Skip to main content

Advertisement

SpringerLink
Log in

Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression of Small-Conductance Ca2+-Activated K+ Channels

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

This study investigated the expression pattern, regulation of expression, and the role of hippocampal small-conductance Ca2+-activated K+ (SK) channels in memory deficits after cerebral hypoperfusion (CHP) with or without melatonin treatment, in rats. Adults male Wistar rats (n = 20/group) were divided into (1) a sham (2) a sham + melatonin (3) a two-vessel occlusion (2-VO) model, and (4) a 2-VO + melatonin. Melatonin was administered (i.p.) to all rats at a daily dose of 10 mg kg−1 for 7 days starting at the time of 2-VO-induction. In contrast to 2-VO rats, melatonin increased the latency of the passive avoidance learning test and decreased time to find the hidden platform in Water Morris Test in all tested rats. In addition, it concomitantly downregulated SK1, SK2, and SK3 channels, downregulated mRNA levels of TNFα and IL-1β, enhanced BDNF levels and activity of PKA levels, and restored the levels of cholinergic markers in the hippocampi of the treated-rats. Mechanistically, melatonin significantly prevented CHP-induced activation of ERK1/2, JNK, and P38 MAPK at least by inhibiting ROS generation and enhancing the total antioxidant potential. In cultured hypoxic hippocampal neurons, individual blockage of MAPK signaling by the MEK1/2 inhibitor (U0126), but not by the P38 inhibitor (SB203580) or JNK inhibitor (SP600125), completely prevented the upregulation of all three kinds of SK channels. These data clearly confirm that upregulation of SK channels plays a role in CHP-induced memory loss and indicate that melatonin reverses memory deficits after CHP in rats, at least by, downregulation of SK1, SK2, and SK3 channels in their hippocampi.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Liu H, Zhang J, Yang Y, Zhang L, Zeng X (2012) Decreased cerebral perfusion and oxidative stress result in acute and delayed cognitive impairment. Curr Neurovasc Res 9:152–158

    Article  CAS  PubMed  Google Scholar 

  2. Zhao Y, Gong CX (2015) From chronic cerebral hypoperfusion to Alzheimer-like brain pathology and neurodegeneration. Cell Mol Neurobiol 35:101–110

    Article  CAS  PubMed  Google Scholar 

  3. Stackman RW, Bond CT, Adelman JP (2008) Contextual memory deficits observed in mice overexpressing small conductance Ca2+-activated K+ type 2 (KCa2.2, SK2) channels are caused by an encoding deficit. Learn Mem 15:208–213

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sailer A, Hu H, Kaufmann WA, Trieb M, Schwarzer C, Storm JF, Knaus HG (2002) Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain. J Neurosci 22:9698–9707

    Article  CAS  PubMed  Google Scholar 

  5. Stackman RW, Hammond RS, Linardatos E, Gerlach A, Maylie J, Adelman JP, Tzounopoulos T (2002) Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J Neurosci 22:10163–10171

    Article  CAS  PubMed  Google Scholar 

  6. Kuiper EF, Nelemans A, Luiten P, Nijholt I, Dolga A, Eisel U (2012) K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration. Front Pharmacol 3:11107

    Article  CAS  Google Scholar 

  7. Blank T, Nijholt I, Kye MJ, Radulovic J, Spiess J (2003) Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits. Nat Neurosci 6:911–912

    Article  CAS  PubMed  Google Scholar 

  8. Reiter RJ, Tan DX, Manchester LC, Qi W (2001) Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys 34:237–256

    Article  CAS  PubMed  Google Scholar 

  9. Reiter RJ, Tan DX, Leon J, Kilic U, Kilic E (2005) When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med 230:104–117

    Article  CAS  Google Scholar 

  10. Zhang HM, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57:131–146

    Article  CAS  Google Scholar 

  11. Das A, McDowell M, Pava MJ, Smith JA, Reiter RJ, Woodward JJ, Varma AK, Ray SK, Banik NL (2010) The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors. J Pineal Res 48:157–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Corrales A, Martinez P, Garcia S, Vidal V, Garcia E, Florez J, Sanchez-Barcelo EJ, Martinez-Cue C, Rueda N (2013) Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome. J Pineal Res 54:346–358

