Neuroprotective Effects of Autophagy Induced by Rapamycin in Rat Acute Spinal Cord Injury Model

Abstract

Background/Aims: To explore the effects of rapamycin-induced autophagy on apoptosis in a rat model of acute spinal cord injury (SCI), and to explore the effect of rapamycin on apoptosis in primary spinal cord cell culture. Methods: SCI was induced at T10 in female adult Sprague-Dawley rats. After injury was induced, the rats were injected with rapamycin and/or methylprednisolone and were sacrificed at various days after injury. Apoptosis and autophagy were examined with TUNEL staining and electron microscopy. Hind limb function was assessed by the Gale scale. Results: The expression of the apoptosis-related protein caspase-3 did not significantly increase until 21 days following injury, while increases in LC3II and LC3I began 10 days after injury, but then declined. TUNEL staining and electron microscopy confirmed that following injury autophagy occurred before apoptosis, but by 14 days after the injury, the level of autophagy had decreased significantly while the level of apoptosis showed a continued increase. Following treatment with rapamycin, apoptosis was significantly higher than in the vehicle control group, but significantly lower than in the sham-operated group, showing a protective effect of rapamycin. Gale scale grades in rats treated with rapamycin were significantly higher compared with the vehicle control group, suggesting a functional effect of rapamycin-induced inhibition of apoptosis. Conclusions: The results indicate thatrapamycin significantly improved the prognosis of acute SCI in rats by inhibiting cell apoptosis. Rapamycin might be useful as a therapeutic agent for acute SCI.

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…Consistent with the hypothesis that autophagy is beneficial, but usually impaired, in the context of neurotrauma, rapamycin and other molecules with autophagy-inducing potential (for example, melatonin and retinoic acid) limit CNS damage, support regeneration and improve the restoration of neuromuscular functions in rodents experiencing spinal cord injury (SCI) 95 or subarachnoid haemorrhage (SAH) 96–98 . Chemical inhibitors of autophagy, including 3-MA, wortmannin and the antimalarial drug chloroquine (which blocks lysosomal degradation), aggravated neurological damage imposed by SCI or SAH 96,99 , and abolished the neuroprotective effects of autophagy inducers 98,100 .…”

A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies

“…A better understanding of autophagy regulation by LKE and similar compounds could lead to improved treatment for a host of CNS and peripheral conditions where autophagy dysfunction recently has been implicated, including such diverse conditions as Batten disease (Thelen et al, 2012); diabetic neuropathy (Qu et al, 2014); hearing loss (Menardo et al, 2012); lysosomal storage diseases (Pivtoraiko et al, 2009); muscular dystrophies (De Palma et al, 2012; Bibee et al, 2014); spinal cord injury (Wang et al, 2014); and traumatic brain injury (Sarkar et al, 2014). Work is underway in our laboratory, and others, to test LK derivatives in appropriate preclinical models of these pathologies.…”

Effects of calcitriol on experimental spinal cord injury in rats

“…It has been confirmed that promotion of autophagy confers a neuroprotective function in SCI. 26 Moreover, oxidative stress injury can be relieved by autophagy, whereas apoptosis can be inhibited by the activation of autophagy. Therefore, the effects of calcitriol on attenuating oxidative stress and Effects of calcitriol on SCI K-l Zhou et al decreasing apoptosis after SCI in rats may be mediated through activation of autophagy.…”