Question And Answer Session

SESSION CO-CHAIR NAMBOODIRI: Thank you, Dr. Verbalis. Now we will have a few questions.

DR. PHILIPPART: Philippart, Los Angeles. I wonder if you also look at plasma bicarbonate.

DR. VERBALIS: Plasma bicarbonate is basically unchanged, as it is in humans with hyponatremia. It doesn't appear to be a major factor in this disorder.

SESSION CO-CHAIR KOLODNY: Brian Ross?

DR. ROSS: First is just a comment. I presume since we can measure all of these osmolytes with MR spectroscopy in the human brain, that you now routinely use spectroscopy in your patients.

DR. VERBALIS: You presume wrong, but it has been done. The same kind of decreases in osmolytes shown in the animal models has also been documented in human brains at UCLA using magnetic resonance spectroscopy. But it's not being used routinely for therapeutic purposes at this time.

DR. ROSS: I am challenging you to do so since you see these patients. But, my next point is a comment which I discussed briefly with you earlier and then hearing Dr. Baslow's presentation, you note that creatine is a major osmolyte in the brain.

If creatine is truly a major osmolyte and fluctuates with this huge 15-20 percent decrease with hypoosmolality, how do we explain the maintenance of energy metabolism because creatine and phosphocreatine are one and the same thing in your hands? And in Dr. Baslow's theory, he needs to demonstrate changes in energy metabolism.

DR. VERBALIS: I actually went one step further than that. I showed you my rats playing basketball, despite a 30 percent decrease in brain glutamate in those rats.

DR. ROSS: I understand.

DR. VERBALIS: So, how can a rat have normal motor transmission and normal motor function with a 30 percent decrease in a major excitatory amino acid in addition to a 20% decrease in creatine?

DR. VERBALIS: And I think that I gave you my explanation to both of those points, which is I believe that one of the factors that has not been taken into account in understanding brain energy metabolism, or even neurotransmission, are the separate pools of these various osmolytes that are involved with distinct cellular processes.

So, I believe that creatine, glutamate, aspartate, and NAA all have an osmoregulatory role which is separate from their other cellular roles, both metabolic and neurotransmission, and that it is possible to decrease one of these pools without necessarily impacting on the functions of the other pools.

That's the only way, for example, that I could explain normal motor function of these animals with those kinds of decreases in amino acids that we think are crucial for normal neural transmission, certainly in motor neurons but probably in all types of neurons for that matter. It's the only way one could understand it.

DR. ROSS: I had one more point to make. In all seriousness, I think you're absolutely right, of course, but we still do have the problems of these equilibria.

The proposal that was made - not in recent years, and this may have, therefore, not been brought to any of our attention, was actually made, in part, by R. L. Veech from 1979 or '80, in which he combines the Nernst equation, the Gibbs equation, and the osmotic equilibrium, the Donnan equilibrium, into one huge equation, saying that, actually, all of these things are linked.

So I think that there is a way in which Dr. Baslow's hypothesis and yours could really be saying the same thing.

DR. VERBALIS: Certainly, the water movement in association with the movement of both ions and organic particles across cell membranes is potentially very large. And so I am not by any means saying that I don't believe that inhibition of one part of that system might not result in what would be predicted, which is retention of water by the cell.

What I'm saying, however, is that based on our studies in this field, the brain has many other systems that are able to compensate for deficiencies, or excesses, of individual osmolytes.

So I'm not saying that that excess NAA might not produce exactly the effects that Dr. Baslow, and others, are postulating. What I am questioning is, why wouldn't the same kinds of mechanisms that allow brains to adapt to an even more severe osmotic stresses allow them to regulate their volume in this situation as well? Why wouldn't the same mechanisms come into play in a situation in which one molecular water pump was paralyzed, nonexistent, or somehow impaired? Why wouldn't these other osmolytes be able to regulate the volume of these cells with increased water retention?

That's where I have trouble fitting the molecular water pump hypothesis together as a viable single hypothesis to explain the observations in Canavan disease.

PARTICIPANT: Sir, there is also hypernatremia. So can you give an explanation for that in this way?

DR. VERBALIS: Yes, you're right that severe hypernatremia has also produced pontine and extrapontine myelinolysis. And the answer is that hypernatremia is also an osmotic stress. If you take an animal, or a human, from a normal plasma osmolality up to 360 or 370 mOsm/kg H2O, then the blood brain barrier will be disrupted; complement and other immune proteins can then gain access into the brain and potentially can produce the same kind of demyelinating syndrome.

The difference between correction of hyponatremia and induction of hypernatremia is that in the chronic hyponatremic state, the brain has lost its pool of excess osmolytes, its osmotic "buffering capacity", so it's more susceptible to shrinkage and breaking the blood brain barrier with a lesser increase in plasma osmolality.

But if you take a normal human or animal up high enough in plasma osmolality, yes, you would break the blood brain barrier as well. If the increased osmolality is prolonged and sufficient, then the same pathophysiology as is seen with rapid correction of hyponatremia can and does occur.

The fact that this does occur is further proof for the blood-brain barrier disruption mechanism underlying the pathogenesis of pontine and extrapontine myelinolysis.

DR. COYLE: I just want to say that I concur with your suggestion that there are probably at least two pools of glutamate. The lesion studies indicate that probably less than ten percent of the total glutamate is in the neurotransmitter pool and the other ninety percent is in another pool. I'm not surprised that there's still a slam-dunk even when you have thirty percent of the brain glutamate decreased.

DR. VERBALIS: But would you expect, at least over prolonged periods of time, that this might, at least in some ways, impact upon the transmitter pool? Again, we don't see any evidence for that, not that we have measured those pools separately, nor would I know how to at this point. But it is impressive that, even for long periods of time, with severe depletion of these excitatory amino acids from the brain, there still is no apparent functional neurological effect of that dramatic phenomenon.

But, if I'm right and you're right, then just separate pools could explain that and allow one component to be markedly decreased without really impacting too severely on the others. If this is true, then it would imply preferential shunting into the neurotransmitter pool at the expense of the free cytosolic pool, which comprises the osmotically active component of cells.

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