Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

Zhou-Shan Tao,Wan-Shu Zhou,Hong-Guang Xu,Min Yang

doi:10.1016/j.ejphar.2021.174268

Abstract

The present work was aimed to evaluate the effect of different administration modes of sodium valproate (VPA) on bone strength, bone mass and bone mineral density in ovariectomized (OVX) rats and further investigation of the possible mechanism. 60 female SD rats were randomly divided into 4 groups: Sham group (Sham, n = 15), OVX group (OVX, n = 15), OVX rats received intermittent VPA treatment group (IVPA, n = 15) and OVX rats received daily VPA treatment group (EVPA, n = 15). After 12 weeks of treatment, the rats were sacrificed, and serum and femur samples were harvested. DEXA, Micro-CT, history, biomechanical testing, biochemical index and western blot analysis were used to observe the therapeutic effect and explore the possible mechanism. Micro-CT and DEXA analysis of bones revealed better BMD and higher BV/TV, Tb. Th, Tb. N, Conn. D and lower Tb. Sp at femoral metaphysis evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). Histological, fluorescent analysis and biological strength revealed more trabecular bone and higher relative mineral apposition rate, maximal load, elastic modulus and energy at break with evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). The levels of P1NP, estrogen, CTX, TRAP-5b and RANKL of the IVPA group showed a significant increase when compared with the OVX and EVPA group (P < 0.05). We confirm adverse effects on protein expressions including Notch1, Jagged1, HEY1, Wnt 1, β-catenin and RUNX2 following daily VPA treatment in OVX female rats. Our current study demonstrated that intermittent administration of sodium valproate has a protective effect on bone health in OVX rats and these effects may be achieved by activating Notch/Wnt/β-catenin/RUNX2 signal axis.

Highlights

Epilepsy is a serious and life-threatening neurological disease characterized by unpredictable and recurrent seizures and is one of the most common chronic disorders[1]
Our current study demonstrated that intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats and these effects may be achieved by activating Notch/Wnt/β-catenin/ RUNX2 signal axis
Previous studies have reported that antiepileptic drugs represented by carbamazepine have a notable impact on vitamin D metabolism and bone density reduction[6]

Summary

Introduction

Epilepsy is a serious and life-threatening neurological disease characterized by unpredictable and recurrent seizures and is one of the most common chronic disorders[1]. It was estimated that more than report 50% bone abnormalities are affected by epilepsy worldwide[2]. Due to seizure-related falls, ataxia, immobility leading to falls and long-term use of anti-epileptic drugs causing bone loss and abnormal bone metabolism, the incidence of osteoporosis and osteoporotic fracture in these patients is significantly higher than that of normal people[3, 4]. The relationship between epilepsy, antiepileptic drugs and bone mineral density has been explored for more than 30 years[3,4,5]. Previous studies have reported that antiepileptic drugs represented by carbamazepine have a notable impact on vitamin D metabolism and bone density reduction[6]. Some studies based on new antiepileptic drugs did not find a statistically significant changes in calcium, vitamin D, BMD in patients with epilepsy[7]

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