Sleep deprivation disrupts striatal anti-apoptotic responses in 6-hydroxy dopamine-lesioned parkinsonian rats

Document Type: Original Article


1 Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Department of Molecular Medicine, Faculty of Advanced Biomedical Sciences, Tabriz, Iran

3 Pharmaceutical Biotechnology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

4 Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark

5 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): The present study was conducted to examine the effect of sleep deprivation (SD) on the anti-apoptotic pathways in Parkinsonian rats.
Materials and Methods: Male Wistar rats (n = 40) were assigned to four groups (10 animals each): sham surgery (Sham), 6-hydroxydopamine (6-OHDA)-lesioned (OH), 6-OHDA-lesioned plus grid control (OH+GC), 6-OHDA-lesioned plus SD (OH+SD). Parkinson’s disease (PD) model was induced by the unilateral intra-striatal infusion of 6-OHDA (10 µg/rat). SD (4 hr/day, for 14 days) was induced using a multiple platforms water tank. On the last day of interventions, animals were subjected to open field test for horizontal motor performance assessment. Also, brain-derived neurotrophic factor (BDNF), Bcl-2 and Bax were assessed in the striatum of study groups.
Results: SD obscured the motor deficits of PD animals observed in open field test. BDNF level and Bcl2/Bax ratio significantly increased in the OH group, and SD reduced their levels in the PD animals.
Conclusion: SD suppressed the anti-apoptotic compensatory responses in the striatum; therefore, it may accelerate continual neuronal cell death in PD.


