Fructose: at least it's good for the prevention of hemolysis, induced by glycerol, in the treatment of intracranial hemorrhage

I don't think anyone uses glycerol to actually treat stroke, but doctors do still use mannitol, as far as I know, to reduce cerebral edema in people with hepatic encephalopathy due to liver failure. But here's an old article that mentions the main complication of using glycerol as this osmotic hemolysis (lysis of red blood cells, to a degree that can reduce the hemoglobin levels significantly). The authors mention that fructose has sometimes been used to prevent it, but this is starting to sound worse by the minute:

http://stroke.ahajournals.org/cgi/content/abstract/23/7/967

I wonder if the mechanism of the increases in cerebral blood flow, an effect that the authors mention, is partly due to a glycerol-induced increase in the cytosolic NADH/NAD+ ratio and lactate/pyruvate ratio. It looks like glycerol didn't even work well in this study, though, but I think that effect, the way it's been shown to enhance blood flow temporarily, is interesting (as far as understanding mechanisms, etc.). That effect, increasing the NADH/NAD+ ratio, could increase cerebral blood flow by giving the NADH/NAD+ ratio the push it would need, by increasing it artificially, to allow the autoregulation of cerebral blood flow, by the lactate/pyruvate ratio, to be restored, at least in the short term (http://www.pnas.org/content/101/2/659.abstract). I think it causes problems, though, in the long term. I probably don't need to mention the relevance of this hemolytic effect to my past postings on related topics. I know glycerol, though, can produce renal failure by its osmotic diuretic effect, at least when the doses of glycerol are very high. I don't think anyone's using glycerol anymore, and mannitol apparently isn't supposed to produce hemolysis.

But I'll bet this glycerol-1-phosphate accumulation, and phosphate sequestration, contributes to the osmotic hemolysis. I tried to find an article describing the mechanism of glycerol-induced hemolysis, but I couldn't find one. All one of the articles said is that glycerol builds up in the red blood cells and draws water into it, and that's like saying it causes hemolysis by setting up an osmotic gradient. It says nothing about the mechanism. It's probably that the fructose isn't an ideal prophylactic but just leads to increased glucose output by the liver (or is used directly by the red blood cells), to support glycolysis in red blood cells.

Here's an article showing the worrisome effects of these types of osmotic effects, in this case by glycerol. I haven't looked at the full text of this article, but the abstract mentions the liver-ATP-depleting effect of glycerol (similar to the effect of fructose) and basically is saying glycerol may be increasing blood-brain-barrier permeability and thereby allowing more glucose uptake into the brain. That helps explain some of these sort of very-short-term beneficial effects of glycerol, in the old articles using it to treat hypoperfusion following stroke, and also some of the adverse effects. I remember reading something about the blood-brain barrier permeabilizing effects of glycerol. It also interferes with astrocyte volume regulation, and the authors mention the hyponatremic effect. The combination of hemolysis, volume depletion, and hyponatremia could certainly explain this old article that discusses glycerol-induced hemorrhages in animals (http://www.ncbi.nlm.nih.gov/pubmed/13621341). Acute volume depletion can cause a hemorrhage, and that technique used to be used in animal models of hemorrhages (to induce a hemorrhage experimentally). Here's that article (it mentions the increases in the products of glycolysis that glycerol can induce):

http://www3.interscience.wiley.com/journal/119571924/abstract
(pubmed unique id: http://www.ncbi.nlm.nih.gov/pubmed/7193713)

I'm not saying all of these sugars or sugar alcohols are equally potent in inducing adenine nucleotide depletion or osmotic effects, because they aren't. That's one of the things that's interesting. For example, in this article, 5 mM xylulose produced twice as large a percentage of adenine nucleotide depletion as 5 mM xylitol did, but xylitol is actually converted into xylulose by xylitol dehydrogenase (maybe there's a more generic name for this enzyme now) (http://www.jbc.org/cgi/content/abstract/246/24/7623 OR http://www.ncbi.nlm.nih.gov/pubmed/4332557?dopt=Abstract). Here's the article:

http://www.fasebj.org/cgi/content/abstract/3/7/1855
(pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/2523832?dopt=Abstract)

This reaction generates reducing equivalents (NADH), but the conversion of xylulose into xylulose-5-phosphate consumes ATP. That would help explain the difference, I guess. Normally, one doesn't think of a single enzymatic step as being that important and potentially producing such a big effect, given that the activities of so many enzymes consume ATP. But that's one of the interesting things about these different sugars, the way bypassing one step can produce these drastically different effects. It's partly the amounts of the sugars, the concentrations. These studies are done in millimolar concentrations, and those are very high concentrations (physiologically speaking). In any case, I know some of this is subjective.