412 G.A. Cabral and A. Staab
of CNS tissue revealed a marked reduction of inflammation in the THC-treated
animals. Wirguin et al. (1994) examined the effect of∆^8 -THC, a more stable
and less psychotropic analog of THC, on EAE using two strains of rats.∆^8 -THC
significantly reduced the incidence and severity of neurological deficit in both
strains. It was suggested that suppression of EAE by cannabinoids was related to
their effect on corticosterone secretion. Pryce et al. (2003), using the EAE model,
also reported that cannabinoids could inhibit neurodegeneration. In addition,
exogenously introduced CB 1 agonists provided significant neuroprotection from
the consequences of inflammatory CNS disease in an animal model of experimental
allergic uveitis.
Molina-Holgado et al. (1998) utilized Theiler’s murine encephalomyelitis virus
(TMEV) to produce persistent brain infection in mice with attendant chronic
primary immune-mediated demyelination resembling MS. The effects of anan-
damide on astrocytes infected with TMEV were examined, since these glial cells
in the brain are potent producers of pro-inflammatory cytokines upon virus in-
fection. Astrocytes from susceptible (SJL/J) and resistant (BALB/c) strains of mice
infected with TMEV exhibited increased IL-6 release that was enhanced by anan-
damide. Treatment of TMEV-infected astrocytes with arachidonyl trifluoromethyl
ketone, a potent inhibitor of the amidase that degrades anandamide, potentiated
this anandamide effect. SR141617A, the CB 1 antagonist, blocked the enhancing
effects of anandamide on IL-6 release by TMEV-infected astrocytes, suggesting
a cannabinoid receptor-mediated pathway. The investigators indicated that, while
the physiological implications of these results were unknown, they could be re-
lated to the postulated protective effects of cannabinoids on neurological disorders
such as MS. Arevalo-Martin et al. (2003), using the TMEV model, demonstrated
that treatment with WIN 55,212-2, the potent highly selective CB 1 agonist ACEA,
or the CB 2 receptor high-affinity cannabimimetic JWH-015 during established
disease resulted in significant long-term improvement of neurological deficits.
Similarly, Croxford et al. (2003) demonstrated that WIN 55,212-2 ameliorated pro-
gression of clinical disease symptoms in mice with preexisting Theiler murine
encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Ablation of
disease was associated with down-regulation of virus and myelin epitope-specific
Th 1 effector functions (i.e., delayed-type hypersensitivity and IFN-γproduction)
and the inhibition of CNS mRNA expression for the pro-inflammatory cytokines
TNF-α,IL-1β, and IL-6. Killestein et al. (2003) assessed the immunomodulatory
effects of orally administered cannabinoids in 16 MS patients. A modest increase
of TNF-αin LPS-stimulated whole blood was found during cannabis plant-extract
treatment, but changes in levels of other cytokines were not observed. In pa-
tients with high adverse event scores, it was found that an increase in plasma
IL-12p40 occurred. The investigators suggested that cannabinoids had a potential
for modifying MS in humans. Li et al. (2001) examined the immunosuppressive
effects of THC in streptozotocin (STZ)-induced autoimmune diabetes. THC ad-
ministered orally to CD-1 mice attenuated, in a transient manner, the STZ-induced
elevation in serum glucose and loss of pancreatic insulin. STZ-induced insuli-
tis and increases in IFN-γ, TNF-α, and IL-12 mRNA levels were reduced by co-
administrationofTHC.Studiesperformedusing(B 6 C 3 )F 1 miceshowedamoderate