Parinari curatellifolia aqueous leaf-bark extract mitigates chronic Plasmodium berghei-induced bone loss in Wistar rats through anti-inflammatory and osteoregenerative mechanisms.

Chronic Plasmodium infections can promote parasite sequestration in bone tissue, leading to progressive skeletal damage and increased fracture risk. In Cameroon, Parinari curatellifolia is traditionally used to treat both malaria and bone fractures. Previous studies demonstrated protective effects of an aqueous leaves and stem bark mixture extract of this plant (PCM) against acute malaria-induced bone damage. This study investigated the osteoregenerative potential of PCM extract in a chronic Plasmodium berghei ANKA-induced bone loss model in Wistar rats using in vivo and in silico approaches. Female Wistar rats were alternately inoculated intraperitoneally with P. berghei ANKA for 28 days. They received distilled water, chloroquine sulfate (10 mg/kg), or PCM (75, 150, or 300 mg/kg) daily for 14 days. Parasitemia was monitored throughout treatment. Blood was collected for hematological evaluation, while femurs were excised for biochemical, immunological, oxidative stress, histopathological, and morphometric analyses. Drug-likeness properties and molecular docking of previously identified compounds were evaluated against NLRP3 and Plasmodium falciparum falcipain-2, using Molecular Operating Environment 14. Chronic Plasmodium berghei was characterized by an increase (p < 0.001) in parasitemia and femoral levels of CRP, TNF-α, IL-1β, and IL-6, with a decrease (p < 0.001) of IL-4, IL-10, and IFN-γ levels. Histological analysis revealed femoral head alterations characterized by porous cartilage and significant reductions (p < 0.001) in cartilage thickness and trabecular parameters in infected rats. PCM administration reduced (p < 0.001) parasitemia, restored bone abnormalities by increasing (p < 0.001) alkaline phosphatase activity, calcium, and phosphorus levels. PCM also reduced (p < 0.001) femoral levels of proinflammatory markers, while increasing (p < 0.001) the levels of anti-inflammatory parameters. The extract restored femoral microarchitecture compared with untreated control. Most identified compounds complied with Lipinski's rule of five and exhibited favorable predicted binding affinity toward NLRP3 receptor and falcipain-2. P. curatellifolia aqueous extract promoted bone regeneration in a model of chronic Plasmodium-induced osteoporosis. Molecular docking analyses suggested potential interactions between its phytoconstituents and NLRP3 as well as falcipain-2, providing mechanistic hypotheses that warrant further experimental validation. The extract could act through antiplasmodial, osteogenic and anti-inflammatory mechanisms, thus providing a rationale for its traditional use in the management of malaria and bone defects.