Early intervention with gastrodin reduces striatal neurotoxicity in adult rats with experimentally‑induced diabetes mellitus

Qi,Yu‑Han; Zhu,Rui; Wang,Qing; Li,Qian; Liu,Yi‑Dan; Qian,Zhong‑Yi; Yang,Zhi‑Hong; Mu,Zhi‑Hao; Liu,Xin‑Jie; Zhang,Mei‑Yan; Wang,Xie; Liao,Xin‑Yu; Wan,Qi; Lu,Di; Zou,Ying‑Ying

doi:10.3892/mmr.2019.9954

Early intervention with gastrodin reduces striatal neurotoxicity in adult rats with experimentally‑induced diabetes mellitus

Authors:
- Yu‑Han Qi
- Rui Zhu
- Qing Wang
- Qian Li
- Yi‑Dan Liu
- Zhong‑Yi Qian
- Zhi‑Hong Yang
- Zhi‑Hao Mu
- Xin‑Jie Liu
- Mei‑Yan Zhang
- Xie Wang
- Xin‑Yu Liao
- Qi Wan
- Di Lu
- Ying‑Ying Zou
View Affiliations

Affiliations: Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, P.R. China, Institute of Drug Discovery and Development, Kunming Pharmaceutical Corporation, Kunming, Yunnan 650500, P.R. China, Department of Morphological Laboratory, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, P.R. China, Institute of Neuroregeneration and Neurorehabilitation, Department of Neurosurgery of The Affiliated Hospital, Qingdao University, Qingdao, Shandong 266071, P.R. China, Biomedical Engineering Research Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
Published online on: February 14, 2019 https://doi.org/10.3892/mmr.2019.9954
Pages: 3114-3122
Copyright: © Qi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glutamate‑induced excitotoxicity in the striatum has an important role in neurodegenerative diseases. It has been reported that diabetes mellitus (DM) induces excitotoxicity in striatal neurons, although the underlying mechanism remains to be fully elucidated. The present study aimed to investigate the effect of gastrodin on DM‑induced excitotoxicity in the striatal neurons of diabetic rats. Adult Sprague‑Dawley rats were divided into control, diabetic, and gastrodin intervention groups. Diabetes in the rats was induced with a single intraperitoneal injection of streptozotocin (65 mg/kg). In the gastrodin groups, the rats were gavaged with 60 or 120 mg/kg/day gastrodin for 6 weeks, 3 weeks following the induction of diabetes. Pathological alterations in the striatum were assessed using hematoxylin and eosin (H&E) staining. The protein expression levels of phosphorylated (p)‑extracellular signal‑regulated kinase (ERK)1/2, p‑mitogen‑activated protein kinase kinase (MEK)1/2, tyrosine receptor kinase B (TrKB) and brain‑derived neurotrophic factor (BDNF) in the striatal neurons were evaluated by western blotting and double immunofluorescence. Additionally, the extracellular levels of glutamate were measured by microanalysis followed by high‑pressure‑liquid‑chromatography. In diabetic rats, striatal neuronal degeneration was evident following H&E staining, which revealed the common occurrence of pyknotic nuclei. This was coupled with an increase in glutamate levels in the striatal tissues. The protein expression levels of p‑ERK1/2, p‑MEK1/2, TrKB and BDNF in the striatal tissues were significantly increased in the diabetic rats compared with those in the normal rats. In the gastrodin groups, degeneration of the striatal neurons was ameliorated. Furthermore, the expression levels of glutamate, p‑ERK1/2, p‑MEK1/2, TrKB and BDNF in the striatal neurons were decreased. From these findings, it was concluded that reduced neurotoxicity in striatal neurons following treatment with gastrodin may be attributed to its suppressive effects on the expression of p‑ERK1/2, p‑MEK1/2, BDNF and TrKB.

