Open Access

Cerebralcare Granule® attenuates cognitive impairment in rats continuously overexpressing microRNA-30e

  • Authors:
    • Yong Xu
    • Zhifen Liu
    • Xi Song
    • Kerang Zhang
    • Xingrong Li
    • Jianhong Li
    • Xu Yan
    • Yuan Li
    • Zhongchen Xie
    • Hui Zhang
  • View Affiliations

  • Published online on: October 22, 2015     https://doi.org/10.3892/mmr.2015.4469
  • Pages: 8032-8040
  • Copyright: © Xu 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: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Previous studies have demonstrated that dysregulation of micro (mi)RNAs is associated with the etiology of various neuropsychiatric disorders, including depression and schizophrenia. Cerebralcare Granule® (CG) is a Chinese herbal medicine, which has been reported to have an ameliorative effect on brain injury by attenuating blood‑brain barrier disruption and improving hippocampal neural function. The present study aimed to evaluate the cognitive behavior of rats continuously overexpressing miRNA‑30e (lenti‑miRNA‑30e), prior to and following the administration of CG. In addition, the mechanisms underlying the ameliorative effects of CG were investigated. The cognitive ability of the rats was assessed using an open‑field test and a Morris water maze spatial reference/working memory test. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to detect neuronal apoptosis in the dentate gyrus of the hippocampus. Immunohistochemical analysis and western blotting were conducted to detect the expression levels of B‑cell lymphoma 2 (BCL‑2) and ubiquitin‑conjugating enzyme 9 (UBC9), in order to examine neuronal apoptosis. The lenti‑miRNA‑30e rats exhibited increased signs of anxiety, depression, hyperactivity and schizophrenia, which resulted in a severe impairment in cognitive ability. Furthermore, in the dentate gyrus of these rats, the expression levels of BCL‑2 and UBC9 were reduced and apoptosis was increased. The administration of CG alleviated cognitive impairment, enhanced the expression levels of BCL‑2 and UBC9, and reduced apoptosis in the dentate gyrus in the lenti‑miRNA‑30e rats. No significant differences were detected in behavioral indicators between the lenti‑miRNA‑30e rats treated with CG and the normal controls. These findings suggested that CG exerts a potent therapeutic effect, conferred by its ability to enhance the expression levels of BCL‑2 and UBC9, which inhibits the apoptotic process in neuronal cells. Therefore, CG may be considered a potential therapeutic strategy for the treatment of cognitive impairment in mental disorders.

References

1 

Caspi A and Moffitt TE: Gene-environment interactions in psychiatry: Joining forces with neuroscience. Nat Rev Neurosci. 7:583–590. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Tsuang MT, Bar JL, Stone WS and Faraone SV: Gene-environment interactions in mental disorders. World Psychiatry. 3:73–83. 2004.

3 

Cross-Disorder Group of the Psychiatric Genomics Consortium: Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet. 381:1371–1379. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Meister G and Tuschl T: Mechanisms of gene silencing by double-stranded RNA. Nature. 431:343–349. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Martinez NJ and Gregory RI: MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. Cell Stem Cell. 7:31–35. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Olde Loohuis NF, Kos A, Martens GJ, Van Bokhoven H, Nadif Kasri N and Aschrafi A: MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci. 69:89–102. 2012. View Article : Google Scholar :

9 

Bravo JA and Dinan TG: MicroRNAs: A novel therapeutic target for schizophrenia. Curr Pharm Des. 17:176–188. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Dwivedi Y: Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat. 42:142–156. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Forero DA, van der Ven K, Callaerts P and Del-Favero J: miRNA genes and the brain: Implications for psychiatric disorders. Hum Mutat. 31:1195–1204. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Hunsberger JG, Austin DR, Chen G and Manji HK: MicroRNAs in mental health: From biological underpinnings to potential therapies. Neuromolecular Med. 11:173–182. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Miller BH and Wahlestedt C: MicroRNA dysregulation in psychiatric disease. Brain Res. 1338:89–99. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Siew WH, Tan KL, Babaei MA, Cheah PS and Ling KH: MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome. Front Cell Neurosci. 7(41)2013. View Article : Google Scholar : PubMed/NCBI

15 

Brinton RD: Estrogen-induced plasticity from cells to circuits: Predictions for cognitive function. Trends Pharmacol Sci. 30:212–222. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Li Y, Pehrson AL, Waller JA, Dale E, Sanchez C and Gulinello M: A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression. Front Neurosci. 9(279)2015. View Article : Google Scholar

