Comparative Evaluation of the Early Immunological Effects of a Novel Piperidine α-Hydroxyphosphonate and a Phosphorodiamidate Morpholino Oligomer in an Imiquimod-Induced Psoriasis Model

Psoriasis is a chronic immune-mediated inflammatory disease associated with dysregulation of T-cell responses and cytokine signaling. The aim of this study was to synthesize and structurally characterize a piperidine α-hydroxyphosphonate (OPP) and to comparatively evaluate the effects of OPP and the vivo-phosphorodiamidate morpholino oligomer (vPMO) in a preclinical model of imiquimod-induced psoriasis. OPP was synthesized by hydrophosphorylation of 1-(3-isopropoxypropyl)piperidin-4-one with dimethyl phosphite; its structure was confirmed by IR, NMR spectroscopy, and elemental analysis. Psoriasis was induced in rats by topical application of imiquimod (IMQ). The animals were randomly allocated into six groups: control (C), experimental psoriasis (Ps), vehicle-treated (Ps/V), glucocorticosteroid-treated (Ps/GCS), piperidine α-hydroxyphosphonate-treated (Ps/OPP), and vivo-phosphorodiamidate morpholino oligomer-treated (Ps/vPMO) groups. Clinical manifestations were assessed on Days 3, 5, and 7 using a modified Psoriasis Area and Severity Index (PASI). During the 7-day observation period, body weight and the modified Psoriasis Area and Severity Index (PASI) score were assessed on Days 3, 5, and 7. Histopathological changes were evaluated using hematoxylin and eosin (H&E) staining. On day 7, CD3+CD45R−, CD4+CD8−, and CD4+CD25+ T-cell subpopulations were determined by flow cytometry, while serum concentrations of IL-6, TNF-α, IL-10, TGF-β1, IL-17A, and IL-22 were measured using an enzyme-linked immunosorbent assay (ELISA). IMQ administration resulted in the progressive development of psoriasiform skin lesions characterized by hyperkeratosis, acanthosis, inflammatory infiltration of the dermis, body weight loss, decreased numbers of CD3+CD45R− and CD4+CD8− cells, increased levels of IL-6, IL-17A, and IL-22, and reduced IL-10 levels. OPP treatment was associated with a reduction in the total PASI score and the severity of scaling, as well as decreased serum concentrations of IL-6, IL-17A, and IL-22 and an increased IL-10 concentration. In addition, OPP increased the number of CD4+CD8− cells compared with the psoriasis group, whereas the number of CD4+CD25+ cells remained below the control level. In contrast, vPMO treatment exhibited a distinct response profile characterized by increased numbers of CD3+CD45R− and CD4+CD8− cells, decreased IL-17A and IL-22 levels, increased IL-10 levels, and a particularly pronounced increase in TGF-β1 while producing less pronounced changes in certain cutaneous manifestations. Overall, OPP was characterized by a more consistent pattern of clinical, histopathological, and immunological changes, whereas vPMO treatment predominantly resulted in more pronounced alterations in systemic immunological parameters. These findings indicate distinct patterns of biological effects of OPP and vPMO in the IMQ-induced psoriasiform skin lesion model and support further preclinical investigation of these compounds. However, the observed changes do not allow definitive conclusions to be drawn regarding the underlying molecular mechanisms or the involvement of specific cellular pathways and should be interpreted in light of the limited observation period, the restricted panel of cellular markers examined, the absence of certain experimental controls, and the lack of pharmacokinetic data.