    Article  CAS  PubMed  Google Scholar 

  13. Rosales-Corral SA, Acuna-Castroviejo D, Coto-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, Korkmaz A, Ma S, Tan DX, Reiter RJ (2012) Alzheimer's disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202

    Article  CAS  PubMed  Google Scholar 

  14. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  CAS  PubMed  Google Scholar 

  15. Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10

    Article  CAS  PubMed  Google Scholar 

  16. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317

    Article  CAS  PubMed  Google Scholar 

  17. Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E (2000) Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 20:4506–4514

    Article  CAS  PubMed  Google Scholar 

  18. Jin K, Mao XO, Zhu Y, Greenberg DA (2002) MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem 80:119–125

    Article  CAS  PubMed  Google Scholar 

  19. Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879–7887

    Article  CAS  PubMed  Google Scholar 

  20. Kilic U, Yilmaz B, Reiter RJ, Yuksel A, Kilic E (2013) Effects of memantine and melatonin on signal transduction pathways vascular leakage and brain injury after focal cerebral ischemia in mice. Neuroscience 237:268–276

    Article  CAS  PubMed  Google Scholar 

  21. Lee C, Park J, Ahn J, Won M (2019) Effects of melatonin on cognitive impairment and hippocampal neuronal damage in a rat model of chronic cerebral hypoperfusion. Exp Ther Med 11:2240–2246

    Article  CAS  Google Scholar 

  22. OzacmaK VH, Barut F, Ozacmak HS (2009) Melatonin provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats. J Pineal Res 47:156–163

    Article  CAS  PubMed  Google Scholar 

  23. Sakr HF, Khalil K, Hussein AM, Zaki MS, Eid RA, Alkhateeb M (2014) Effect of dehydroepiandrosterone (DHEA) on memory and brain derived neurotrophic factor (BDNF) in a rat model of vascular dementia. J Physiol Pharmacol 65:41–53

    CAS  PubMed  Google Scholar 

  24. Lee CH, Yoo KY, Choi JH, Park OK, Hwang IK, Kwon YG, Kim YM, Won MH (2010) Melatonin's protective action against ischemic neuronal damage is associated with up-regulation of the MT2 melatonin receptor. J Neurosci Res 88:2630–2640

    Article  CAS  PubMed  Google Scholar 

  25. Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Di Yang X, Di S, Yue L, Liang G, Reiter RJ, Qu Y (2019) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 58:61–70

    Article  CAS  Google Scholar 

  26. Barkur RR, Bairy LK (2015) Evaluation of passive avoidance learning and spatial memory in rats exposed to low levels of lead during specific periods of early brain development. Int J Occup Med Environ Health 28:533–544

    Article  Google Scholar 

  27. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  CAS  Google Scholar 

  28. Chansard M, Iwahana E, Liang J, Fukuhara C (2005) Regulation of cAMP-induced arylalkylamine N-acetyltransferase, Period1, and MKP-1 gene expression by mitogen-activated protein kinases in the rat pineal gland. Mol Brain Res 139:333–340

    Article  CAS  PubMed  Google Scholar 

  29. Chen J, Aguilera G (2010) Vasopressin protects hippocampal neurones in culture against nutrient deprivation or glutamate-induced apoptosis. J Neuroendocrinol 22:1072–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Seibenhener ML, Wooten MW (2012) Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp 65:3634

    Google Scholar 

  31. Ong Q, Guo S, Zhang K, Cui B (2015) U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor. ACS Chem Neurosci 6:130–137

    Article  CAS  PubMed  Google Scholar 

  32. Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA (2003) Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells. Stroke 34:2483–2488

    Article  CAS  PubMed  Google Scholar 

  33. Hu L, Chang L, Zhang Y, Zhai L, Zhang S, Qi Z et al (2017) Platelets express activated P2Y12 receptor in patients with diabetes mellitus. Circulation 136:817–833

    Article  CAS  PubMed  Google Scholar 

  34. Francis P (2006) Targeting cell death in dementia. Alzheimer Dis Assoc Disord 20:S3–S7

    Article  PubMed  Google Scholar 

  35. He XL, Wang YH, Bi MG, Du GH (2012) Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats. Eur J Pharmacol 680:41–48

    Article  CAS  PubMed  Google Scholar 

  36. Xi Y, Wang M, Zhang W, Bai M, Du Y, Zhang Z, Li Z, Miao J (2014) Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion. Neurobiol Learn Mem 109:7–19

