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

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Abstract

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.

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