View Figures

View References

1	Ding Y, Sun X and Shan PF: MicroRNAs and cardiovascular disease in diabetes mellitus. Biomed Res Int. 2017:40803642017. View Article : Google Scholar : PubMed/NCBI
2	Gispen WH and Biessels GJ: Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci. 23:542–549. 2000. View Article : Google Scholar : PubMed/NCBI
3	Ashafaq M, Varshney L, Khan MH, Salman M, Naseem M, Wajid S and Parvez S: Neuromodulatory effects of hesperidin in mitigating oxidative stress in streptozotocin induced diabetes. Biomed Res Int. 2014:2490312014. View Article : Google Scholar : PubMed/NCBI
4	Kong FJ, Ma LL, Guo JJ, Xu LH, Li Y and Qu S: Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice. Clin Sci (Lond). 132:111–125. 2017. View Article : Google Scholar
5	Zhang Y, Huang NQ, Yan F, Jin H, Zhou SY, Shi JS and Jin F: Diabetes mellitus and Alzheimer's disease: GSK-3β as a potential link. Behav Brain Res. 339:57–65. 2018. View Article : Google Scholar : PubMed/NCBI
6	Li Y, Zhang Y, Wang L, Wang P, Xue Y, Li X, Qiao X, Zhang X, Xu T, Liu G, et al: Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. Autophagy. 13:1145–1160. 2017. View Article : Google Scholar : PubMed/NCBI
7	Zhong Y, Zhu Y, He T, Li W, Li Q and Miao Y: Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway. Int J Mol Med. 43:294–304. 2019.PubMed/NCBI
8	Huang EJ and Reichardt LF: Trk receptors: Roles in neuronal signal transduction. Annu Rev Biochem. 72:609–642. 2003. View Article : Google Scholar : PubMed/NCBI
9	Yamada K and Nabeshima T: Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci. 91:267–270. 2003. View Article : Google Scholar : PubMed/NCBI
10	Huang EJ and Reichardt LF: Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci. 24:677–736. 2001. View Article : Google Scholar : PubMed/NCBI
11	Arundine M and Tymianski M: Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium. 34:325–337. 2003. View Article : Google Scholar : PubMed/NCBI
12	Rivera-Cervantes MC, Castañeda-Arellano R, Castro-Torres RD, Gudino-Cabrera G, Feria y Velasco AI, Camins A and Beas-Zarate C: P38 MAPK inhibition protects against glutamate neurotoxicity and modifies NMDA and AMPA receptor subunit expression. J Mol Neurosci. 55:596–608. 2015. View Article : Google Scholar : PubMed/NCBI
13	Sakai N, Yamada M, Numakawa T, Ogura A and Hatanaka H: BDNF potentiates spontaneous Ca2+ oscillations in cultured hippocampal neurons. Brain Res. 778:318–328. 1997. View Article : Google Scholar : PubMed/NCBI
14	Jayanarayanan S, Smijin S, Peeyush KT, Anju TR and Paulose CS: NMDA and AMPA receptor mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rat: Ameliorating effects of curcumin. Chem Biol Interact. 201:39–48. 2013. View Article : Google Scholar : PubMed/NCBI
15	Junpei T, Koki F, Marie M, Takeshi S, Yuko S and Kaoru S: L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: The ‘collusion’ hypothesis for increased extracellular L-glutamate concentration in neuroinflammation. J Neuroinflammation. 9:2752012.PubMed/NCBI
16	Li ZY, Huang Y, Yang YT, Zhang D, Zhao Y, Hong J, Liu J, Wu LJ, Zhang CH, Wu HG, et al: Moxibustion eases chronic inflammatory visceral pain through regulating MEK, ERK and CREB in rats. World J Gastroenterol. 23:6220–6230. 2017. View Article : Google Scholar : PubMed/NCBI
17	Birkner K, Wasser B, Loos J, Plotnikov A, Seger R, Zipp F, Witsch E and Bittner S: The role of ERK signaling in experimental autoimmune encephalomyelitis. Int J Mol Sci. 18:E19902017. View Article : Google Scholar : PubMed/NCBI
18	Plotnikov A, Chuderland D, Karamansha Y, Livnah O and Seger R: Nuclear extracellular signal-regulated kinase 1 and 2 translocation is mediated by casein kinase 2 and accelerated by autophosphorylation. Mol Cell Biol. 31:3515–3530. 2011. View Article : Google Scholar : PubMed/NCBI