    Article  CAS  PubMed  Google Scholar 

  37. Farkas E, Luiten PG, Bari F (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 54:162–180

    Article  CAS  Google Scholar 

  38. Kumaran D, Udayabanu M, Kumar M, Aneja R, Katyal A (2008) Involvement of angiotensin converting enzyme in cerebral hypoperfusion induced anterograde memory impairment and cholinergic dysfunction in rats. Neuroscience 155:626–639

    Article  CAS  PubMed  Google Scholar 

  39. Zhu H, Gao W, Jiang H, Jin QH, Shi YF, Tsim KW, Zhang XJ (2007) Regulation of acetylcholinesterase expression by calcium signaling during calcium ionophore A23187- and thapsigargin-induced apoptosis. Int J Biochem Cell Biol 39:93–108

    Article  CAS  PubMed  Google Scholar 

  40. Shu Y, Zhang H, Kang T, Zhang JJ, Yang Y, Liu H, Zhang L (2013) PI3K/Akt signal pathway involved in the cognitive impairment caused by chronic cerebral hypoperfusion in rats. PLoS ONE 8:e81901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tang F, Nag S, Shiu SY, Pang SF (2002) The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with beta-amyloid 1–40. Life Sci 71:2625–2631

    Article  CAS  PubMed  Google Scholar 

  42. Tyagi E, Agrawal R, Nath C, Shukla R (2010) Effect of melatonin on neuroinflammation and acetylcholinesterase activity induced by LPS in rat brain. Eur J Pharmacol 640:206–210

    Article  CAS  PubMed  Google Scholar 

  43. Messier C, Mourre C, Bontempi B, Sif J, Lazdunski M, Destrade C (1991) Effect of apamin, a toxin that inhibits Ca(2+)-dependent K+ channels, on learning and memory processes. Brain Res. 551:322–326

    Article  CAS  PubMed  Google Scholar 

  44. Deschaux O, Bizot JC (1997) Effect of apamin, a selective blocker of Ca2+-activated K+-channel, on habituation and passive avoidance responses in rats. Neurosci Lett 27:57–60

    Article  Google Scholar 

  45. Kramar EA, Lin B, Lin CY, Arai AC, Gall CM, Lynch G (2004) A novel mechanism for the facilitation of theta-induced long-term potentiation by brain-derived neurotrophic factor. J Neurosci 24:5151–5161

    Article  CAS  PubMed  Google Scholar 

  46. Allo G, Ernst AF, McLoon SC, Letourneau PC (2002) Transient PKA activity is required for initiation but not maintenance of BDNF-mediated protection from nitric oxide-induced growth-cone collapse. J Neurosci 22:5016–5023

    Article  Google Scholar 

  47. Ren Y, Barnwell LF, Alexander JC, Lubin FD, Adelman JP, Pfaffinger PJ, Schrader LA, Anderson AE (2006) Regulation of surface localization of the small conductance Ca2+-activated potassium channel, Sk2, through direct phosphorylation by cAMP-dependent protein kinase. J Biol Chem 281:11769–11779

    Article  CAS  PubMed  Google Scholar 

  48. Dolga AM, Culmsee C (2012) Protective roles for potassium SK/KCa2 channels in microglia and neurons. Front Pharmacol 3:196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schlichter LC, Kaushal V, Moxon-Emre I, Sivagnanam V, Vincent C (2010) The Ca2+ activated SK3 channel is expressed in microglia in the rat striatum and contributes to microglia-mediated neurotoxicity in vitro. J Neuroinflammation 7:4. https://doi.org/10.1186/1742-2094-7-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Han HS, Yenari MA (2003) Cellular targets of brain inflammation in stroke. Curr Opin Investig Drugs. 4:522–529

    CAS  PubMed  Google Scholar 

  51. Simi A, Tsakiri N, Wang P, Rothwell NJ (2007) Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans. 35:1122–1126

    Article  CAS  PubMed  Google Scholar 

  52. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68

    Article  CAS  PubMed  Google Scholar 

  53. Cechetti F, Pagnussat AS, Worm PV, Elsner VR, Ben J, da Costa MS, Mestriner R, Weis SN, Netto CA (2012) Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment. Brain Res Bull 87:109–116

