Open Access

Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice

  • Authors:
    • Jun Go
    • Tae‑Shin Park
    • Geun‑Hee Han
    • Hye‑Yeon Park
    • Young‑Kyoung Ryu
    • Yong‑Hoon Kim
    • Jung Hwan Hwang
    • Dong‑Hee Choi
    • Jung‑Ran Noh
    • Dae Youn Hwang
    • Sanghee Kim
    • Won Keun Oh
    • Chul‑Ho Lee
    • Kyoung‑Shim Kim
  • View Affiliations

  • Published online on: July 18, 2018     https://doi.org/10.3892/ijmm.2018.3782
  • Pages: 1875-1884
  • Copyright: © Go 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

Piperlongumine (PL), a biologically active compound from the Piper species, has been shown to exert various pharmacological effects in a number of conditions, including tumours, diabetes, pain, psychiatric disorders and neurodegenerative disease. In this study, we evaluated the therapeutic effects of PL on hippocampal function and cognition decline in aged mice. PL (50 mg/kg/day) was intragastrically administrated to 23‑month‑old female C57BL/6J mice for 8 weeks. Novel object recognition and nest building behaviour tests were used to assess cognitive and social functions. Additionally, immunohistochemistry and western blot analysis were performed to examine the effects of PL on the hippocampus. We found that the oral administration of PL significantly improved novel object recognition and nest building behaviour in aged mice. Although neither the percentage area occupied by astrocytes and microglia nor the level of 4‑hydroxynonenal protein, a specific marker of lipid peroxidation, were altered by PL treatment, the phosphorylation levels of N‑methyl‑D‑aspartate receptor subtype 2B (NR2B), calmodulin‑dependent protein kinase II alpha (CaMKIIα) and extracellular signal‑regulated kinase 1/2 (ERK1/2) were markedly increased in the hippocampus of aged mice following the administration of PL. We also found that PL treatment resulted in a CA3‑specific increase in the phosphorylation level of cyclic AMP response element binding protein, which is recognized as a potent marker of neuronal plasticity, learning and memory. Moreover, the number of doublecortin‑positive cells, a specific marker of neurogenesis, was significantly increased following PL treatment in the dentate gyrus of the hippocampus. On the whole, these data demonstrate that PL treatment may be a potential novel approach in the treatment of age‑related cognitive impairment and hippocampal changes.

References

1 

Morrison JH and Hof PR: Life and death of neurons in the aging brain. Science. 278:412–419. 1997. View Article : Google Scholar : PubMed/NCBI

2 

Bettio LEB, Rajendran L and Gil-Mohapel J: The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev. 79:66–86. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Aaboe K, Knop FK, Vilsboll T, Vølund A, Simonsen U, Deacon CF, Madsbad S, Holst JJ and Krarup T: KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. J Clin Endocrinol Metab. 94:603–608. 2009. View Article : Google Scholar

4 

Geinisman Y, Detoledo-Morrell L, Morrell F and Heller RE: Hippocampal markers of age-related memory dysfunction: Behavioral, electrophysiological and morphological perspectives. Prog Neurobiol. 45:223–252. 1995. View Article : Google Scholar : PubMed/NCBI

5 

Driscoll I, Howard SR, Stone JC, Monfils MH, Tomanek B, Brooks WM and Sutherland RJ: The aging hippocampus: A multi-level analysis in the rat. Neuroscience. 139:1173–1185. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Griffin R, Nally R, Nolan Y, McCartney Y, Linden J and Lynch MA: The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem. 99:1263–1272. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Ojo JO, Rezaie P, Gabbott PL and Stewart MG: Impact of age-related neuroglial cell responses on hippocampal deterioration. Front Aging Neurosci. 7:572015. View Article : Google Scholar : PubMed/NCBI

8 

Gureviciene I, Gurevicius K and Tanila H: Aging and alpha-synuclein affect synaptic plasticity in the dentate gyrus. J Neural Transm (Vienna). 116:13–22. 2009. View Article : Google Scholar

