|
|
The effect of vildagliptin on neural cell apotosis and locomotor recovery in a rat model of spinal cord injury |
XU Tianzhen, WANG Chenjian, TANG Chengxuan |
Department of Orthopaedics, the Third Affiliated Hospital of Wenzhou Medical University, Rui’an People’s Hospital, Wenzhou 325200, China |
|
Cite this article: |
XU Tianzhen,WANG Chenjian,TANG Chengxuan. The effect of vildagliptin on neural cell apotosis and locomotor recovery in a rat model of spinal cord injury[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2019, 49(7): 523-528.
|
|
Abstract Objective: To investigate the effect of Vildagliptin (Vilda) on locomotor function recovery and neural cell apotosis in a rat model of spinal cord injury. Methods: Forty-eight SD rats were randomly divided into 3 groups (n=16): the Sham group, the SCI group and the SCI+Vilad group. Clip compression SCI model was established as previously described. The SCI+Vilad group was treated with Vilad at a dose of 10 mg·kg-1·d-1 by gavage for 7 days in a row, then once every 3 days; the SCI group was treated with the same dosage of normal saline. The Basso-Beattie-Bresnahan (BBB) score was obtained at 1, 3, 7, 14, 21, 28 d after operation. Immunofluorescence staining and Western blot were used to detect the expression of apoptotic related proteins expression (Bcl-2, Bax, Cleaved Caspase 3) at 3 d after operation. Nissl staining was performed at 7 d after operation to detect the surviving neurons. At 28 d, the, the footprint analysis was used to assess the locomotor recovery. Results: Compared with the Sham group, SCI group showed significantly lower BBB scores and inconsistent footprints; the number of VMNs was decreased significantly. Immunofluorescence staining and western blot results showed enhanced expression of apoptotic related proteins (Bax, Cleaved Caspase 3), but the expression of anti-apoptotic related protein (Bcl-2) was decreased (P<0.05). Compared with the SCI group, the rats in SCI+Vilda group got higher BBB scores, more consistent footprints; the number of VMNs was also increased. At the same time, the expression of apoptotic related proteins (Bax, Cleaved Caspase 3) was decreased significantly and the expression of anti-apoptotic related protein (Bcl-2) was increased obviously (P<0.05). Conclusion: All of these findings indicated that Vildagliptin shows neuroprotective effect after SCI in rats via inhibiting the VMNs apoptosis, and finally promotes the locomotor recovery.
|
Received: 10 December 2018
|
|
|
|
|
[1] RAMER L, RAMER M S, BRADBURY E J. Restoring function after spinal cord injury: towards clinical translation of experimental strategies[J]. Lancet Neurol, 2014, 13(12): 1241-1256.
[2] VALENZUELA V, ONATE M, HETZ C, et al. Injury to the nervous system: A look into the ER[J]. Brain Res, 2016, 1648(Pt B): 617-625
[3] CROWE M, BRESNAHAN J, SHUMAN S, et al. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys[J]. Nat Med, 1997, 3(1): 73-76
[4] NARANG A, QIAO F, ATKINSON C, et al. Natural IgM antibodies that bind neoepitopes exposed as a result of spinal cord injury, drive secondary injury by activating com-plement[J]. J Neuroinflammation, 2017, 14(1): 120.
[5] BEATTIE M, FAROOQUI A, BRESNAHAN. J Review of current evidence for apoptosis after spinal cord injury[J]. J Neurotrauma, 2000, 17(10): 915-925.
[6] THURET S, MOON L, GAGE F. Therapeutic interventions after spinal cord injury[J]. Nat Rev Neurosci, 2006, 7(8): 628-643.
[7] KEATING G M. Vildagliptin: a review of its use in type 2 diabetes mellitus[J]. Drugs, 2014, 74(5): 587-610.
[8] SA-NGUANMOO P, TANAJAK P, KERDPHOO S, et al. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats[J]. Toxicol Appl Pharmacol, 2017, 333: 43-50
[9] AVILA DDE L, ARAUJO G R, SILVA M, et al. Vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabetic rats[J]. Arch Med Res, 2013, 44(3): 194-202.
[10] MA Q H, JIANG L F, MAO J L, et al. Vildagliptin prevents cognitive deficits and neuronal apoptosis in a rat model of Alzheimer’s disease[J]. Mol Med Rep, 2018, 17(3): 4113-4119.
[11] ABDELSALAM R M, SAFAR M M. Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways[J]. J Neurochem, 2015, 133(5): 700-707.
[12] MARQUES S A, GARCEZ V F, DEL BEL E A, et al. A simple, inexpensive and easily reproducible model of spinal cord injury in mice: morphological and functional assess-ment[J]. J Neurosci Methods, 2009, 177(1): 183-193.
[13] CHERIYAN T, RYAN D J, WEINREB J H, et al. Spinal cord injury models: a review[J]. Spinal Cord, 2014, 52(8): 588-595.
[14] HE Z L, ZHOU Y L, HUANG Y, et al. Dl-3-n-butylphthalide improves functional recovery in rats with spinal cord injury by inhibiting endoplasmic reticulum stress-induced apopto-sis[J]. Am J Transl Res, 2017, 9(3): 1075-1087.
[15] BASSO D M, BEATTIE M S, BRESNAHAN J C. A sensitive and reliable locomotor rating scale for open field testing in rats[J]. J Neurotrauma, 1995, 12(1): 1-21.
[16] WU F, WEI X, WU Y, et al. Chloroquine promotes the recovery of acute spinal cord injury by inhibiting autophagy-associated inflammation and endoplasmic reticulum stress [J]. J Neurotrauma, 2018, 35(12): 1329-1344.
[17] STIRLING D P, KHODARAHMI K, LIU J, et al. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury[J]. J Neurosci, 2004, 24(9): 2182-2190.
[18] KJELL J, OLSON L. Rat models of spinal cord injury: from pathology to potential therapies[J]. Dis Model Mech, 2016, 9(10): 1125-1137.
[19] MCDONALD J W, SADOWSKY C. Spinal-cord injury[J]. Lancet, 2002, 359(9304): 417-425.
[20] GRUMBLES R M, THOMAS C K. Motoneuron death after human spinal cord injury[J]. J Neurotrauma, 2017, 34(3): 581-590.
[21] KWON B K, TETZLAFF W, GRAUER J N, et al. Pathophysiology and pharmacologic treatment of acute spinal cord injury[J]. Spine J, 2004, 4(4): 451-464.
[22] Ahuja C S, Wilson J R, Nori S, et al. Traumatic spinal cord injury[J]. Nat Rev Dis Primers, 2017, 3: 17018.
[23] WILSON J R, FORGIONE N, FEHLINGS M G. Emerging therapies for acute traumatic spinal cord injury[J].CMAJ, 2013,185(6):485-492.
[24] ANILKUMAR U, PREHN J H. Anti-apoptotic BCL-2 family proteins in acute neural injury[J]. Front Cell Neurosci, 2014 ,8:281.
[25] KIRKLAND R A, FRANKLIN J L. Bax, reactive oxygen, and cytochrome c release in neuronal apoptosis[J]. Antioxid Redox Signal, 2003, 5(5): 589-596.
[26] HYMAN B T, YUAN J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology[J].Nat Rev Neurosci, 2012, 13(6): 395-406. |
|
|
|