Autophagy Reduces Neuronal Damage and Promotes Locomotor Recovery via Inhibition of Apoptosis After Spinal Cord Injury in Rats

Abstract

Autophagy is an intracellular catabolic mechanism that maintains the balance of proteins, lipids and aging organelles. 3-Methyladenine (3-MA) is a selective inhibitor of autophagy, whereas rapamycin, an antifungal agent, is a specific inducer of autophagy, inhibiting the protein mammalian target of rapamycin. In the present study, we examined the role of autophagy, inhibited by 3-MA and enhanced by rapamycin, in a model of acute spinal cord injury in rats. We found that rapamycin could significantly increase the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin1 at the injury site. At the same time, the number of neurons and astrocytes with LC3 positive in the spinal cord was upregulated with time. In addition, administration of rapamycin produced an increase in the Basso, Beattie and Bresnahan scores of injured rats, indicating high recovery of locomotor function. Furthermore, expression of the proteins Bcl-2 and Bax was upregulated and downregulated, respectively. By contrast, the results for rats treated with 3-MA, which inhibits autophagy, were the opposite of those seen with the rapamycin-treated rats. These results show that induction of autophagy can produce neuroprotective effects in acute spinal cord injury in rats via inhibition of apoptosis.

Effects of calcitriol on experimental spinal cord injury in rats

“…24 Over the past few years, calcitriol has been reported to upregulate the level of autophagy-that is, it can induce autophagy in the SH-SY5Y neuroblastoma cell line as a model of Parkinson's disease. 7 In addition, calcitriol shows biochemical protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease through induction of autophagy. 25 The present study showed the levels of LC3-II and Beclin1 proteins, representing increased autophagy flux, but the level of p62 protein, which was degraded through the autophagy-lysosomal pathway, decreased in the SCI rats treated with calcitriol compared with the SCI group.…”

“…Furthermore, recent evidence suggests that stimulation of autophagy after SCI contributes to nerve cell selfprotection and locomotive recovery. 7 Calcitriol (C 44 H 80 O 4 Si 2 , also known as 1,25-dihydroxyvitamin D 3 ), which has biological functions in bone and calcium metabolism, has a key role in osteoporosis. However, calcitriol has recently been shown to have a number of bioactivities.…”

Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

“…Kanno et al [18] found that rapamycin reduced locomotor impairment and neuronal death after spinal cord injury in mice. This effect of rapamycin was reported to be mediated through activation of autophagy by inhibiting the mammalian target of rapamycin (mTOR) signaling pathways [36].…”

Intrathecal Injection of 3-Methyladenine Reduces Neuronal Damage and Promotes Functional Recovery <i>via</i> Autophagy Attenuation after Spinal Cord Ischemia/Reperfusion Injury in Rats

“…30,31) Moreover, poor therapeutic value of 3-MA treatment has also been reported in traumatic spinal injury models. 32,33) In cerebral ischemia studies, substantial evidence suggests 3-MA inhibits autophagy activation and maturation, reduces I/R injury, and improves cell survival in vivo and in vitro. 34,35) An intrathecal injection of 3-MA was administered to enable the drug to enter the cerebrospinal fluid to directly act on the injured spinal nerves.…”