9 

Lister JP and Barnes CA: Neurobiological changes in the hippocampus during normative aging. Arch Neurol. 66:829–833. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Nyffeler M, Zhang WN, Feldon J and Knuesel I: Differential expression of PSD proteins in age-related spatial learning impairments. Neurobiol Aging. 28:143–155. 2007. View Article : Google Scholar

11 

Bezerra DP, Pessoa C, de Moraes MO, Saker-Neto N, Silveira ER and Costa-Lotufo LV: Overview of the therapeutic potential of piplartine (piperlongumine). Eur J Pharm Sci. 48:453–463. 2013. View Article : Google Scholar

12 

Cícero Bezerra Felipe F, Trajano Sousa Filho J, de Oliveira Souza LE, Alexandre Silveira J, Esdras de Andrade Uchoa D, Rocha Silveira E, Deusdênia Loiola Pessoa O and de Barros Viana GS: Piplartine, an amide alkaloid from Piper tuberculatum, presents anxiolytic and antidepressant effects in mice. Phytomedicine. 14:605–612. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Rodrigues RV, Lanznaster D, Longhi Balbinot DT, de Gadotti VM, Facundo VA and Santos AR: Antinociceptive effect of crude extract, fractions and three alkaloids obtained from fruits of Piper tuberculatum. Biol Pharm Bull. 32:1809–1812. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, et al: Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 475:231–234. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Rao VR, Muthenna P, Shankaraiah G, Akileshwari C, Babu KH, Suresh G, Babu KS, Chandra Kumar RS, Prasad KR, Yadav PA, et al: Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs). Eur J Med Chem. 57:344–361. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Navickiene HM, Alécio AC, Kato MJ, Bolzani VD, Young MC, Cavalheiro AJ and Furlan M: Antifungal amides from Piper hispidum and Piper tuberculatum. Phytochemistry. 55:621–626. 2000. View Article : Google Scholar : PubMed/NCBI

17 

Go J, Ha TKQ, Seo JY, Park TS, Ryu YK, Park HY, Noh JR, Kim YH, Hwang JH, Choi DH, et al: Piperlongumine activates Sirtuin1 and improves cognitive function in a murine model of Alzheimer's disease. J Funct Foods. 43:103–111. 2018. View Article : Google Scholar

18 

Peng S, Zhang B, Meng X, Yao J and Fang J: Synthesis of piper-longumine analogues and discovery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators as potential neuroprotective agents. J Med Chem. 58:5242–5255. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Tabuneng W, Bando H and Amiya T: Studies on the constituents of the crude drug 'piperis longi fructus'. On the alkaloids of fruits of piper longum L. Chem Pharm Bull. 31:3562–3565. 1983. View Article : Google Scholar

20 

Jang S, Dilger RN and Johnson RW: Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr. 140:1892–1898. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Park HY, Ryu YK, Kim YH, Park TS, Go J, Hwang JH, Choi DH, Rhee M, Lee CH and Kim KS: Gadd45β ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model. Neurobiol Dis. 89:169–179. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Park TS, Ryu YK, Park HY, Kim JY, Go J, Noh JR, Kim YH, Hwang JH, Choi DH, Oh WK, et al: Humulus japonicus inhibits the progression of Alzheimer's disease in a APP/PS1 transgenic mouse model. Int J Mol Med. 39:21–30. 2017. View Article : Google Scholar

23 

Deacon RM, Cholerton LL, Talbot K, Nair-Roberts RG, Sanderson DJ, Romberg C, Koros E, Bornemann KD and Rawlins JN: Age-dependent and -independent behavioral deficits in Tg2576 mice. Behav Brain Res. 189:126–138. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Kim YJ, Kang Y, Park HY, Lee JR, Yu DY, Murata T, Gondo Y, Hwang JH, Kim YH, Lee CH, et al: STEP signaling pathway mediates psychomotor stimulation and morphine withdrawal symptoms, but not for reward, analgesia and tolerance. Exp Mol Med. 48:e2122016. View Article : Google Scholar : PubMed/NCBI

