TY - JOUR
T1 - Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection
AU - Chen, Hsien Chih
AU - Fong, Tsorng Harn
AU - Hsu, Peng Wei
AU - Chiu, Wen Ta
N1 - Funding Information:
This research was supported by a grant from Chang Gung Memorial Hospital ( CMRPG290311 ). The authors thank Ms. Yu-Tze Lin and Huei-Ting Tsai for technical assistance, and the animal care team at Laboratory Animal Center of Chang Gung Memorial Hospital at Keelung for the animal care in this study.
PY - 2013/1
Y1 - 2013/1
N2 - Background: Spinal cord injuries (SCIs) are serious and debilitating health problems that lead to severe and permanent neurological deficits resulting from the primary mechanical impact followed by secondary tissue injury. During the acute stage after an SCI, the expression of autophagy and inflammatory responses contribute to the development of secondary injury. In the present study, we examined the multifaceted effects of rapamycin on outcomes of rats after an SCI. Materials and methods: We used 72 female Sprague-Dawley rats for this study. In the SCI group, we performed a laminectomy at T10, followed by impact-contusion of the spinal cord. In the control group, we performed only a laminectomy without contusion. We evaluated the effects of rapamycin using the Basso, Beattie, and Bresnahan scale for functional outcomes, Western blot analyses for analyzing LC3-II, tumor necrosis factor expression, and p70S6K phosphorylation, and an immunostaining technique for localization and enumeration of microglial and neuronal cells. Results: Basso, Beattie, and Bresnahan scores after injury significantly improved in the rapamycin-treated group compared with the vehicle group (on Day 28 after the SCI; P <.05). The Western blot analysis demonstrated that rapamycin enhanced LC3-II expression and decreased p70S6K phosphorylation compared with the vehicle (P <.01), which implies promotion of autophagy through mammalian target of rapamycin inhibition. Furthermore, rapamycin treatment significantly attenuated tumor necrosis factor production and microglial expression (P <.05). Immunohistochemistry of NeuN (antibodies specific to neurons) showed remarkable neuronal cell preservation in the rapamycin-treated group compared with the vehicle-treated group (P <.05), which suggests a neuroprotective effect of rapamycin. Conclusions: Rapamycin is a novel neuroprotectant with multifaceted effects on the rat spinal cord after injury. Use of such a clinically established drug could facilitate early clinical trials in selected cases of human SCIs.
AB - Background: Spinal cord injuries (SCIs) are serious and debilitating health problems that lead to severe and permanent neurological deficits resulting from the primary mechanical impact followed by secondary tissue injury. During the acute stage after an SCI, the expression of autophagy and inflammatory responses contribute to the development of secondary injury. In the present study, we examined the multifaceted effects of rapamycin on outcomes of rats after an SCI. Materials and methods: We used 72 female Sprague-Dawley rats for this study. In the SCI group, we performed a laminectomy at T10, followed by impact-contusion of the spinal cord. In the control group, we performed only a laminectomy without contusion. We evaluated the effects of rapamycin using the Basso, Beattie, and Bresnahan scale for functional outcomes, Western blot analyses for analyzing LC3-II, tumor necrosis factor expression, and p70S6K phosphorylation, and an immunostaining technique for localization and enumeration of microglial and neuronal cells. Results: Basso, Beattie, and Bresnahan scores after injury significantly improved in the rapamycin-treated group compared with the vehicle group (on Day 28 after the SCI; P <.05). The Western blot analysis demonstrated that rapamycin enhanced LC3-II expression and decreased p70S6K phosphorylation compared with the vehicle (P <.01), which implies promotion of autophagy through mammalian target of rapamycin inhibition. Furthermore, rapamycin treatment significantly attenuated tumor necrosis factor production and microglial expression (P <.05). Immunohistochemistry of NeuN (antibodies specific to neurons) showed remarkable neuronal cell preservation in the rapamycin-treated group compared with the vehicle-treated group (P <.05), which suggests a neuroprotective effect of rapamycin. Conclusions: Rapamycin is a novel neuroprotectant with multifaceted effects on the rat spinal cord after injury. Use of such a clinically established drug could facilitate early clinical trials in selected cases of human SCIs.
KW - Autophagy
KW - Inflammation
KW - Neuroprotection
KW - Rapamycin
KW - Spinal cord injury
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U2 - 10.1016/j.jss.2012.02.023
DO - 10.1016/j.jss.2012.02.023
M3 - Article
C2 - 22482761
AN - SCOPUS:84870676088
SN - 0022-4804
VL - 179
SP - E203-E210
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -