[extropy-chat] Trees-hemp cannabinoid antioxidants]

Wed Jan 12 22:46:42 UTC 2005

Below is one reason why I include 20-30 grams per day of dried hemp bud 
which contains arginine rich
seed protein, omega spectrum of oils and a wide array of compounds 
including Cannabidiol, a no psychogenic cannabinoid.

You can essentialy consume hemp until the sight of it sickens you or 
like zuchini , you run out of new ways to hide it in your diet.
But given its efficacy as a small molecule antioxidant and capacity to 
mimimic other antioxidants it seems to be for real.

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 293, No. 3
Copyright © 2000 by The American Society for Pharmacology and 
Experimental Therapeutics Printed in U.S.A.
JPET 293:807–812, 2000 /2483/828669

Cannabinoids Protect Cells from Oxidative Cell Death: A
Receptor-Independent Mechanism1
YANQIU CHEN and JOCHEN BUCK
Department of Pharmacology, Joan & Sanford I. Weill Medical College of 
Cornell University, New York, New York
Accepted for publication March 9, 2000 This paper is available online at 
http://www.jpet.org
ABSTRACT
Serum is required for the survival and growth of most animal
cells. In serum-free medium, B lymphoblastoid cells and fibroblasts
die after 2 days. We report that submicromolar concentrations
of D9-tetrahydrocannabinol (THC), D8-THC, cannabinol,
or cannabidiol, but not WIN 55,212-2, prevented serumdeprived
cell death. D9-THC also synergized with plateletderived
growth factor in activating resting NIH 3T3 fibroblasts.
The cannabinoids’ growth supportive effect did not correlate
with their ability to bind to known cannabinoid receptors and
showed no stereoselectivity, suggesting a nonreceptor-mediated
pathway. Direct measurement of oxidative stress revealed
that cannabinoids prevented serum-deprived cell death by antioxidation.
The antioxidative property of cannabinoids was
confirmed by their ability to antagonize oxidative stress and
consequent cell death induced by the retinoid anhydroretinol.
Therefore, cannabinoids act as antioxidants to modulate cell
survival and growth of B lymphocytes and fibroblasts.
Marijuana has been known for centuries to be a psychoactive
medicinal plant (Nahas, 1984). Among its .60 different
cannabinoids, (2)-D9-tetrahydrocannabinol (THC) and cannabidiol
are most abundant (Turner et al., 1980). (2)-D9-THC
is the most potent psychoactive compound in marijuana and
cannabidiol is nonpsychoactive (Dewey, 1986). In recent
years, two cannabinoid receptors, CB1 and CB2, have been
identified as G protein-coupled 7-transmembrane-spanning
receptor proteins (Matsuda et al., 1990; Munro et al., 1993).
CB1, preferentially expressed in brain, mediates the psychoactivity
of cannabinoids. CB2 is highly expressed in immune
cells; however, its biological functions have yet to be determined.
There are numerous, sometimes contradictory, reports
of cannabinoid effects on proliferation and cytolysis of T
cells, proliferation and antibody production of B cells, nitric
oxide (NO) release by macrophages, and cytolysis of natural
killer cells (Thomas et al., 1998).
During metabolic cellular processes, oxidative species such
as superoxide radical anion, hydrogen peroxide, and lipid
peroxides are generated intracellularly (Scandalios, 1997).
These oxidative species, if not eliminated, damage DNA,
protein, or membrane lipids and cause oxidative cell death.
Thus, endogenous antioxidative enzymes such as superoxide
dismutase, catalase, and peroxidase, as well as endogenous
small-molecule antioxidants such as vitamin E, vitamin C,
and ubiquinol are required for cells to survive (Scandalios,
1997). Exogenous small-molecule antioxidants also have
been shown to effectively prevent oxidative cell death in
cultured cells (Busciglio and Yankner, 1995; Johnson et al.,
1996; Nakao et al., 1996; Hampson et al., 1998). In this
report, we study the mechanism whereby cannabinoids affect
cultured human B lymphoblastoid cells and mouse fibroblasts.

