I

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(ajtperemia) . VASCULAR SYSTEM

waste metabolic products

Figure 2. Dynamic interactions of the NAA-NAAG system with neuron energy flux, neuron energy dependent minimal re-polarization and refractory periods, and neuron maximal firing rate 1,2,3,4

1 Energy flux used in this example is based on complete oxidation of Glc. However, the neuron energy source may be lactate, which has a lower ATP value. Also, Glc is subject to "proton leak in mitochondria" which would reduce the Glc/ATP ratio to 31 (Attwell and Laughlin, 2001).

2 Neurons transmit information in the form of single spikes or bursts of spikes, and in either case, the relative refractoriness is related to interspike intervals, and therefore to information processing (Chacron et al., 2001).

3 Any reduction in rate of energy supply that increases the minimal refractory period reduces the maximum firing rate, thereby truncating a neuron's signaling repertoire at it's highest rates. However, that portion of information transmitted at less than the maximal firing rate would not be affected (Berry and Meister, 1998).

4 From Baslow, 2004

NAAG, and its specific signal effect on the mGluR3 astrocyte receptor, suggests that an important neuron-microcirculatory control mechanism is inoperative in this case. This could explain why it is in this case, that neurons survive (brain structure is normal), are myelinated (unremarkable MRI), and signal one another (normal EEG), but cannot process information well (Boltshauser et al., 2004).

2.9. Supporting evidence based on enzyme inhibition

There are two lines of enzyme inhibition evidence in support of the MWP and signal hypotheses presented in this review.

2.9.1. Inhibition of amidohydrolase II

It has been proposed that a primary function of NAA is to transport neuron metabolic water to ECF against a water gradient, and that release of the NAA-obligated water in ECF is a function of amidohydrolase II activity. Based on this hypothesis, a predictable outcome of amidohydrolase II inhibition would be a buildup of NAA-water and hydrostatic pressure in ECF. In support of a role for NAA and NAAG as MWP's, are the outcomes of the many natural experiments in which amidohydrolase II (enzyme "D" in figure 1) is inactivated by inborn errors that alter the structure of the enzyme. These result in human CD, a genetic osmotic disease characterized by the buildup of NAA and NAAG in brain, brain cell and ECF edema, and an osmotic-hydrostatic imbalance resulting in increased hydrostatic pressure (with megalocephaly) on the brain side of brain-barrier membranes (Baslow, 2003a). In CD, the primary osmotic defect is that only half of the NAA metabolic sequence (catabolic) is inactivated, which results in a buildup of NAA-water in ECF. In the singular case of hypoacetylaspartia, in which the entire NAA metabolic sequence appears to be absent, there is no evident osmotic component associated with the inborn error.

2.9.2. Inhibition of NAAG peptidase

It has been proposed that a primary function of NAAG is to initiate focal hyperemic responses in the brain in order to provide neurons with required energy components and remove products associated with generation of ATP, and that NAAG peptidase is a key component in this process. If true, a predictable outcome of NAAG peptidase inhibition would be a change in cerebral blood flow. In support of an important neuron-NAAG microcirculatory role via the astrocyte mGluR3 receptor are the results of a murine MRI experiment in which NAAG peptidase (enzyme "C" in figure 1) was inhibited by 2-(phosphonomethyl) pentanedioic acid (2-PMPA). In this study, inhibition of NAAG peptidase resulted in a rapid and sustained global attenuation of T2* related BOLD signals, an indication of elevated deoxyhemoglobin that is associated with decreased cerebral blood flow (Baslow et al., 2005). These 2-PMPA induced decreases in BOLD signals appear to indicate that blood deoxyhemoglobin is elevated when endogenous NAAG cannot be hydrolyzed, thus linking the efflux of NAAG from neurons and its hydrolysis by astrocytes, to hyperemic oxygenation responses in brain.

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