Issue 16.pdf - Treating Yourself

HEALTH
in HIV-induced CNS cell damage
(31) and at least one study
has found that CP-55,940 can
suppress release of NO by
macrophages through CB1 and
CB2 mediated mechanisms.
Another way in which cannabinoids
have been found to
potentially inhibit the dementia-inducing
nature of HIV is
through restoring the blood
brain barrier (BBB) after HIV
assault. Although HIV does not
directly infect the endothelial
cells in the BBB it can produce
several changes in them which
alter their ability to effectively
bar entry into the brain.
Cannabinoid agonists have
been found to block or even
reverse many of these changes
both in culture and animal
models. Cannabinoids also
inhibited the ability of the
macrophage/microglial precursor
cells (monocytes) to move
across the BBB (32). The ability
to restore the BBB after HIV
assault by cannabinoid agonists
is likely to suppress HIV
infection of the CNS and thus
the eventual development of
dementia.
Although the concerns posed by
Benito, et al. 2005, with their
work on SIV-induced changes in
monkey brains (26) may not be
presented by HIV itself, there is
always the concern of secondary
infection to consider. Cabral and
Marciano-Cabral, 2004, were
stimulated by the observation
that CNS infections by opportunistic
amoebae were more
common in AIDS patients to
investigate how THC affected
infection rates of the amoebae in
mice. There was a dose-dependent
increase in infection-related
mortality rate for mice treated
with THC compared to those
that were not. The increase in
infection-related deaths appeared
to be the result of the immuno-
46 - Treating Yourself, Issue 16 - 2009
suppressive effects on macrophages
and microglia produced by THC.
THC inhibited the ability of these
cells to fight off the infection in the
brain, indicating that it might also
make HIV patients more susceptible
to opportunistic secondary infections
of the CNS (33). However
this implication has yet to be confirmed.
Can We Exploit
HIV/Endocannabinoid
Interactions?
The answer to this question is most
certainly yes. Early research on
HIV/endocannabinoid interactions
did not look promising (27, 34, 35)
and it was concluded (36), possibly
correctly, that these interactions
featured prominently in disease
progression and ultimate downfall
of the immune system. Some more
recent work such as Benito, et al.
2005, with monkeys have added to
this concerning knowledge base,
finding over expression of not just
CB2 receptors in specific cells but
also fatty acid amide hydrolase
(FAAH ) production as well (26).
FAAH is responsible for the enzymatic
breakdown of anandamide
after it has been released. In some
cases, these interactions may indicate
that CB1 agonist drugs like
cannabis may not always be the
best choice or may even potentially
exacerbate some particular process
in the progression of HIV to AIDS.
Instead, many cases would suggest
manipulating the endocannabinoid
system itself may be a more suitable
approach.
Research into HIV/endocannabinoid
interactions have found many
possible targets for therapeutic
manipulation of the endocannabinoid
system to either aid in the
body's natural attempts to fight the
drug or counteract the ways in
which HIV alters the endocannabinoid
system to facilitate its own
spread and development. One of
the issues, however, with interpreting
how to use these interactions to
our advantage successfully is that
often the particular action observed
is very cell-type dependent. In
2002, Esposito and colleagues
found that a line of rat neuroimmune
cells when treated with HIV
proteins would release high levels
of NO resulting in a toxic effect on
the cells. This HIV-induced over
expression of NO resulted in a
down regulation of CB1 receptors
and in anandamide transporter
activity in the cells. On the other
hand, it was found that CB1 receptor
activation significantly inhibited
the NO release, development of cell
toxicity, and CB1 receptor/anandamide
transporter downregulation
resulting from HIV protein
assault (37). Here both direct CB1
activation through exogenous
drugs like THC or WIN could be
beneficial as well as therapies targeting
means of up regulating the
endocannabinoid system through
FAAH inhibition and stimulation
of endocannabinoid production.
In 2004 Maccarrone, et al., found
significant changes to endocannabinoid
system functioning in the neocortex
of rats following assault by a
particularly toxic HIV protein. The
protein, gp120, was found to
induce increased FAAH production
and anandamide transporter activity
while suppressing levels of anandamide
itself. However, the enzyme
responsible for anandamide production
was unaffected. The activity
of an enzyme capable of creating
endogenous FAAH inhibitors from
anandamide was also drastically
reduced following HIV gp120
assault. As a result of this up regulation
of FAAH and subsequent
down regulation of anandamide in
the rat neocortex, a delayed apoptotic
response to HIV gp120 protein
assault was observed in neocortex
cells. Apoptosis is pro-