25 

Ryu YK, Kang Y, Go J, Park HY, Noh JR, Kim YH, Hwang JH, Choi DH, Han SS, Oh WK, et al: Humulus japonicus prevents dopaminergic neuron death in 6-hydroxydopamine-induced models of Parkinson's disease. J Med Food. 20:116–123. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Ryu YK, Park HY, Go J, Choi DH, Kim YH, Hwang JH, Noh JR, Lee TG, Lee CH and Kim KS: Metformin inhibits the development of L-DOPA-induced dyskinesia in a murine model of Parkinson's disease. Mol Neurobiol. 55:5715–5726. 2018. View Article : Google Scholar

27 

Wesson DW and Wilson DA: Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice. Behav Brain Res. 216:408–413. 2011. View Article : Google Scholar

28 

Filali M, Lalonde R and Rivest S: Subchronic memantine administration on spatial learning, exploratory activity, and nest-building in an APP/PS1 mouse model of Alzheimer's disease. Neuropharmacology. 60:930–936. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Deacon RM, Croucher A and Rawlins JN: Hippocampal cytotoxic lesion effects on species-typical behaviours in mice. Behav Brain Res. 132:203–213. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ and Cotman CW: Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: A microarray study. J Neuroinflamm. 9:1792012. View Article : Google Scholar

31 

Harman D: Aging: A theory based on free radical and radiation chemistry. J Gerontol. 11:298–300. 1956. View Article : Google Scholar : PubMed/NCBI

32 

Stebbings KA, Choi HW, Ravindra A and Llano DA: The impact of aging, hearing loss, and body weight on mouse hippocampal redox state, measured in brain slices using fluorescence imaging. Neurobiol Aging. 42:101–109. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Cini M and Moretti A: Studies on lipid peroxidation and protein oxidation in the aging brain. Neurobiol Aging. 16:53–57. 1995. View Article : Google Scholar : PubMed/NCBI

34 

von Bernhardi R, Eugenín-von Bernhardi L and Eugenín J: Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci. 7:1242015. View Article : Google Scholar : PubMed/NCBI

35 

Lee SW, Clemenson GD and Gage FH: New neurons in an aged brain. Behav Brain Res. 227:497–507. 2012. View Article : Google Scholar :

36 

Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Adam A, Torres D, Zhang X, Dobrolecki LE, Wei W, Lewis MT, et al: Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene. 34:1341–1353. 2015. View Article : Google Scholar

37 

Balducci L and Ershler WB: Cancer and ageing: A nexus at several levels. Nat Rev Cancer. 5:655–662. 2005. View Article : Google Scholar : PubMed/NCBI

38 

Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M and Soininen H: Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci. 34:3–11. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Campisi J: Aging, cellular senescence, and cancer. Ann Rev Physiol. 75:685–705. 2013. View Article : Google Scholar

40 

Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, Zhou D and Zheng G: Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 8:2915–2926. 2016. View Article : Google Scholar

41 

Nichols NR, Day JR, Laping NJ, Johnson SA and Finch CE: GFAP mRNA increases with age in rat and human brain. Neurobiol Aging. 14:421–429. 1993. View Article : Google Scholar : PubMed/NCBI

42 

Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, Mishina M, Manabe T and Yamamoto T: Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 276:693–699. 2001. View Article : Google Scholar

43 

Lisman J, Schulman H and Cline H: The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 3:175–190. 2002. View Article : Google Scholar : PubMed/NCBI

44 

Asrican B, Lisman J and Otmakhov N: Synaptic strength of individual spines correlates with bound Ca2+-calmodulin-dependent kinase II. J Neurosci. 27:14007–14011. 2007. View Article : Google Scholar : PubMed/NCBI

45 

Giese KP, Fedorov NB, Filipkowski RK and Silva AJ: Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 279:870–873. 1998. View Article : Google Scholar : PubMed/NCBI

46 

Fang T, Kasbi K, Rothe S, Aziz W and Giese KP: Age-dependent changes in autophosphorylation of alpha calcium/calmodulin dependent kinase II in hippocampus and amygdala after contextual fear conditioning. Brain Res Bull. 134:18–23. 2017. View Article : Google Scholar : PubMed/NCBI

47 

Elgersma Y, Sweatt JD and Giese KP: Mouse genetic approaches to investigating calcium/calmodulin-dependent protein kinase II function in plasticity and cognition. J Neurosci. 24:8410–8415. 2004. View Article : Google Scholar : PubMed/NCBI

