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Brain Slices, THC and PGE2.

John H. johnh at faraway.hgmp.mrc.ac.uk
Mon Jan 5 15:42:00 EST 2004

Another damning question in neuroscience. In vitro studies tend to support a
neurotoxic potential for cannabinoids but in vivo the picture is very
different. If the neurotoxicity purported from the in vitro studies were
real and substantial, and given the Cheech and Chong habits of some
potheads, then long term heavy M users should have brains like dried
cabbages. However, contined exposure quickly internalises CB 1 and 2
receptors, hence the relatively high tolerance that can quickly develop upon
chronic exposure. Various longitudinal studies demonstrate limited if any
cognitive impairment (though immunological impairment is noted - however
questionable is this actually results in reduced immunological efficacy) and
imaging studies on humans do not demonstrate tissue pathology.

One report last year claimed that a major problem with in vitro studies is
that the cultures are typically exposed to much higher oxygen concentrations
than occurs physiologically.

The culture medium could be an important factor.

Another matter to consider is that cannabinoids are highly lipid soluble, so
what is deemed to be a physiologically relevant level of exposure may be
incorrect because in the body most cannabinoids could be absorbed by lipid
tissues rather than activating CB 1 and or 2 receptors. This level of lipid
solubility is such that some have suggested, and I think this has been
experimentally demonstrated, that cannabinoids directly impact on second
messengers independently of CB 1 or 2 occupation. In this regard I recall
one study which stated that CB occupation can be relatively low to generate
a psychoactive effect, circa 8-10% of total receptors. So it may be
interesting to measure CB occupation in the culture and slice studies.
Another approach may be to look at PLA 2 and PKC activation under these
conditions, I suspect it may be much higher than occurs physiologically. As
PGE 2 increases vasodilation excess oxygen exposure may become an issue. I'd
be interested to see what levels of PAF occur under the experimental
conditions re slice and brain studies as PAF is usually neurotoxic.

Another approach may be to look at other compounds and their effects
relative to the various experimental paradigms.

Another issue to consider is that cannabinoids inhibit NMDA activity, so
their protective effect in the body may be mediated via this and other
factors such as cannabinoids possessing considerable anti-oxidant capacities
which may be negated by the relatively high oxygen concentrations in slice
and culture preparations.
Also cannabinoids generally have a marked anti-inflammatory response,
strongly limiting tnf and il1 from mononuclear cells, though at higher
concentrations the reverse may occur.

I think this is an important issue that could help elucidate the issues
surrounding slice and culture studies. I haven't had a chance to look
closely at this matter but am  interested in what others have to say.

John H.

"BilZ0r" <BilZ0r at TAKETHISOUThotmail.com> wrote in message
news:Xns9466DBC86298BilZ0rhotmailcom at
> Anything immuno/cytokine related is always a bit out of my depth, so I
> was wondering if anything had anything to add to this hypothesis.
> I've been interested in in vitro THC-induced neurotoxicity since: Chan et
> al., J Neurosci. 1998 Jul 15;18(14):5322-32. He shows that THC induced
> pronouced apoptosis in hippocampal slices, and that this was PGE2
> mediated.
> Now whether THC induces neurotoxicity in whole animals is a point of much
> contension. Its been shown that THC induces PGE2 release in animals, and
> that PGE2 mediates behavioural changes due to THC, as well as the fact
> that inhibiting eicosinoid synthesis inhibits some behavioural changes
> normally seen in THC treated -HUMANS-.
> So, although it looks likely that THC increases the level of PGE2 in
> human brains, what if the trauma that a brain slice recieves, causes the
> production of heaps of PGE2, and then THC just pushes it over the edge as
> far as PGE2 production goes?
> So, basically my question is, do you think brain slices have a much
> higher PGE2 concentration or COX activity?
> But then, THC is also toxic to cultured neurons. Do you think cells in
> culture have a higher PGE2 concentration or COX activity?
> Thanks for any input.

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