Excitotoxics (long) and Neuroendocrine Damage (fwd)

MJ Duggan sgex400 at uk.ac.lon.sghms
Fri Aug 13 05:25:05 EST 1993

Dear Douglas

Thanks for a very interesting and thorough analysis of this subject. I have 
one query that arises out of your comments; about what you say on the
mechanism of cell-death:

> To fill in the gap:  the cell probably dies because so much electrolyte
> enters the cell during this frenetic excitatory activity that water
> is drawn osmotically inside the cell until it bursts like an
> overfilled water balloon.  

This is a mechanism for excitotoxin-induced cell death that I have not
heard before. I am not sure that it makes sense; as I understand it the various
ion channels should be able to pass ions in either direction and so it
seems logical that the cell should come to an chemiosmotic equilibrium
with the extracellular space. I have been lead to believe that this is the
problem, or more specifically the consequent rise in intracellular Ca2+
concentration, which should activate all sorts of Ca2+-dependent enzymes 
(phospholipases, proteases) that will cause the cell to self-destruct.
Is there any evidence to support the "over-filled water balloon" model?

> >The blood-brain barrier protects the brain from  the  effects  of
> >most toxins circulating in the blood (Olney, 1988) but excitotox-
> >ins circumvent this protective system; they act on  some  of  the
> >circumventricular  organs  (CVO's),  areas  which lie outside the
> >blood-brain barrier, specifically the median eminence and the ar-
> >cuate  nucleus  of the hypothalamus, the pituitary gland, and the
> >area postrema (Olney, 1988). 
Also it seems imperative to me that glutamate should be able to cross
the blood-brain barrier, along with all other amino acids required for
protein synthesis. Is aminoacid uptake so controlled at the BBB that
spiking is prevented, or is it that in the mature brain there are cellular
mechanisms protecting neurons from excitotoxicity (maybe a more likely
idea is that the susceptibility of immature neurons that still have 
the potential for apoptosis is decreased).
I would be interested to read any views that anyone else has on these
points, especially people who know the cell death/ apoptosis literature 
better. It is not really my field.


PS do you suffer horribly from people making puns about your work on
excitotoxins and being called Douglas *Fitts*?

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