Effects of calcitriol on experimental spinal cord injury in rats

Abstract

Study design: Experimental, controlled, animal study. Objectives: To evaluate the effects of calcitriol on oxidative stress, apoptosis, autophagy and locomotor recovery in rats after spinal cord injury (SCI). Setting: China. Methods: Ninety female rats were randomly divided into three groups. Laminectomy only was performed in the control group. The SCI group received laminectomy as well as spinal cord compression injury. In the calcitriol group, SCI rats received an intraperitoneal injection of calcitriol (2 μg kg − 1 day − 1 ). Oxidative stress was assessed by the tissue superoxide dismutase (SOD) activity and the contents of glutathione (GSH) and malondialdehyde (MDA). The extent of apoptosis was assessed by immunohistochemistry for C-caspase3, TUNEL staining and western blotting for C-caspase3, Bax and Bcl2. Transmission electron microscopy was used to examine autophagosomes in the injured spinal cord of calcitriol-treated rats. Autophagy was detected by western blotting for LC3-II, Beclin1 and p62. Histological changes were assessed by haematoxylin and eosin staining and Nissl staining. Functional recovery was reflected by the Basso, Beattie and Bresnahan locomotion rating scale and the inclined plane test. Results: With calcitriol treatment, oxidative stress was decreased, SOD activity and GSH content were increased and MDA content was decreased. Moreover, apoptosis was inhibited in the SCI plus calcitriol group. However, a higher level of autophagy was detected in the lesions of the calcitriol group compared with the SCI group. Histological damage and neuron loss after SCI were reduced in calcitrioltreated rats, and functional recovery was significantly promoted in the calcitriol group compared with controls. Conclusions: Calcitriol promotes locomotor recovery after SCI by reducing oxidative stress and inhibiting apoptosis, as well as promoting autophagy.

Induction of the Vitamin D Receptor Attenuates Autophagy Dysfunction-Mediated Cell Death Following Traumatic Brain Injury

“…We found that the rate of apoptotic cells in the cortex region was markedly reduced in the calcitriol group compared with the TBI group, indicating that calcitriol inhibits cell death induced by TBI. Furthermore, previous studies have demonstrated that calcitriol could exert neuroprotective actions in multiple models of acquired brain injury, such as traumatic brain injury, stroke, spinal cord injury and Parkinson's disease [18, 21, 22]. These findings, together with the observations of the present study, may aid in improving the current understanding of calcitriol-mediated neuroprotection in neurological disorders.…”

“…Therefore, strategies that regulate autophagy may guard against or cure human disorders [13-16]. Recently, in vitro and in vivo studies have demonstrated that autophagy could be enhanced following supplementation with an active metabolite of VD (calcitriol) [17, 18]. However, it is unclear whether autophagy participates in the protective effects of calcitriol after TBI.…”

The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury

“…Zhang et al demonstrated that the expression level of p62 in lesion was increased at day 3 after the severe compression injury induced by vascular clip (30 g force) compression for 1 min to the spinal cord [38]. However, in our previous studies, the increased expression of p62 was found in injured spinal cord at day 7 after relatively moderate compression injury (15 g for 1 min) [38,77]. According to the current results, severe compression injury may contribute to autophagic flux blockade, and moderate compression injury may result in autophagic flux enhancement.…”

“…Furthermore, increasing the level of autophagic flux can therefore inhibit apoptosis in those SCI models [38,44]. However, this mechanism does not seem to explain the inhibition of apoptosis by autophagy in hemisection injury [27] and moderate compression injury [77], where the flux of autophagy was enhanced. It is important to note that mitophagy (autophagy of mitochondria) also plays a role in inhibition of apoptosis by autophagy in various diseases [90,91].…”

“…Specifically, calcitriol promoted locomotor recovery after SCI by reducing oxidative stress and inhibition of apoptosis, and increased autophagy activity [77]. Metformin administration was found to provide neuroprotection for SCI by decreasing lesion issue damage and neurons apoptosis, and increasing the level of autophagy [38].…”