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Discussion
In this study, we showed that (2)-D9-THC, (2)-D8-THC,
cannabinol, or cannabidiol at submicromolar concentrations
prevented serum-deprived cell death of human B lymphoblastoid
cells and mouse fibroblast cells. The cannabinoids’
growth supportive effect did not correlate with their ability to
bind to known cannabinoid receptors and showed no stereoselectivity,
suggesting a nonreceptor-mediated pathway. Direct
measurement with flow cytometry revealed that cannabinoids
prevented cell death by antioxidation. The antioxidative
property of cannabinoids was supported by the same action of
cannabinoids and a-tocopherol in our assays and by the ability
of cannabinoids to antagonize the oxidative stress and consequent
cell death induced by anhydroretinol. Our results expand
on the knowledge that the antioxidative effect of (2)-D9-THC
and cannabinol protects cultured rat cortical neurons from glutamate
induced excitatory cell death (Hampson et al., 1998).
The observed cannabinoids’ effect on 5/2 and NIH 3T3 cells
may be attributed to their antioxidative property. Human
lymphoblastoid 5/2 cells, on Epstein-Barr virus transformation,
no longer require cytokines for growth; thus, supplementation
with antioxidants alone in serum-free ITLB medium
is sufficient to maintain cell growth. However, NIH 3T3
cells arrested by serum-starvation still require growth factors
such as PDGF to grow. [3H]Thymidine incorporation
quantifies the total number of cycling cells; therefore, it measures
both the degree of activation and the survival of activated
cells. Our data suggest that cannabinoids may act as
antioxidants to prevent oxidative cell death of activated cells
occurring under serum-free conditions without directly promoting
cell activation.
Cannabinoids’ antioxidative properties also may explain
the conflicting reports about NO release on treatment with
cannabinoids in cultured mammalian macrophages (Coffey
et al., 1996; Jeon et al., 1996; Stefano et al., 1996). Cannabinoids
increase NO release by coupling to their receptors
(Stefano et al., 1996). But at higher concentrations antioxidation
by cannabinoids dominates, leading to a decrease in
NO release by inhibition of the redox-sensitive nuclear factor-
kB activation, which is required for the expression of
NO-producing enzyme inducible NO synthase (Coffey et al.,
1996; Jeon et al., 1996).
The potency of the antioxidative activity of naturally occurring
and synthetic cannabinoids in our assay agrees with
that predicated from their chemical structures (Hampson et
al., 1998). (2)-D9-THC, (2)-D8-THC, and cannabinol highly
resemble the antioxidant vitamin E and have a benzopyrene
moiety substituted with a phenoxyl group and a hydrophobic
alkyl chain. Cannabidiol contains a phenolic structure typical
of many antioxidants isolated from plants. In contrast,
the synthetic cannabinoid WIN 55,212-2 lacks the structural
moieties that chemically define the antioxidative activity.
Cannabinoids, depending on concentration, exert at least
three cellular effects via distinct mechanisms: receptor mediated,
antioxidative, and cytotoxic. In immune cells at nanomolar
concentrations, cannabinoids bind to CB2 and activate
Gia(Bayewitch et al., 1995; Slipetz et al., 1995) and mitogenactivated
protein kinases (Bouaboula et al., 1996), thus may
enhance cell activation as demonstrated in B-cell proliferation
assays (Derocq et al., 1995). The receptor-mediated action
is stereospecific and is blocked by the CB2-specific antagonist
SR 144528 (Rinaldi-Carmona et al., 1998). At
submicromolar concentrations, both receptor-mediated and
antioxidative mechanisms are in play. The relative importance
of the two mechanisms depends on assay conditions. In
low-serum or serum-free conditions, antioxidation may outweigh
the CB2-mediated processes; cannabinoids, acting as
antioxidants, prevent oxidative cell death and enhance cell
proliferation. At concentrations .1026 M, the nonreceptormediated
cytotoxic effect of cannabinoids often dominates
(Schwarz et al., 1994; Zhu et al., 1998).
Cells constantly produce oxidants such as superoxide radical
anion, hydrogen peroxide, and lipid peroxide (Scandalios,
1997). They rely on antioxidative enzymes such as superoxide
dismutases and catalases, and small-molecule antioxidants
such as vitamins A, C, E, and ubiqiunol found in serum
to maintain the right balance of cellular redox potential (Frei
et al., 1992). Cellular oxidative stress affects cell proliferation
and cell death and is involved in physiological as well as
pathological events such as fertilization (Shapiro, 1991), host
defense (Babior, 1978), aging (Sohal and Weindruch, 1996),
tumorigenesis (Cerutti, 1985), stroke (Coyle and Puttfarcken,
1993), and AIDS (Baier-Bitterlich et al., 1996). Cannabinoids,
especially the nonpsychoactive cannabinoids, may
become clinically useful antioxidants in preventing and
treating the oxidative stress-related diseases.
enhance human B-cell growth at low nanomolar concentrations.

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