title: Parasiticidal effect of delta-aminolevulinic acid-based photodynamic therapy for cutaneous leishmaniasis is indirect and mediated through the killing of the host cells.
abstract: Several clinical reports have shown promising, but not optimal, results from photodynamic therapy with delta-aminolevulinic acid-derived protoporphyrin IX, termed ALA-PDT, as a treatment for cutaneous leishmaniasis (CL). Therefore, understanding the basis of the phototoxic response of Leishmania parasites to ALA-PDT may be critical for optimization. We report here both in vitro and in vivo mechanistic studies of ALA-PDT against CL. Following in vitro co-incubation of Leishmania major with 0.1 microM ALA, the PpIX concentration remained at the basal level, whereas after co-incubation with 0.1 microM exogenous PpIX, the PpIX level was 100-fold higher. No differences in ALA-derived PpIX levels were detected between Leishmania-infected and non-infected J774.2 cells, and PDT did not demonstrate any parasiticidal effects on amastigotes. In contrast, in vivo topical ALA-PDT, performed on a murine CL model, resulted in significant reductions of the parasite loads and vigorous tissue destruction. After ALA-PDT, a dramatically decreased percentage of macrophages and increased levels of interleukin-6 were observed in the infected skin. The clinical outcome observed with ALA-PDT is likely the result of unspecific tissue destruction accompanied by depopulation of macrophages rather than direct killing of parasites.
authors.affiliation: Department of Dermatology, Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Akilov
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kosaka
authors.forename: Katie
authors.initials: K
authors.lastname: O'Riordan
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
mesh_terms: D000622:Aminolevulinic Acid / Q000493:pharmacokinetics*; D000818:Animals; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004431:Ear, External / Q000276:immunology / Q000469:parasitology; D015850:Interleukin-6 / Q000378:metabolism; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics*; D011524:Protoporphyrins / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX