Cannabinoids as Immune Therapeutic Agents

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Cannabinoids, as immunosuppressive compounds, have been proposed as having therapeutic potential in chronic inflammatory disorders and neurodegenerative disease triggered by inflammatory attack. Lyman et al. (1989) inoculated Lewis rats and strain 13 guinea pigs with myelin-basic protein emulsified in complete Freund's adjuvant to induce experimental autoimmune encephalomyelitis (EAE) to mimic MS and indicated that THC-treated animals had either no clinical signs or exhibited mild signs with delayed onset and greater survival. Examination of CNS tissue revealed a marked reduction of inflammation in the THC-treated animals. Wirguin et al. (1994) examined the effect of 48-THC, a more stable and less psychotropic analog of THC, on EAE using two strains of rats. 48-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 CB1 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 infection. 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 CBi 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 related 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 CB1 agonist ACEA, or the CB2 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 progression 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 Th1 effector functions (i.e., delayed-type hypersensitivity and IFN-y production) and the inhibition of CNS mRNA expression for the pro-inflammatory cytokines TNF-a, IL-1^, and IL-6. Killestein et al. (2003) assessed the immunomodulatory effects of orally administered cannabinoids in 16 MS patients. A modest increase of TNF-a in LPS-stimulated whole blood was found during cannabis plant-extract treatment, but changes in levels of other cytokines were not observed. In patients 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 administered 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-y, TNF-a, and IL-12 mRNA levels were reduced by coadministration of THC. Studies performed using (B6C3)F1 mice showed a moderate hyperglycemia and a significant reduction in pancreatic insulin by STZ in the absence 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 concomitantly with antibiotics. Shohami et al. (1997) developed an experimental rat model for closed head injury (CHI), in which edema, blood-brain barrier disruption, and motor and memory dysfunctions were demonstrated. Using this model, spatial and temporal induction of IL-1, IL-6, and TNF-a gene mRNA transcription and TNF-a and IL-6 activity in rat brain after CHI were demonstrated. HU-211 acted as an effective cerebroprotectant in that it suppressed TNF-a production. 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-a production 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 of Cannabis sativa on trypanosome-infected rats. It was reported that an aqueous extract of the seeds cured animals infected with Trypanosome brucei brucei of blood stream parasites. Berdyshev et al. (1998) investigated the effects of WIN 55,212-2, THC, anandamide, and palmitoylethanolamide on LPS-induced bronchopulmonary inflammation in mice. WIN 55,212-2 and THC induced a concentration-dependent decrease in TNF-a levels in bronchoalveolar lavage fluid. This effect was accompanied by moderately reduced neutrophil recruitment. Palmitoylethanolamide diminished levels of TNF-a in bronchoalveolar lavage fluid but had no effect on neutrophil recruitment. Anandamide did not influence the inflammatory process but TNF-a levels and neutrophil recruitment were decreased. Gross et al. (2000) reported that the CBi antagonist SR141716A was a potent inhibitor of macrophage infection by the intracellular gram-negative bacterial pathogen Brucella suis . These investigators assessed the influence of the CB1 or CB2 antagonists SR141716A and SR144528, respectively, as well as the nonselective CB1/CB2 cannabinoid receptor agonists CP55,940 or WIN 55,212-2 on macrophage infection. The intracellular multiplication of Brucella was dose-dependently inhibited in cells treated with SR141716A, which exerted a potent microbicidal effect. The involvement of CB1 receptors in the protective effect was proposed. Furthermore, SR141716A was able to pre-activate macrophages and to trigger an activation signal that inhibited Brucella development. Collectively, the results indicated that SR141716A up-regulated the antimicrobial properties of macrophages in vitro and that it might serve as a pharmaceutical compound for counteracting the propagation of intra-macrophagic gram-negative bacteria.

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