Effects on the Immune System 413hyperglycemia and a significant reduction in pancreatic insulin by STZ in the ab-
sence of insulitis. The investigators suggested that THC was capable of attenuating
the severity of autoimmune responses in this experimental model of autoimmune
diabetes.
In addition, it has been proposed that cannabinoids may protect against septic
shock and brain trauma. Bass et al. (1996) suggested that Dexanabinol, the nonpsy-
chotropic cannabinoid HU-211, had potential for use in treatment based on use
of an experimental rat model of meningitis in which rats were inoculated with
Streptococcus pneumoniae. HU-211 was efficacious when used in combination
with antimicrobial therapy in reducing brain damage, especially when given con-
comitantly with antibiotics. Shohami et al. (1997) developed an experimental rat
model for closed head injury (CHI), in which edema, blood–brain barrier disrup-
tion, and motor and memory dysfunctions were demonstrated. Using this model,
spatial and temporal induction of IL-1, IL-6, and TNF-αgene mRNA transcription
and TNF-αand IL-6 activity in rat brain after CHI were demonstrated. HU-211
acted as an effective cerebroprotectant in that it suppressed TNF-αproduction.
HU-211, pentoxifylline and TNF-binding protein improved the outcome of CHI.
These studies were extended by Gallily et al.(1997) who demonstrated that HU-
211 not only suppressed TNF-αproduction but also rescued mice and rats from
endotoxic shock after LPS inoculation.
It has been proposed, also, that cannabinoids have therapeutic potential in
the management of select microbial infections. Nok et al. (1994) examined the
effect ofCannabis sativaon trypanosome-infected rats. It was reported that an
aqueous extract of the seeds cured animals infected withTrypanosome brucei
bruceiof blood stream parasites. Berdyshev et al. (1998) investigated the ef-
fects of WIN 55,212-2, THC, anandamide, and palmitoylethanolamide on LPS-
induced bronchopulmonary inflammation in mice. WIN 55,212-2 and THC in-
duced a concentration-dependent decrease in TNF-αlevels in bronchoalveolar
lavage fluid. This effect was accompanied by moderately reduced neutrophil re-
cruitment. Palmitoylethanolamide diminished levels of TNF-αin bronchoalveolar
lavage fluid but had no effect on neutrophil recruitment. Anandamide did not
influence the inflammatory process but TNF-αlevels and neutrophil recruitment
were decreased. Gross et al. (2000) reported that the CB 1 antagonist SR141716A
was a potent inhibitor of macrophage infection by the intracellular gram-negative
bacterial pathogenBrucella suis. These investigators assessed the influence of
the CB 1 or CB 2 antagonists SR141716A and SR144528, respectively, as well as the
nonselective CB 1 /CB 2 cannabinoid receptor agonists CP55,940 or WIN 55,212-2
on macrophage infection. The intracellular multiplication ofBrucellawas dose-
dependently inhibited in cells treated with SR141716A, which exerted a potent
microbicidal effect. The involvement of CB 1 receptorsintheprotectiveeffect
was proposed. Furthermore, SR141716A was able to pre-activate macrophages
and to trigger an activation signal that inhibitedBrucelladevelopment. Collec-
tively, the results indicated that SR141716A up-regulated the antimicrobial prop-
erties of macrophages in vitro and that it might serve as a pharmaceutical com-
pound for counteracting the propagation of intra-macrophagic gram-negative
bacteria.