17 

Perri R, Nares S, Zhang S, Barros SP and Offenbacher S: MicroRNA modulation in obesity and periodontitis. J Dent Res. 91:33–38. 2012. View Article : Google Scholar :

18 

Markou A, Sourvinou I, Vorkas PA, Yousef GM and Lianidou E: Clinical evaluation of microRNA expression profiling in non small cell lung cancer. Lung Cancer. 81:388–396. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Xu Y, Li F, Zhang B, Zhang K, Zhang F, Huang X, Sun N, Ren Y, Sui M and Liu P: MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. Schizophr Res. 119:219–227. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Liao Y and Lönnerdal B: Beta-catenin/TCF4 transactivates miR-30e during intestinal cell differentiation. Cell Mol Life Sci. 67:2969–2978. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Wu F, Zhu S, Ding Y, Beck WT and Mo YY: MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res. 15:1550–1557. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Wang J, Guan X, Guo F, Zhou J, Chang A, Sun B, Cai Y, Ma Z, Dai C, Li X, et al: miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6. Cell Death Dis. 4:e8452013. View Article : Google Scholar : PubMed/NCBI

23 

Khanna A, Muthusamy S, Liang R, Sarojini H and Wang E: Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging (Albany NY). 3:223–236. 2011.

24 

Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA and Cairns MJ: Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry. 17:827–840. 2012. View Article : Google Scholar :

25 

Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E and Akbarian S: Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry. 65:1006–1014. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J and Hammond SM: microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 8:R272007. View Article : Google Scholar : PubMed/NCBI

27 

Rege SD, Geetha T, Pondugula SR, Zizza CA, Wernette CM and Babu JR: Noncoding RNAs in neurodegenerative diseases. ISRN Neurol. 2013(375852)2013. View Article : Google Scholar : PubMed/NCBI

28 

Banigan MG, Kao PF, Kozubek JA, Winslow AR, Medina J, Costa J, Schmitt A, Schneider A, Cabral H, Cagsal-Getkin O, et al: Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One. 8:e488142013. View Article : Google Scholar : PubMed/NCBI

29 

Xu XS, Ma ZZ, Wang F, Hu BH, Wang CS, Liu YY, Zhao XR, An LH, Chang X, Liao FL, et al: The antioxidant Cerebralcare Granule attenuates cerebral microcirculatory disturbance during ischemia-reperfusion injury. Shock. 32:201–209. 2009. View Article : Google Scholar

30 

Wang F, Hu Q, Chen CH, Xu XS, Zhou CM, Zhao YF, Hu BH, Chang X, Huang P, Yang L, et al: The protective effect of Cerebralcare Granule® on brain edema, cerebral microcirculatory disturbance, and neuron injury in a focal cerebral ischemia rat model. Microcirculation. 19:260–272. 2012. View Article : Google Scholar

31 

Huang P, Zhou CM, Qin-Hu, Liu YY, Hu BH, Chang X, Zhao XR, Xu XS, Li Q, Wei XH, et al: Cerebralcare Granule® attenuates blood-brain barrier disruption after middle cerebral artery occlusion in rats. Exp Neurol. 237:453–463. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Sun K, Hu Q, Zhou CM, Xu XS, Wang F, Hu BH, Zhao XY, Chang X, Chen CH, Huang P, et al: Cerebralcare Granule, a Chinese herb compound preparation, improves cerebral microcirculatory disorder and hippocampal CA1 neuron injury in gerbils after ischemia-reperfusion. J Ethnopharmacol. 130:398–406. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Xiong L, Zhang JJ, Sun D and Liu H: Therapeutic benefit of Yangxue Qingnao Granule on cognitive impairment induced by chronic cerebral hypoperfusion in rats. Chin J Integr Med. 17:134–140. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Abordo-Adesida E, Follenzi A, Barcia C, Sciascia S, Castro MG, Naldini L and Lowenstein PR: Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses. Hum Gene Ther. 16:741–751. 2005. View Article : Google Scholar : PubMed/NCBI

35 

Miyoshi H, Blömer U, Takahashi M, Gage FH and Verma IM: Development of a self-inactivating lentivirus vector. J Virol. 72:8150–8157. 1998.PubMed/NCBI

36 

Naldini L, Blömer U, Gage FH, Trono D and Verma IM: Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA. 93:11382–11388. 1996. View Article : Google Scholar : PubMed/NCBI

37 

Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L and Trono D: Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol. 72:9873–9880. 1998.PubMed/NCBI

38 

Rattiner LM, Davis M, French CT and Ressler KJ: Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J Neurosci. 24:4796–4806. 2004. View Article : Google Scholar : PubMed/NCBI