19	Ortuño-Sahagún D, González RM, Verdaguer E, Huerta VC, Torres-Mendoza BM, Lemus L, Rivera-Cervantes MC, Camins A and Zarate CB: Glutamate excitotoxicity activates the MAPK/ERK signaling pathway and induces the survival of rat hippocampal neurons in vivo. J Mol Neurosci. 52:366–377. 2014. View Article : Google Scholar : PubMed/NCBI
20	Shepherd GM: Corticostriatal connectivity and its role in disease. Nat Rev Neurosci. 14:278–291. 2013. View Article : Google Scholar : PubMed/NCBI
21	Caligiore D, Mannella F, Arbib MA and Baldassarre G: Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome. PLoS Comput Biol. 13:e10053952017. View Article : Google Scholar : PubMed/NCBI
22	Chang C, Crottaz-Herbette S and Menon V: Temporal dynamics of basal ganglia response and connectivity during verbal working memory. Neuroimage. 34:1253–1269. 2007. View Article : Google Scholar : PubMed/NCBI
23	Murty VP, DuBrow S and Davachi L: The simple act of choosing influences declarative memory. J Neurosci. 35:6255–6264. 2015. View Article : Google Scholar : PubMed/NCBI
24	van Duinkerken E, Schoonheim MM, Steenwijk MD, Klein M, Ijzerman RG, Moll AC, Heymans MW, Snoek FJ, Barkhof F and Diamant M: Ventral striatum, but not cortical volume loss, is related to cognitive dysfunction in type 1 diabetic patients with and without microangiopathy. Diabetes Care. 37:2483–2490. 2014. View Article : Google Scholar : PubMed/NCBI
25	Gerfen CR and Surmeier DJ: Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 34:441–466. 2011. View Article : Google Scholar : PubMed/NCBI
26	Reinius B, Blunder M, Brett FM, Eriksson A, Patra K, Jonsson J, Jazin E and Kullander K: Conditional targeting of medium spiny neurons in the striatal matrix. Front Behav Neurosci. 9:712015. View Article : Google Scholar : PubMed/NCBI
27	Stansfield KH, Bichell TJ, Bowman AB and Guilarte TR: BDNF and Huntingtin protein modifications by manganese: Implications for striatal medium spiny neuron pathology in manganese neurotoxicity. J Neurochem. 131:655–666. 2014. View Article : Google Scholar : PubMed/NCBI
28	Zhang J, Saur T, Duke AN, Grant SG, Platt DM, Rowlett JK, Isacson O and Yao WD: Motor impairments, striatal degeneration, and altered dopamine-glutamate interplay in mice lacking PSD-95. J Neurogenet. 28:98–111. 2014. View Article : Google Scholar : PubMed/NCBI
29	Liu Y, Gao J, Peng M, Meng H, Ma H, Cai P, Xu Y, Zhao Q and Si G: A review on central nervous system effects of gastrodin. Front Pharmacol. 9:242018. View Article : Google Scholar : PubMed/NCBI
30	Lin LC, Chen YF, Tsai TR and Tsai TH: Analysis of brain distribution and biliary excretion of a nutrient supplement, gastrodin, in rat. Anal Chim Acta. 590:173–179. 2007. View Article : Google Scholar : PubMed/NCBI
31	Zhan HD, Zhou HY, Sui YP, Du XL, Wang WH, Dai L, Sui F, Huo HR and Jiang TL: The rhizome of Gastrodia elata Blume-an ethnopharmacological review. J Ethnopharmacol. 189:361–385. 2016. View Article : Google Scholar : PubMed/NCBI
32	Lee YS, Ha JH, Yong CS, Lee DU, Huh K, Kang YS, Lee SH, Jung MW and Kim JA: Inhibitory effects of constituents of Gastrodia elata Bl. on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells. Arch Pharm Res. 22:404–409. 1999. View Article : Google Scholar : PubMed/NCBI
33	Zhao X, Zou Y, Xu H, Fan L, Guo H, Li X, Li G, Zhang X and Dong M: Gastrodin protect primary cultured rat hippocampal neurons against amyloid-beta peptide-induced neurotoxicity via ERK1/2-Nrf2 pathway. Brain Res. 1482:13–21. 2012. View Article : Google Scholar : PubMed/NCBI
34	Jang JH, Son Y, Kang SS, Bae CS, Kim JC, Kim SH, Shin T and Moon C: Neuropharmacological potential of Gastrodia elata Blume and its components. Evid Based Complement Alternat Med. 2015:3092612015. View Article : Google Scholar : PubMed/NCBI
