Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine.

Rosenthal, Robert; Williams, Ruth; Bogaert, Yolanda E.; Getson, Pamela R.; Fiskum, Gary

doi:10.1161/01.str.23.9.1312

Cited by 133 publications

(98 citation statements)

References 36 publications

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“…We believe that the brain increases utilization of exogenous bHB after TBI to bypass upstream metabolic disruption. This mechanism is similar to acetyl-L-carnitine neuroprotection following global ischemia (Rosenthal et al 1992), whereby inhibition of pyruvate dehydrogenase and increased lactate production are alleviated with a 'downstream' metabolic substrate. Although the upstream enzymatic dysfunction has been better defined in the ischemia models, further studies exploring the functionality of key biochemical enzymes after TBI are required.…”

Section: Discussionmentioning

confidence: 90%

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

101

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There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate b-hydroxybutyrate (bHB). Arterio-venous differences were used to determine global cerebral uptake of bHB and production of 14 CO 2 from [ 14 C]3-bHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available bHB showed no significant increase in cerebral uptake of bHB or 14 CO 2 production. Increasing arterial bHB concentrations 2.9-fold with 3 h of bHB infusion failed to increase cerebral uptake of bHB or 14 CO 2 production in adult sham animals. Only CCI animals that received a 3-h bHB infusion showed an 8.5-fold increase in cerebral uptake of bHB and greater than 10.7-fold increase in 14 CO 2 production relative to sham bHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of bHB infusion beginning immediately after CCI injury. Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al. 1986a) (Edmond et al. 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al. 1971). However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al. 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al. 1971;Dahlquist and Persson 1976), following starvation (Owen et al. 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.The evidence for the use of bHB by the brain under conditions of cerebral metabolic stress suggests a role for this alternative substrate in cerebral metabolism after ...

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Section: Discussionmentioning

confidence: 90%

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

101

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“…This mechanism of action might be particularly important during reperfusion after cerebral ischemia, when the mitochondrial redox state is hyperoxidized, ROS production is elevated, and there are increased markers of oxidative molecular modification (Perez-Pinzon et al, 1999;Fiskum et al, 2004). There is evidence for mitochondrial metabolism of both ketone bodies, e.g., b-hydroxybutyrate, and acetyl-L-carnitine after acute brain injury, which is associated with a reduction in oxidative stress and neuroprotection (Rosenthal et al, 1992;Liu et al, 1993;Prins et al, 2005;Scafidi et al, 2010Scafidi et al, , 2011. While there is less evidence that neuroprotection by exogenous pyruvate is a consequence of its oxidative metabolism, support for this mechanism comes from recent measurements of brain slice O 2 consumption indicating that exogenous pyruvate significantly elevates endogenous respiration (Schuh et al, 2011).…”

Section: Protection Against Mitochondrial Oxidative Stressmentioning

confidence: 99%

Novel Mitochondrial Targets for Neuroprotection

Pérez-Pinzón

Stetler

Fiskum

2012

J Cereb Blood Flow Metab

126

108

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Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca 2 + overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O 2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca 2 + -activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.

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“…16 Fourth, ALCAR induces post-ischemic return of neurological function in a post cardiac arrest dog model via its effects on restoring aerobic brain metabolism. 17 Fifth, the accumulation of carnitine and ALCAR in spermatozoa is correlated with progressive motility, suggesting that carnitine and ALCAR have importance in the maintenance of progressive motility which is dependent on efficient energy metabolism. 18 The increase in adenosine levels before ATP after ALCAR administration suggests a role for ALCAR in the turnover of adenosine.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression

2000

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Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the ␤-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multiple neurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH 2 and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population. Molecular Psychiatry (2000) 5, 616-632.

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Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine.

Cited by 133 publications

References 36 publications

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Novel Mitochondrial Targets for Neuroprotection

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression

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