    Article  CAS  PubMed  Google Scholar 

  54. Bordeleau M, El Ali A, Rivest S (2016) Severe chronic cerebral hypoperfusion induces microglial dysfunction leading to memory loss in APPswe/PS1 mice. Oncotarget 11:11864–11880

    Google Scholar 

  55. Lees GJ (1993) The possible contribution of microglia and macrophages to delayed neuronal death after ischemia. J Neurol Sci 114(2):119–122

    Article  CAS  PubMed  Google Scholar 

  56. Kaushal V, Koeberla PD, Wang Y, Schlichter LC (2007) The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci 2:234–244

    Article  CAS  Google Scholar 

  57. Hayashi Y, Kawaji K, Sun L, Zhang X, Koyano K, Yokoyama T, Kohsaka S, Inoue K, Nakanishi H (2011) Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. J Neurosci 31:17370–17382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kye MJ, Spiess J, Blank T (2007) Transcriptional regulation of intronic calcium-activated potassium channel SK2 promoters by nuclear factor-kappa B and glucocorticoids. Mol Cell Biochem 300:9–17

    Article  CAS  PubMed  Google Scholar 

  59. Dolga AM, Terpolilli N, Kepura F, Nijholt IM, Knaus HG, D’Orsi B et al (2011) KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. Cell Death Dis 2:e147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wu UI, Mai FD, Sheu JN, Chen LY, Liu YT, Huang HC, Chang HM (2011) Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis. J Pineal Res 50:159–170

    CAS  PubMed  Google Scholar 

  61. Lin SH, Huang YN, Kao JH, Tien LT, Tsai RY, Wong CS (2016) Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression. Life Sci 152:38–43

    Article  CAS  PubMed  Google Scholar 

  62. Tsai TH, Lin CJ, Chua S, Chung SY, Yang CH, Tong MS, Hang CL (2017) Melatonin attenuated the brain damage and cognitive impairment partially through MT2 melatonin receptor in mice with chronic cerebral hypoperfusion. Oncotarget 87:4320–74330

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank the technical staff of the animal facility at the Medical College of King Khalid University for their help in the experimental procedure and care of animals this study. The authors also would like to express their gratitude to the deanship of scientific research at King Khalid University for their financial support of the current study via their grant to HFS.

Funding

This research is fully funded by the deanship of scientific research at King Khalid University (Grant number KKU_S099_33, 2014).

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, College of Medicine At King Saud, Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Kingdom of Saudi Arabia

    Hussain Al Dera, Mohammed Alassiri, Mahmoud A. AlKhateeb & Sultan Alqahtani

  2. King Abdullah International Medical Research Center (KAIMRC), Riyadh, Kingdom of Saudi Arabia

    Hussain Al Dera, Mohammed Alassiri & Sultan Alqahtani

  3. Department of Applied Medical Sciences, College of Health Sciences, Dept., PAAET, Adailiyah, Kuwait

    Samy M. Eleawa

  4. Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Abdelaziz M. Hussein, Mohammad Dallak & Hussein F. Sakr

  5. Department of Medical Physiology, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia

    Hussein F. Sakr

  6. Department of Basic Medical Sciences, College of Medicine, King Fahid Medical City, Riyadh, Kingdom of Saudi Arabia

    Mohammad A. Khalil

Authors
  1. Hussain Al Dera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammed Alassiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samy M. Eleawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahmoud A. AlKhateeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdelaziz M. Hussein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad Dallak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hussein F. Sakr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sultan Alqahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohammad A. Khalil
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HAD, SME, MAK, and HFS conceived and designed the experimental procedures. HAD, HFS, AMH, and MAA performed the experimental procedure and wrote the material and methods. IH, MA, SME, SA and MAA, MD performed the analysis and revised the final version of the manuscript. HAD, MD, and MAA, MAK, and SA were responsible for the interpretation of the results and wrote the manuscript.

Corresponding author

Correspondence to Hussain Al Dera.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al Dera, H., Alassiri, M., Eleawa, S.M. et al. Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression of Small-Conductance Ca2+-Activated K+ Channels. Neurochem Res 44, 1851–1868 (2019). https://doi.org/10.1007/s11064-019-02820-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02820-6

Keywords

Search

Navigation