Friday, February 10, 2012

PLoS ONE - Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration


Creatine . . . it's not just for bodybuilders anymore. I have periodically reported on the various health benefits of creatine over the years, including virus suppression (herpes), memory enhancement, and neurocognitive benefits. This new research supports another aspect of its cognitive benefits - it can suppress some of the excititory activity that leads to neurodegeneration.

As an aside, one of the authors is named Just Genius - how cool is that?!

Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration

Just Genius1, Johanna Geiger1, Andreas Bender2, Hans-Jürgen Möller1, Thomas Klopstock2, Dan Rujescu1*

1 Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany, 2 Department of Neurology, Ludwig-Maximilians-University, Munich, Germany

Abstract

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.

Citation: Genius J, Geiger J, Bender A, Möller H-J, Klopstock T, et al. (2012). Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration. PLoS ONE, 7(2): e30554. doi:10.1371/journal.pone.0030554

Here is the introduction to the article:

Introduction

The protective potential of creatine (1-methyl-guanidino acetic acid) has been extensively assessed in various models of neurodegeneration, including in vivo models of oxidative stress [1], [2].

Aging, neurodegenerative diseases like Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, and potentially also neuropsychiatric disorders like schizophrenia share some bioenergetic core features, specifically the contribution of oxidative stress caused by a progressive dysfunction of the respiratory chain along with mitochondrial DNA damage [3][5]. Thus, as a potential antioxidative agent and buffer of intracellular energy stores, creatine - specifically in a preventive approach - may also become an interesting new agent to increase life span and to delay the progression of the disorders mentioned above.

In neuronal cells, aerobic glycolysis is the primary source for ATP synthesis [6]. As stores of glucose, glycogen and O2 are limited in the brain, the availability of the creatine kinase/phosphocreatine (CK/PCr) system may operate as an important alternative energy source in tissues or subcellular compartments with high and fluctuating energy demands, e.g. in neurons [7]. Based on substrate level phosphorylation of adenine with CK/PCr this system is capable of rapidly restoring ATP levels within certain limits, determined by the tissue concentrations of creatine/CPK itself and the enzymatic system required for phosphorylation and phosphate group transfer. ATP is required to maintain the function of energy-demanding Na+/K+-ATPase and Ca2+-ATPase, thus preserving the membrane potential [8]. Considering that high relative CK activity could be demonstrated in the brain [9], it has been concluded that this enzyme serves as a key factor in the CNS energy metabolism. In support of this notion, a direct correlation between CK flux and brain activity has been provided by in vivo 31P nuclear magnetic resonance transfer determinations [10], [11]. The brain-specific isoform of the CK (CK-BB) in concert with a mitochondrial isoform (uMT-CK) and the required substrates (creatine/PCr) regulate intracellular ATP levels [12]. Via formation of an CK “energy shuttle”, CK activity has moreover been discussed to be directly implicated in neurotransmitter release, maintainance of membrane potentials and restoration of ion gradients over the membrane after depolarization [12][14].

Primarily, creatine is synthesized in a two step mechanism via AGAT (arginine: glycine amidinotransferase) in the kidney and pancreas [15]. The resultant guanidinoacetate is then shuttled to the liver, where it is subsequently methylated by GAMT (guanidinoacetate methyltransferase to result in creatine which ultimately is actively exported to tissues where it is energetically required. Loss of GAMT activity results in a well-defined creatine deficiency syndrome, which is characterized by developmental delay, neurological dysfunction and mental retardation [16]. In Huntington's disease, a further neurodegenerative condition, brain-type creatine kinase expression is reduced, which might contribute to damage in specifically energy-demanding tissues such as the brain and the cochlea, where intact energy shuttling processes are crucial [17]. The endogenous de novo creatine synthetic activity in the brain is rather low. It is interesting to note, that GAMT was identified to act as a novel target for p53, which serves as a further mechanism for metabolic stress adaptation [18]. Under normal conditions dietary intake constitutes about 50% of the total creatine content of the organism. Moreover, the blood-brain barrier permits passage of systemically supplemented creatine to the brain [19], which ultimately reaches the neuronal cytoplasm via a specific sodium and chloride dependent transmembrane transporter (CRT) working against a concentration gradient [20]. We thus speculate, that a specific diet should serve as an efficient strategy to enhance brain tissue creatine concentrations and establish an “energy buffer”.

In a previous report, we demonstrated that creatine supplementation in mice could increase healthy life span. Beyond a moderately increased life span, the most favourable effects of creatine related to neurobehavioral performance, most markedly in memory tests [21]. In an attempt to gain a better understanding of these neuroprotective properties on the cellular level, we conducted a study on a hippocampal cell culture model.
Read the whole article.

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