title: β-Adrenergic blockade protects BALB/c mice against infection with a small inoculum of Leishmania mexicana mexicana (LV4).
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 (5mg/kg thrice a day), the β2-AR agonist clenbuterol (1mg/kg once a day) or the α2-AR antagonist yohimbine (2mg/kg twice a day) during 5days. During the second day of treatments, mice were inoculated in the footpad with 1×10(6) or 1×10(3) 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 1×10(6) 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 1×10(3) 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.
authors.affiliation: Departamento de Neurociencias, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Avenida Itzáes No. 490×59, Mérida, Yucatán, Mexico 97000. Electronic address: gmiss@uady.mx.
authors.forename: María del R
authors.initials: Mdel R
authors.lastname: García-Miss
authors.affiliation: Departamento de Neurociencias, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Avenida Itzáes No. 490×59, Mérida, Yucatán, Mexico 97000.
authors.forename: Mirza C
authors.initials: MC
authors.lastname: Mut-Martín
authors.affiliation: Departamento de Neurociencias, Centro de Investigaciones Regionales "Dr. Hideyo Noguchi", Universidad Autónoma de Yucatán, Avenida Itzáes No. 490×59, Mérida, Yucatán, Mexico 97000.
authors.forename: José L
authors.initials: JL
authors.lastname: Góngora-Alfaro
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D002976:Clenbuterol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007894:Leishmania mexicana / Q000276:immunology*; D054332:Leishmaniasis Vaccines / Q000008:administration & dosage; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D011433:Propranolol / Q000008:administration & dosage*; D011576:Psychodidae / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D015016:Yohimbine / Q000008:administration & dosage
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D054332:Leishmaniasis Vaccines; D015016:Yohimbine; D007371:Interferon-gamma; D011433:Propranolol; D002976:Clenbuterol
keywords: Catecholamines; Cellular immunity; Cytotoxic lymphocytes; Innate immunity; Neuroimmunomodulation