β-Adrenergic blockade protects BALB/c mice against infection with a small inoculum of Leishmania mexicana mexicana (LV4)

• Drugs modulating adrenergic transmission were tested in Leishmania-infected mice.
• The β-adrenergic blocker (S)-propranolol reduced footpad swelling and parasite load.
• (S)-propranolol increased proliferation of CD4+ and CD8+ T cells producing IFN-γ.
• The α2-blocker yohimbine partially reduced footpad swelling and parasite load.
• β-Antagonists could be used as adjuvants in treatments or vaccines for leishmaniasis.

In order to test the influence of the sympathetic nervous system on Leishmania mexicana infection, groups of female BALB/c mice were treated (i.p.) with the non-selective β-adrenergic receptor (β-AR) antagonist (S)-propranolol (5 mg/kg thrice a day), the β2-AR agonist clenbuterol (1 mg/kg once a day) or the α2-AR antagonist yohimbine (2 mg/kg twice a day) during 5 days. During the second day of treatments, mice were inoculated in the footpad with 1 × 106 or 1 × 103 metacyclic promastigotes of L. mexicana mexicana (LV4). The lesion size was measured weekly, and parasite burden on week 12. In mice treated with (S)-propranolol, the percentage of splenic T lymphocytes producing IFN-γ after antigen challenge was determined by flow cytometry. In mice infected with 1 × 106 parasites, only (S)-propranolol caused a reduction of footpad swelling (p < 0.05, weeks 11–12), without effects on parasite burden, or in the percentage of IFN-γ-immunopositive CD4+ or CD8+ T lymphocytes. In mice infected with 1 × 103 parasites, the effects of treatments vs. control group were as follows: (a) inhibition of footpad swelling by (S)-propranolol (p < 0.01, weeks 3–12), clenbuterol (p < 0.05, weeks 7–10), and yohimbine (p < 0.01, week 7); (b) a decrease of the parasite burden by (S)-propranolol (p < 0.01) and yohimbine (p < 0.05); (c) in control mice the percentage of CD4+ T-cells producing IFN-γ was 6.2 ± 0.5%, while in those treated with (S)-propranolol it increased to 8.7 ± 0.6% (p < 0.01); (d) in control mice the percentage of CD8+ T-cells producing IFN-γ was 3.1 ± 0.4%, while in those treated with (S)-propranolol it increased to 10.4 ± 0.2% (p < 0.01). These results indicate that the blockade of β-ARs during infection of BALB/c mice with an inoculum of L. mexicana mexicana similar to that delivered by the bite of a sand fly produces a Th1 bias in the immune response, favoring an increment of T lymphocytes secreting IFN-γ, which correlated with a reduced parasite burden (p < 0.05, Spearman's test). We suggest that β-AR antagonists could be of therapeutic value, either as treatment or as adjuvant of vaccines for L. mexicana.