Hematopoietic and T-lymphopoiesis-stimulating effects of a fluorinated pyrazolopiperidine β-cyclodextrin complex in cyclophosphamide-induced hematopoietic suppression.

BACKGROUND: Cyclophosphamide is widely used in oncology, autoimmune disorders, and transplantation-related conditioning or post-transplant immunosuppression. However, its therapeutic value is limited by hematopoietic and lymphoid toxicity, including leukopenia, neutropenia, anemia, thrombocytopenia, bone marrow suppression, thymic injury, and prolonged impairment of T-cell recovery. These effects may occur after pulsed intravenous administration, high-dose regimens used in transplantation or severe refractory disease, and continuous low-dose/metronomic exposure. Therefore, there is a medical need for pharmacological agents capable of compensating cyclophosphamide-induced hematopoietic and lymphopoietic suppression without causing uncontrolled stimulation of early progenitor cells. AIM: To evaluate the hematopoietic and T-lymphopoiesis-stimulating activity of BIV under cyclophosphamide-induced hematopoietic and T-lymphopoietic suppression. METHODS: Cyclophosphamide-induced hematopoietic- and T-lymphopoiesis-suppressive models were established on laboratory albinos rats and C57BL6/J mice. Peripheral blood hematological indices in rats were measured using hematology analyzers. Hematopoietic stem cells, thymocyte subsets, Thact, Treg, Tmem, CTL cell populations, and erythroid cells from the bone marrow, thymus, and spleen were analyzed by flow cytometry. Statistical analysis was performed using one-way ANOVA (p < 0.05). RESULTS: In rats with CPh-induced hematopoietic suppression, BIV supported partial recovery of erythrocyte and hemoglobin parameters and improved leukopoietic indices under CPh-induced hematopoietic suppression. The β-cyclodextrin complex of 5-benzyl-7-(o-fluorobenzylidene)-2,3-bis(o-fluorophenyl)-3,3a,4,5,6, 7-hexahydro-2H-pyrazolo[4,3-c]pyridine (BIV) demonstrated a consistent moderate activity in restoring the overall level of CD3ε+CD19- T lymphocytes in the bone marrow and thymus. In the bone marrow, BIV uniformly increased the reduced levels of CD3ε+CD19- T lymphocytes and CD3ε+CD44+ Tmem memory T cells to physiological normal values. In the spleen, BIV restored the decreased levels of CD25+FoxP3+ Treg regulatory lymphocytes and CD28+CD44+ Tmem memory T cells to physiological normal levels, while reducing the elevated levels of CD3ε+CD8a+ CTL cytotoxic T lymphocytes and CD4+CD25+ Thact activated helper T cells to values corresponding to the physiological norm. CONCLUSION: BIV demonstrated notable hematopoietic- and T-lymphopoiesis-modulating activity. The compound partially restored erythropoiesis as well as central and peripheral T-lymphopoiesis, while providing balanced regulation of cytotoxic, regulatory, and memory T-cell subsets in cyclophosphamide-induced T-lymphopoiesis-suppressive models. Several evaluated T-lymphocyte subpopulations approached or returned to physiological control levels under the experimental conditions, although full translational validation requires further pharmacological and toxicological investigation.