!! Yet More on Baroness Greenfield

[Peter Webster <vignes@xxxxxxxxx>]

A commentary from a member of the MAPS discussion list:

From: "chola chola" <cholamine@xxxxxxxxxxx>
To: vignes@xxxxxxxxx
Subject: Re: MAPS: !! More on Baroness Greenfield
Date: Mon, 28 Jan 2002 17:34:00 +0000

I wanted to comment on this matter with you (feel free to post this info to
the group if you like).  I am a neuroscientist (pharmacologist) and am very
familiar with models of neurotoxicity in cell culture.  the quoted toxicity
limit is misleading in the text of the original manuscript.   Also, the
Chan et al. study does not actually measure toxicity (cell death) in
dissociated hippocampal cells (there is no assurance that their cultures
are completely or even mostly neurons-but likely include astrocytes and
glia), but rather cell survival.  MTT is a color stain that indicates
living cells.  MTT stains actively respiring mitochondria in a cell.  So to
define toxicity the Chan study showed that after THC treatment, there was
less MTT staining which they interpreted as more dead cells and THC is
neurotoxic.

However, neurotoxicity aint that simple.  There is strong evidence (see
attached) that cannabinoids hold antioxidant capacity.  One possibility is
that in highly reductive environments (such as in this particular cell
culture environment) antioxidants such as vitamin C can actually induce a
free-radicle cascade that causes cell death.   The Chan article is
interesting, but hardly damning.  There is a LARGE body of literature that
argues against this case (See the work of Sam Deadwyler at Wake forest for
example).  At the same time THC isnt necessarily tofu either (though there
is some evidence that tofu is neurotoxic, through a calcium-mediated
mechanism!).   I personally would be more convinced if there was toxicity
data in hippocampal slice cultures or even better, in whole animal studies.

[Documents attached to this post are available from me at vignes@xxxxxxxxx]
they are:

Proc. Natl. Acad. Sci. USA
Vol. 95, pp. 8268?8273, July 1998
Medical Sciences

Cannabidiol and (2)D 9 -tetrahydrocannabinol are neuroprotective antioxidants

A. J. HAMPSON* ? ,M.GRIMALDI ? ,J.AXELROD*, AND D. WINK §
*Laboratory of Cellular and Molecular Regulation, National Institutes of
Mental Health, Bethesda, MD 20892; ? Laboratory of Adaptive Systems,
National Institute of Neurological Disorders and Stroke, Bethesda, MD
20892; and § Radiology and Biology Branch, National Cancer Institute,
Bethesda, MD 20892

Contributed by Julius Axelrod, April 27, 1998

ABSTRACT The neuroprotective actions of cannabidiol and other cannabinoids
were examined in rat cortical neuron cultures exposed to toxic levels of
the excitatory neurotrans-mitter glutamate. Glutamate toxicity was reduced
by both cannabidiol, a nonpsychoactive constituent of marijuana, and the
psychotropic cannabinoid (2)D 9 -tetrahydrocannabinol (THC). Cannabinoids
protected equally well against neuro-toxicity mediated by
N-methyl-D-aspartate receptors, 2-ami-no-
3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid recep-tors, or kainate
receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to
be calcium dependent; this study demonstrates that
2-amino-3-(4-butyl-3-hydroxyisox-azol- 5-yl)propionic acidykainate
receptor-type neurotoxicity is also calcium-dependent, partly mediated by
voltage sensi-tive calcium channels. The neuroprotection observed with
cannabidiol and THC was unaffected by cannabinoid receptor antagonist,
indicating it to be cannabinoid receptor indepen-dent. Previous studies
have shown that glutamate toxicity may be prevented by antioxidants.
Cannabidiol, THC and several synthetic cannabinoids all were demonstrated
to be antioxi-dants by cyclic voltametry. Cannabidiol and THC also were
shown to prevent hydroperoxide-induced oxidative damage as well as or
better than other antioxidants in a chemical (Fenton reaction) system and
neuronal cultures. Cannabidiol was more protective against glutamate
neurotoxicity than either ascorbate or a-tocopherol, indicating it to be a
potent anti-oxidant. These data also suggest that the naturally occurring,
nonpsychotropic cannabinoid, cannabidiol, may be a poten-tially useful
therapeutic agent for the treatment of oxidative neurological disorders
such as cerebral ischemia.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Hippocampal Neurotoxicity of D 9 -Tetrahydrocannabinol

Guy Chiu-Kai Chan, Thomas R. Hinds, Soren Impey, and Daniel R. Storm
Department of Pharmacology, University of Washington, Seattle, Washington 98195

Marijuana consumption elicits diverse physiological and pschological
effects in humans, including memory loss. Here we report that D 9
-tetrahydrocannabinol (THC), the major psycho-active component of
marijuana, is toxic for hippocampal neu-rons. Treatment of cultured neurons
or hippocampal slices with THC caused shrinkage of neuronal cell bodies and
nuclei as well as genomic DNA strand breaks, hallmarks of neuronal
apoptosis. Neuron death induced by THC was inhibited by nonsteroidal
anti-inflammatory drugs, including indomethacin and aspirin, as well as
vitamin E and other antioxidants. Fur- thermore, treatment of neurons with
THC stimulated a signifi-cant increase in the release of arachidonic acid.
We hypothe-size that THC neurotoxicity is attributable to activation of the
prostanoid synthesis pathway and generation of free radicals by
cyclooxygenase. These data suggest that some of the mem-ory deficits caused
by cannabinoids may be caused by THC neurotoxicity.