It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to b-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) b-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the b-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. Keywords: ATP generation; fatty acid; mitochondria; neural cells; oxidative stress Journal of Cerebral Blood BRAIN ENERGY METABOLISM AT A GLANCEThe minor utilization of the energy-rich long-chain fatty acids in brain energy metabolism has not been well understood. Interestingly, other organs with high energy turnover, such as the heart and kidney, largely oxidize fatty acids. The low fatty acid oxidation in the brain might be explained in terms of (i) a slow passage of fatty acids across the blood-brain barrier (BBB), (ii) a low enzymatic capacity for the fatty acid degradation and, (iii) detrimental side effects of long-chain fatty acids in the nonesterified or activated form on the mitochondrial ATP synthesis and/or on the equilibrium between the generation and the disposal of reactive oxygen species (ROS). Before going into the detailed analysis, a brief summary of the brain energy metabolism will be given.The high ATP demand in the brain tissue is impressively illustrated by the following numbers: the human brain accounts for B2% of the body mass, but consumes 20% of the total oxygen consumed by the whole body. Among the neural cells, neurons demand for most of the energy, whereas the energy consumption of astrocytes contributes to only B5% to 15% of the total energy requirement of the brain. This fact, together with the analysis of metabolites profiles supports the view that the energy metabolism of neurons is mainly aerobic and that of astrocytes mainly anaerobic glycolysis. Moreover, the largest portion of the ATP turnover occurs in the gray matter of the brain, which has a high density of excitatory glutamatergic synapses.1,2 For the rodent brain, it has been estimated that B80% of ...

In the last two decades it has become apparent that thrombin has many extravascular effects that are mediated by a family of protease-activated receptors (PARs). PAR-1, -3 and -4 are activated via cleavage by thrombin. The importance of extravascular thrombin in modulating ischemic, hemorrhagic and traumatic injury in brain has recently become clear. Thus, in vitro, thrombin at low concentration protects neurons and astrocytes from cell death caused by a number of different insults. In vivo, pretreating the brain with a low dose of thrombin (thrombin preconditioning), attenuates the brain injury induced by a large dose of thrombin, an intracerebral hemorrhage or by focal cerebral ischemia. Thrombin may also be an important mediator of ischemic preconditioning. In contrast, high doses of thrombin kill neurons and astrocytes in vitro and cause disruption of the blood-brain barrier, brain edema and seizures in vivo. This review examines the role of thrombin in brain injury and the molecular mechanisms and signaling cascades involved.

We have considered the extracellular serine protease thrombin and its receptor as endogenous mediators of neuronal protection against brain ischemia. Exposure of gerbils to prior mild ischemic insults, here two relatively short-lasting occlusions (2 min) of both common carotid arteries applied at 1-day intervals 2 days before a severe occlusion (6 min), caused a robust ischemic tolerance of hippocampal CA1 neurons. This resistance was impaired if the specific thrombin inhibitor hirudin was injected intracerebroventricularly before each short-lasting insult. Thus, efficient native neuroprotective mechanisms exist and endogenous thrombin seems to be involved therein. In vitro experiments using organotypic slice cultures of rat hippocampus revealed that thrombin can have protective but also deleterious effects on hippocampal CA1 neurons. Low concentrations of thrombin (50 pM, 0.01 unit͞ml) or of a synthetic thrombin receptor agonist (10 M) induced significant neuroprotection against experimental ischemia. In contrast, 50 nM (10 units͞ml) thrombin decreased further the reduced neuronal survival that follows the deprivation of oxygen and glucose, and 500 nM even caused neuronal cell death by itself. Degenerative thrombin actions also might be relevant in vivo, because hirudin increased the number of surviving neurons when applied before a 6-min occlusion. Among the thrombin concentrations tested, 50 pM induced intracellular Ca 2؉ spikes in fura-2-loaded CA1 neurons whereas higher concentrations caused a sustained Ca 2؉ elevation. Thus, distinct Ca 2؉ signals may define whether or not thrombin initiates protection. Taken together, in vivo and in vitro data suggest that thrombin can determine neuronal cell death or survival after brain ischemia. T he extracellular serine protease thrombin, a well known, key player in blood coagulation and platelet activation, has been found to be expressed in different brain regions (1, 2). Its physiological importance in the central nervous system is emphasized further by the parallel expression of the highly specific thrombin inhibitor protease nexin-1 (3, 4) and PAR-1, the classical thrombin receptor (2, 5-7). Some recent evidence indicates that thrombin and its receptor might be involved in neurodegenerative processes observed after different insults such as stroke, traumatic brain injuries, and heart arrest or as a frequent consequence of bypass surgeries (8-11). Normal brain function depends critically on a permanent supply of glucose and oxygen. Depending on its source, a disruption of the cerebrospinal blood flow leads to global or focal ischemia (hypoxia͞ hypoglycemia) and irreversible neuronal damage. Prothrombin as well as the classical thrombin receptor are expressed in brain regions that are particularly vulnerable to ischemia, e.g., neocortex, cortex, striatum, hypothalamus, hippocampus, and cerebellum (2). Furthermore, studies performed on isolated cells (neurons, astrocytes) have demonstrated that nanomolar concentrations of thrombin exert cytotoxic effects (12-14). How...

The intracellular free calcium concentration subserves complex signaling roles in brain. Calcium cations (Ca 2+ ) regulate neuronal plasticity underlying learning and memory and neuronal survival. Homo-and heterocellular control of Ca 2+ homeostasis supports brain physiology maintaining neural integrity. Ca 2+ fluxes across the plasma membrane and between intracellular organelles and compartments integrate diverse cellular functions. A vast array of checkpoints controls Ca 2+ , like G protein-coupled receptors, ion channels, Ca 2+ binding proteins, transcriptional networks, and ion exchangers, in both the plasma membrane and the membranes of mitochondria and endoplasmic reticulum. Interactions between Ca 2+ and reactive oxygen species signaling coordinate signaling, which can be either beneficial or detrimental. In neurodegenerative disorders, cellular Ca 2+ -regulating systems are compromised. Oxidative stress, perturbed energy metabolism, and alterations of disease-related proteins result in Ca 2+ -dependent synaptic dysfunction, impaired plasticity, and neuronal demise. We review Ca 2+ control processes relevant for physiological and pathophysiological conditions in brain tissue.