Main Subjects

1. Lima MM. Sleep disturbances in Parkinson’s disease: the contribution of dopamine in REM sleep regulation. Sleep Med Rev 2013; 17:367-375.
2. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443:787-795.
3. Blum D, Torch S, Lambeng N, Nissou M-F, Benabid A-L, Sadoul R, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65:135-172.
4. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 2006; 396:67-72.
5. Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, McKenzie J, et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson’s disease. Brain 2011; 134:3290-3298.
6. Mole JP, Subramanian L, Bracht T, Morris H, Metzler-Baddeley C, Linden DE. Increased fractional anisotropy in the motor tracts of Parkinson’s disease suggests compensatory neuroplasticity or selective neurodegeneration. Eur Radiol 2016; 26:3327-3335.
7. Knott C, Stern G, Kingsbury A, Welcher A, Wilkin G. Elevated glial brain-derived neurotrophic factor in Parkinson’s diseased nigra. Parkinsonism Relat Disord 2002; 8:329-341.
8. Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM. Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 1990; 13:290-296.
9. Sharifi H, Nayebi AM, Farajnia S, Haddadi R. Effect of Buspirone, fluoxetine and 8-OH-DPAT on striatal expression of Bax, caspase-3 and Bcl-2 Proteins in 6-hydroxydopamine-induced hemi-parkinsonian rats. Adv Pharm Bull 2015; 5:491.
10. Scalzo P, Kümmer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J Neurol 2010; 257:540-545.
11. Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000; 47:493-503.
12. Yurek DM, Fletcher-Turner A. Differential expression of GDNF, BDNF, and NT-3 in the aging nigrostriatal system following a neurotoxic lesion. Brain Res 2001; 891:228-235.
13. Yurek DM, Fletcher-Turner A. Temporal changes in the neurotrophic environment of the denervated striatum as determined by the survival and outgrowth of grafted fetal dopamine neurons. Brain Res 2002; 931:126-134.
14. Gjerstad MD, Wentzel‐Larsen T, Aarsland D, Larsen JP. Insomnia in Parkinson’s disease: frequency and progression over time. J Neurol Neurosurg Psychiatry 2007; 78:476-479.
15. Roth T, Roehrs T. Insomnia: Epidemiology, characteristics, and consequences. Clin Cornerstone 2003; 5:5-15.
16. Okun ML, Kravitz HM, Sowers MF, Moul DE, Buysse DJ, Hall M. Psychometric evaluation of the insomnia symptom questionnaire: a self-report measure to identify chronic insomnia. J Clin Sleep Med 2009; 5:41-51.
17. Chittora R, Jain A, Prasad J, Bhatnagar M. An ameliorative effect of recovery sleep on total sleep deprivation-induced neurodegeneration. Biological Rhythm Research 2016; 47:425-436.
18. Montes-Rodriguez CJ, Alavez S, Soria-Gomez E, Rueda-Orozco PE, Guzman K, Moran J, et al. BCL-2 and BAX proteins expression throughout the light-dark cycle and modifications induced by sleep deprivation and rebound in adult rat brain. J Neurosci Res 2009; 87:1602-1609.
19. Vollert C, Zagaar M, Hovatta I, Taneja M, Vu A, Dao A, et al. Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: potential role of oxidative stress mechanisms. Behav Brain Res 2011; 224:233-240.
20. Mendelsohn AR, Larrick JW. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases. Rejuvenation Res 2013; 16:518-523.
21. Eugene AR, Masiak J. The neuroprotective aspects of sleep. MEDtube Sci 2015; 3:35-40.
22. Vajdi-Hokmabad R, Ziaee M, Sadigh-Eteghad S, Sandoghchian Shotorbani S, Mahmoudi J. Modafinil improves catalepsy in a rat 6-hydroxydopamine model of parkinson’s disease; possible involvement of dopaminergic neurotransmission. Adv Pharm Bull 2017; 7:359-365.
23. Manakova S, Puttonen KA, Raasmaja A, Mannisto PT. The roles of dopamine transporter and Bcl-2 protein in the protection of CV1-P cells from 6-OHDA-induced toxicity. Toxicol Lett 2004; 154:117-123.
24. Hara H, Ohta M, Ohta K, Kuno S, Adachi T. Apomorphine attenuates 6-hydroxydopamine-induced apoptotic cell death in SH-SY5Y cells. Redox Rep 2003; 8:193-197.
25. Kramer BC, Mytilineou C. Alterations in the cellular distribution of bcl-2, bcl-x and bax in the adult rat substantia nigra following striatal 6-hydroxydopamine lesions. J Neurocytol 2004; 33:213-223.
26. Paxinos GW CW. The rat brain in stereotaxic coordinates. . 5th ed: Burlington, MA: Elsevier Academic Press; ; 2005.
27. Mahmoudi J, Nayebi AM, Samini M, Reyhani-Rad S, Babapour V. 5-HT1A receptor activation improves anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats. Daru 2011; 19:338.
28. Alzoubi KH, Khabour OF, Salah HA, Rashid BEA. The combined effect of sleep deprivation and Western diet on spatial learning and memory: role of BDNF and oxidative stress. J Mol Neurosci 2013; 50:124-133.
29. Wang L, Song Y, Li F, Liu Y, Ma J, Mao M, et al. Effects of Wen Dan Tang on insomnia-related anxiety and levels of the brain-gut peptide Ghrelin. Neural Regen Res 2014; 9:205.
30. Koban M, Swinson KL. Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue. Am J Physiol Endocrinol Metab 2005; 289:E68-74.
31. Mahmoudi J, Ahmadian N, Farajdokht F, Majdi A, Erfani M. A protocol for conventional sleep deprivation methods in rats. JECN 2017; 4:1-4.
32. Salehpour F, Farajdokht F, Erfani M, Sadigh-Eteghad S, Shotorbani SS, Hamblin MR, et al. Transcranial near-infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep-deprived mice. Brain Res 2018; 1682:36-43.
33. Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res 2014; 271:116-121.
34. Martinez A, Morgese M, Pisanu A, Macheda T, Paquette M, Seillier A, et al. Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats. Neurobiol Dis 2015; 74:295-304.
35. Motawi TK, Darwish HA, Moustafa YM, Labib MM. Biochemical modifications and neuronal damage in brain of young and adult rats after long-term exposure to mobile phone radiations. Cell Biochem Biophys 2014; 70:845-855.
36. Yuan H, Sarre S, Ebinger G, Michotte Y. Histological, behavioural and neurochemical evaluation of medial forebrain bundle and striatal 6-OHDA lesions as rat models of Parkinson’s disease. J Neurosci Methods 2005; 144:35-45.
