Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton, is known to have a positive effect on bone and ischemic brain. We studied the effect of zileuton on bone, its healing and on the genes for bone-brain cross-talks. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 weeks, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10 or 100 mg/kg body weight) for 5 weeks. In tibiae, bone volume, callus and cortical volume, gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 mg, 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal decreasing their density. The expression level of brain Sema3a, known to positively regulate bone mass, was downregulated after ovariectomy, while bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy while zileuton treatment (10 mg, 100 mg) reversed these effects. Here, we describe for the first time, the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in crosstalk between bones and brain and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s).
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