35	Zhang WJ, Tan YF, Yue JT, Vranic M and Wojtowicz JM: Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand. 117:205–210. 2008. View Article : Google Scholar : PubMed/NCBI
36	Li ZG, Zhang W, Grunberger G and Sima AA: Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res. 946:221–231. 2002. View Article : Google Scholar : PubMed/NCBI
37	Sadeghi A, Hami J, Razavi S, Esfandiary E and Hejazi Z: The effect of diabetes mellitus on apoptosis in hippocampus: Cellular and molecular aspects. Int J Prev Med. 7:572016. View Article : Google Scholar : PubMed/NCBI
38	Zhuang S and Schnellmann RG: A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther. 319:991–997. 2006. View Article : Google Scholar : PubMed/NCBI
39	Murray B, Alessandrini A, Cole AJ, Yee AG and Furshpan EJ: Inhibition of the p44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity. Proc Natl Acad Sci USA. 95:11975–11980. 1998. View Article : Google Scholar : PubMed/NCBI
40	Choi BH, Hur EM, Lee JH, Jun DJ and Kim KT: Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. J Cell Sci. 119:1329–1340. 2006. View Article : Google Scholar : PubMed/NCBI
41	Poitry-Yamate CL, Vutskits L and Rauen T: Neuronal-induced and glutamate-dependent activation of glial glutamate transporter function. J Neurochem. 82:987–997. 2010. View Article : Google Scholar
42	Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, Reynolds I, Klann E, Angiolieri MR, Johnson JW and DeFranco DB: Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem. 275:12200–12206. 2000. View Article : Google Scholar : PubMed/NCBI
43	Cagnol S, Van Obberghen-Schilling E and Chambard JC: Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death. Apoptosis. 11:337–346. 2006. View Article : Google Scholar : PubMed/NCBI
44	de Bernardo S, Canals S, Casarejos MJ, Solano RM, Menendez J and Mena MA: Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. J Neurochem. 91:667–682. 2004. View Article : Google Scholar : PubMed/NCBI
45	Shen GN, Liu L, Feng L, Jin Y, Jin MH, Han YH, Jin CH, Jin YZ, Lee DS, Kwon TH, et al: Knockdown of peroxiredoxin V increases glutamateinduced apoptosis in HT22 hippocampal neuron cells. Mol Med Rep. 17:7827–7834. 2018.PubMed/NCBI
46	Cheng B and Mattson MP: NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res. 640:56–67. 1994. View Article : Google Scholar : PubMed/NCBI
47	Xiong H, Futamura T, Jourdi H, Zhou H, Takei N, Diverse-Pierluissi M, Plevy S and Nawa H: Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons. Neuropharmacology. 42:903–912. 2002. View Article : Google Scholar : PubMed/NCBI
48	Almeida RD, Manadas BJ, Melo CV, Gomes JR, Mendes CS, Graos MM, Carvalho RF, Carvalho AP and Duarte CB: Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 12:1329–1343. 2005. View Article : Google Scholar : PubMed/NCBI
49	Hu P and Kalb RG: BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB. J Neurochem. 84:1421–1430. 2003. View Article : Google Scholar : PubMed/NCBI
50	Koh JY, Gwag BJ, Lobner D and Choi DW: Potentiated necrosis of cultured cortical neurons by neurotrophins. Science. 268:573–575. 1995. View Article : Google Scholar : PubMed/NCBI
51	Glazner GW and Mattson MP: Differential effects of BDNF, ADNF9, and TNFalpha on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity. Exp Neurol. 161:442–452. 2000. View Article : Google Scholar : PubMed/NCBI
52	El IA and Trenkner E: Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J Neurosci. 19:9459–9468. 1999. View Article : Google Scholar : PubMed/NCBI
53	Bian L, Bi X, Ai Q, Guo J, Dong S, Xu J, Zhong L and Lu D: Effects of gastrodin on apoptotic factors of cerebral cortex neuron in epileptic rats. Chin J Neuroanat. 32:37–43. 2016.