37. Schober A. Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 2004; 318:215-224.
38. Stott SR, Barker RA. Time course of dopamine neuron loss and glial response in the 6‐OHDA striatal mouse model of Parkinson’s disease. Eur J Neurosci 2014; 39:1042-1056.
39. Sun M, Wang K, Yu Y, Su W-T, Jiang X-X, Yang J, et al. Electroacupuncture alleviates depressive-like symptoms and modulates bdnf signaling in 6-hydroxydopamine rats. Evid Based Complement Alternat Med 2016; 2016:7842362.
40. Stahl K, Mylonakou M, Skare Ø, Amiry-Moghaddam M, Torp R. Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson’s disease. Brain Res 2011; 1378:105-118.
41. Berghauzen-Maciejewska K, Wardas J, Kosmowska B, Głowacka U, Kuter K, Ossowska K. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson’s disease: an influence of chronic pramipexole in rats. PloS one 2015; 10:e0117698.
42. He Y-Y, Zhang X-Y, Yung W-H, Zhu J-N, Wang J-J. Role of BDNF in central motor structures and motor diseases. Mol Neurobiol 2013; 48:783-793.
43. Nasrolahi A, Mahmoudi J, Akbarzadeh A, Karimipour M, Sadigh-Eteghad S, Salehi R, et al. Neurotrophic factors hold promise for the future of Parkinson’s disease treatment: is there a light at the end of the tunnel? Rev Neurosci 2018; 29:475-489.
44. Baydyuk M, Xu B. BDNF signaling and survival of striatal neurons. Front Cell Neurosci 2014; 8.
45. Bustos G, Abarca J, Bustos V, Riquelme E, Noriega V, Moya C, et al. NMDA receptors mediate an early up‐regulation of brain‐derived neurotrophic factor expression in substantia nigra in a rat model of presymptomatic Parkinson’s disease. J Neurosci Res 2009; 87:2308-2318.
46. Baquet ZC, Bickford PC, Jones KR. Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci Res 2005; 25:6251-6259.
47. Galpern WR, Frim DM, Tatter SB, Altar CA, Beal MF, Isacson O. Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. Cell Transplant 1996; 5:225-232.
48. Sei H, Saitoh D, Yamamoto K, Morita K, Morita Y. Differential effect of short-term REM sleep deprivation on NGF and BDNF protein levels in the rat brain. Brain Res 2000; 877:387-390.
49. Guzman‐Marin R, Ying Z, Suntsova N, Methippara M, Bashir T, Szymusiak R, et al. Suppression of hippocampal plasticity‐related gene expression by sleep deprivation in rats. J Physiol 2006; 575:807-819.
50. Alhaider IA, Aleisa AM, Tran TT, Alkadhi KA. Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine. Mol Cell Neurosci 2011; 46:742-751.
51. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca 2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 1998; 20:709-726.
52. Guzmán‐Marín R, Suntsova N, Stewart DR, Gong H, Szymusiak R, McGinty D. Sleep deprivation reduces proliferation of cells in the dentate gyrus of the hippocampus in rats. J Physiol 2003; 549:563-571.
53. Shrivastava P, Vaibhav K, Tabassum R, Khan A, Ishrat T, Khan MM, et al. Anti-apoptotic and anti-inflammatory effect of piperine on 6-OHDA induced Parkinson’s rat model. J Nutr Biochem 2013; 24:680-687.
54. Kim M, Cho K-H, Shin M-S, Lee J-M, Cho H-S, Kim C-J, et al. Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson’s disease. Int J Mol Med 2014; 33:870-878.
55. Saldaña M, Bonastre M, Aguilar E, Marin C. Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats: role in neurotoxicity and stereotyped behavior. Exp Neurol 2007; 203:302-308.
56. Horowitz JM, Pastor DM, Goyal A, Kar S, Ramdeen N, Hallas BH, et al. BAX protein-immunoreactivity in midbrain neurons of Parkinson’s disease patients. Brain Res Bull 2003; 62:55-61.
57. Biswas S, Mishra P, Mallick BN. Increased apoptosis in rat brain after rapid eye movement sleep loss. Neuroscience 2006; 142:315-331.
58. Somarajan BI, Khanday MA, Mallick BN. Rapid eye movement sleep deprivation induces neuronal apoptosis by noradrenaline acting on Alpha1 adrenoceptor and by triggering mitochondrial intrinsic pathway. Front Neurol 2016; 7.
59. Kim J-A, Mitsukawa K, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y. Cytoskeleton disruption causes apoptotic degeneration of dentate granule cells in hippocampal slice cultures. Neuropharmacology 2002; 42:1109-1118.
60. Almeida R, Manadas B, Melo C, Gomes J, Mendes C, Graos M, et al. Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ 2005; 12:1329-1343.
61. Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004; 15:177-182.
62. Kirkin V, Joos S, Zörnig M. The role of Bcl-2 family members in tumorigenesis. Biochimica et Biophysica Acta 2004; 1644:229-249.
63. Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 1996; 88:386-401.
64. Rahman KM, Aranha O, Glazyrin A, Chinni SR, Sarkar FH. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene 2000; 19:5764-5771.
65. Tamás A, Lubics A, Szalontay L, Lengvári I, Reglődi D. Age and gender differences in behavioral and morphological outcome after 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Behav Brain Res 2005; 158:221-229.
66. Dos Santos ACD, Castro MAV, Jose EAK, Delattre AM, Dombrowski PA, Cunha C, et al. REM sleep deprivation generates cognitive and neurochemical disruptions in the intranigral rotenone model of Parkinson’s disease. J Neurosci Res 2013; 91:1508-1516.
67. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Wong C, et al. Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain. J Neurosci 2008; 28:8454-8461.
68. Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol 2004; 73:379-396.
69. Geisler S, Zahm DS. Afferents of the ventral tegmental area in the rat-anatomical substratum for integrative functions. J Comp Neurol 2005; 490:270-294.
70. Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci U S A 1989; 86:1398-1400.
71. Petersén Å, Larsen K, Behr G, Romero N, Przedborski S, Brundin P, et al. Brain-derived neurotrophic factor inhibits apoptosis and dopamine-induced free radical production in striatal neurons but does not prevent cell death. Brain Res Bull 2001; 56:331-335.
72. Bournival J, Quessy P, Martinoli M-G. Protective effects of resveratrol and quercetin against MPP+-induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons. Cell Mol Neurobiol 2009; 29:1169-1180.