Wednesday, July 22, 2015

Cannabidiol in Asthma Treatment: Now Mice Later Men?

Cannabinoids are components of the Cannabis sativa (marijuana) plant and are known to exert potent anti-inflammatory, immunomodulatory, and analgesic effects through activation of cannabinoid-1 and cannabinoid-2 (CB1 and CB2) receptors located in the central nervous system (CNS) and immune cells, respectively. Cannabidiol (CBD) is the main nonpsychotropic cannabinoid and reported to have beneficial effects in many pathological conditions, including neuropsychiatric disorders and brain inflammatory diseases, without having significant activity on CB1 and CB2 receptors.

Asthma is a disorder of the conducting airways, which contract too much and too easily both spontaneously and in response to a wide range of exogenous and endogenous stimuli. This airway hyper-responsiveness is accompanied by enhanced sensory irritability of airways and increased mucus secretion. Classically, asthma is characterized by chronic airway inflammation and remodeling, hyper-responsiveness, and increase of T-helper cell 2 levels- (Th2-) related cytokines.

Taking a clue form various published results that CBD was shown to have potent immunosuppressive and anti-inflammatory properties, researchers developed a mouse model where they were able to prove protective effect of CBD upon inflammatory response in an animal model of asthma. Researchers determined the levels of 6 cytokines implicated in asthma, which can be divided by the response profiles Th1 (TNF-α and IL-6) and Th2 (IL-4, IL-13, IL-10, and IL-5). Asthma induction resulted in an increase in all cytokines levels when compared to control animals. CBD treatment was able to decrease both Th1 and Th2 cytokines.

Study Design: Rats were immunized by an i.p. injection of 10 µg of chicken ovalbumin (OVA) in 100 µL of aluminum hydroxide (alum) or alum alone. After 14 days, rats were boosted with OVA or alum. Seven days later, rats received aerosol challenges (30 min/for 3 days) with 1% OVA or saline. CBD was suspended in 2% of polyoxyethylenesorbitan monooleate (Tween 80). The solutions were prepared immediately before use and were protected from light during the experimental session. CBD was administered i.p. once a day during the last two days of the OVA challenge at the dose of 5 mg/kg.

All treatments were administered in a volume of 1 mL/kg of CBD or vehicle. For this experiment, 21 rats were used, which were randomly divided into three groups: vehicle (control) (n = 7), OVA + vehicle (asthma control) (n = 7), and OVA + CBD (asthma + treatment) (n = 7). Blood samples were obtained 24 hours after the last challenge by decapitation to determine the levels of cytokines.

Important clinical findings using a mice model:

1. CBD treatment significantly decreased the levels of cytokines involved in the immune response to an allergen, such as IL-4 and IL-5: IL-4 is responsible for the inhibition of Th1 cells differentiation and for Th2 cells differentiation and expansion and has an important role in IgE production. In addition, IL-4 seems to be a requisite for T lymphocytes to produce IL-5. IL-5 is essential for the maturation of eosinophils, and it accumulates in the lung during the inflammatory process of asthma.

2. IL-13 was reduced by CBD administration: IL-13 is considered a major stimulus for mucus hypersecretion, an important characteristic of asthma, which contributes to the exacerbation of symptoms.

3. CBD is able to decrease IL-6 levels: IL-6 levels are increased in sputum and systemic circulation in severe asthmatic patients, which can be responsible for the raise of C-reactive protein circulation in these patients.

4. CBD reduced the levels of TNF-α: TNF-α is a major mediator of severe asthma.

The authors were also candid is pointing outs some limitations on their part in not been able to measure lung function and the effect of CBD in bronchoalveolar lavage fluid cytokines, but they are sure that these results can act as a guide for future experiments.

Article citation: Dal-Pizzol, F.; et. al. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators Inflamm 2015, 538670.