48 

Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE and Medina I: The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron. 40:775–784. 2003. View Article : Google Scholar : PubMed/NCBI

49 

Kreusser MM and Backs J: Integrated mechanisms of CaMKII-dependent ventricular remodeling. Front Pharmacol. 5:362014. View Article : Google Scholar : PubMed/NCBI

50 

Tully T, Bourtchouladze R, Scott R and Tallman J: Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov. 2:267–277. 2003. View Article : Google Scholar : PubMed/NCBI

51 

Silva AJ, Kogan JH, Frankland PW and Kida S: CREB and memory. Ann Rev Neurosci. 21:127–148. 1998. View Article : Google Scholar : PubMed/NCBI

52 

Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD and Kandel ER: Age-related defects in spatial memory are correlated with defects in the late phase of hippo-campal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci USA. 96:5280–5285. 1999. View Article : Google Scholar

53 

Gonzalez GA and Montminy MR: Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 59:675–680. 1989. View Article : Google Scholar : PubMed/NCBI

54 

Monti B, Berteotti C and Contestabile A: Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment. Hippocampus. 15:1041–1049. 2005. View Article : Google Scholar : PubMed/NCBI

55 

Hattiangady B, Rao MS, Shetty GA and Shetty AK: Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol. 195:353–371. 2005. View Article : Google Scholar : PubMed/NCBI

56 

Cowansage KK, Bush DE, Josselyn SA, Klann E and Ledoux JE: Basal variability in CREB phosphorylation predicts trait-like differences in amygdala-dependent memory. Proc Natl Acad Sci USA. 110:16645–16650. 2013. View Article : Google Scholar : PubMed/NCBI

57 

Yu XW, Oh MM and Disterhoft JF: CREB, cellular excitability, and cognition: Implications for aging. Behav Brain Res. 322:206–211. 2017. View Article : Google Scholar :

58 

Fan X, Wheatley EG and Villeda SA: Mechanisms of Hippocampal Aging and the Potential for Rejuvenation. Ann Rev Neurosci. 40:251–272. 2017. View Article : Google Scholar : PubMed/NCBI

59 

Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A and Enikolopov G: Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 8:566–579. 2011. View Article : Google Scholar : PubMed/NCBI

60 

Morgenstern NA, Lombardi G and Schinder AF: Newborn granule cells in the ageing dentate gyrus. J Physiol. 586:3751–3757. 2008. View Article : Google Scholar : PubMed/NCBI

61 

Kempermann G, Gast D and Gage FH: Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 52:135–143. 2002. View Article : Google Scholar : PubMed/NCBI

62 

Herskovits AZ and Guarente L: Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res. 23:746–758. 2013. View Article : Google Scholar : PubMed/NCBI

63 

Michan S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, et al: SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci. 30:9695–9707. 2010. View Article : Google Scholar : PubMed/NCBI

64 

Sellner S, Paricio-Montesinos R, Spieß A, Masuch A, Erny D, Harsan LA, Elverfeldt DV, Schwabenland M, Biber K, Staszewski O, et al: Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1. Acta Neuropathol Commun. 4:1022016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2018
Volume 42 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Go, J., Park, T., Han, G., Park, H., Ryu, Y., Kim, Y. ... Kim, K. (2018). Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice. International Journal of Molecular Medicine, 42, 1875-1884. https://doi.org/10.3892/ijmm.2018.3782
MLA
Go, J., Park, T., Han, G., Park, H., Ryu, Y., Kim, Y., Hwang, J. H., Choi, D., Noh, J., Hwang, D. Y., Kim, S., Oh, W. K., Lee, C., Kim, K."Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice". International Journal of Molecular Medicine 42.4 (2018): 1875-1884.
Chicago
Go, J., Park, T., Han, G., Park, H., Ryu, Y., Kim, Y., Hwang, J. H., Choi, D., Noh, J., Hwang, D. Y., Kim, S., Oh, W. K., Lee, C., Kim, K."Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice". International Journal of Molecular Medicine 42, no. 4 (2018): 1875-1884. https://doi.org/10.3892/ijmm.2018.3782