39 

Heldt SA, Stanek L, Chhatwal JP and Ressler KJ: Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 12:656–670. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Chenghong Zoology experimental guidance. Tsinghua University; ISBN: 978-7-302-10763-72005

41 

Paxinos G and Franklin KBJ: The mouse brain in stereotaxic coordinates. San Diego: Academic Press; 2001

42 

Morris RGM: Spatial localization does not require the presence of local cues. Learn Motiv. 12:239–260. 1981. View Article : Google Scholar

43 

Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, et al: Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 45:1150–1159. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Hobert O: Gene regulation by transcription factors and microRNAs. Science. 319:1785–1786. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Nilsen TW: Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet. 23:243–249. 2007. View Article : Google Scholar : PubMed/NCBI

46 

Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ, Tran N, Dedova I and Cairns MJ: Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet. 17:1156–1168. 2008. View Article : Google Scholar : PubMed/NCBI

47 

Zhang F, Xu Y, Shugart YY, Yue W, Qi G, Yuan G, Cheng Z, Yao J, Wang J, Wang G, et al: Converging evidence implicates the abnormal microRNA system in schizophrenia. Schizophr Bull. 41:728–735. 2015. View Article : Google Scholar

48 

Murphy KC, Jones LA and Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 56:940–945. 1999. View Article : Google Scholar : PubMed/NCBI

49 

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA and Cairns MJ: Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry. 15:1176–1189. 2010. View Article : Google Scholar :

50 

Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ, Tran N, Dedova I and Cairns MJ: Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet. 17:1156–1168. 2008. View Article : Google Scholar : PubMed/NCBI

51 

Feng J, Sun G, Yan J, Noltner K, Li W, Buzin CH, Longmate J, Heston LL, Rossi J and Sommer SS: Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One. 4:e61212009. View Article : Google Scholar : PubMed/NCBI

52 

Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, Andreassen OA, Djurovic S, Melle I, Agartz I, et al: Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One. 2:e8732007. View Article : Google Scholar : PubMed/NCBI

53 

Juhila J, Sipilä T, Icay K, Nicorici D, Ellonen P, Kallio A, Korpelainen E, Greco D and Hovatta I: MicroRNA expression profiling reveals miRNA families regulating specific biological pathways in mouse frontal cortex and hippocampus. PLoS One. 6:e214952011. View Article : Google Scholar : PubMed/NCBI

54 

Rinaldi A, Vincenti S, De Vito F, Bozzoni I, Oliverio A, Presutti C, Fragapane P and Mele A: Stress induces region specific alterations in microRNAs expression in mice. Behav Brain Res. 208:265–269. 2010. View Article : Google Scholar

55 

McLoughlin HS, Fineberg SK, Ghosh LL, Tecedor L and Davidson BL: Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis. Neuroscience. 223:285–295. 2012. View Article : Google Scholar : PubMed/NCBI

56 

Nigro A, Menon R, Bergamaschi A, Clovis YM, Baldi A, Ehrmann M, Comi G, De Pietri Tonelli D, Farina C, Martino G and Muzio L: MiR-30e and miR-181d control radial glia cell proliferation via HtrA1 modulation. Cell Death Dis. 3:e3602012. View Article : Google Scholar : PubMed/NCBI

57 

Xu Y, Liu H, Li F, Sun N, Ren Y, Liu Z, Cao X, Wang Y, Liu P and Zhang K: A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform. J Affect Disord. 127:332–336. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December 2015
Volume 12 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Xu, Y., Liu, Z., Song, X., Zhang, K., Li, X., Li, J. ... Zhang, H. (2015). Cerebralcare Granule® attenuates cognitive impairment in rats continuously overexpressing microRNA-30e. Molecular Medicine Reports, 12, 8032-8040. https://doi.org/10.3892/mmr.2015.4469
MLA
Xu, Y., Liu, Z., Song, X., Zhang, K., Li, X., Li, J., Yan, X., Li, Y., Xie, Z., Zhang, H."Cerebralcare Granule® attenuates cognitive impairment in rats continuously overexpressing microRNA-30e". Molecular Medicine Reports 12.6 (2015): 8032-8040.
Chicago
Xu, Y., Liu, Z., Song, X., Zhang, K., Li, X., Li, J., Yan, X., Li, Y., Xie, Z., Zhang, H."Cerebralcare Granule® attenuates cognitive impairment in rats continuously overexpressing microRNA-30e". Molecular Medicine Reports 12, no. 6 (2015): 8032-8040. https://doi.org/10.3892/mmr.2015.4469