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 Table of Contents  
EDITORIAL
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 17

Preventive role of cannabinoids derivate against methylphenidate-induced oxidative stress and inflammation: the hypothetical function of Keap1/Nrf2/ARE signaling and proposal of a treatment strategy for neurodegeneration


1 Razi Drug Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Addiction department, School of Behavioral Sciences and Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, Iran

Date of Submission11-May-2020
Date of Acceptance13-Jul-2020
Date of Web Publication24-Feb-2021

Correspondence Address:
Majid Motaghinejad
Sheykhfazloohah Highway Iran University of Medical Sciences, P.O. Box: 14496.14525, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpvm.IJPVM_249_20

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How to cite this article:
Sepehr A, Taheri F, Kandezi N, Motaghinejad M, Safari S, Mohammadi N. Preventive role of cannabinoids derivate against methylphenidate-induced oxidative stress and inflammation: the hypothetical function of Keap1/Nrf2/ARE signaling and proposal of a treatment strategy for neurodegeneration. Int J Prev Med 2021;12:17

How to cite this URL:
Sepehr A, Taheri F, Kandezi N, Motaghinejad M, Safari S, Mohammadi N. Preventive role of cannabinoids derivate against methylphenidate-induced oxidative stress and inflammation: the hypothetical function of Keap1/Nrf2/ARE signaling and proposal of a treatment strategy for neurodegeneration. Int J Prev Med [serial online] 2021 [cited 2021 Jul 30];12:17. Available from: https://www.ijpvmjournal.net/text.asp?2021/12/1/17/310137




  Hypothesis Top


Chronic methylphenidate abuse or administration causes oxidative stress, inflammation, and mitochondrial dysfunction in brain cells that require therapeutic approaches to inhibit neurotoxicity and neurodegeneration of these types.[1],[2] Nonetheless, the function of methylphenidate in the induction of neurodegeneration or neuroprotection is uncertain, but most of the data support the function of methylphenidate in neurodegeneration.[3] As we know, Nrf2 (nuclear erythroid 2-related factor 2) is a basic region of leucine-zipper transcription factor that binds to the antioxidant response element (ARE) and thus regulates the expression of a large number of genes involved in cellular antioxidant and antiinflammatory defense as well as mitochondrial protection.[4],[5] Keap1 (Kelch ECH associating protein 1) is a repressor protein which binds to Nrf2 and promotes its degradation through the pathway of ubiquitin-proteasome.[5],[6] Nrf2/ARE signaling pathway is a key neuroprotection mediator.[6] Oxidative stress, inflammation, and mitochondrial dysfunction have been identified as important mechanisms for methylphenidate-induced neurodegeneration.[1],[2] Despite the role of methylphenidate in the induction of neurodegeneration, a previous study has shown controversial data and reported that methylphenidate, by reducing proinflammatory microglia and increasing BDNF and Nrf2 mRNA levels, may increase cognitive deficits and depressive behaviors in myotonic type 1 disease in Mbnl2 knockout mice;[7] however, the exact role of Keap1/Nrf2/ARE signaling pathway in methylphenidate-induced oxidative stress, inflammation, and mitochondrial dysfunction remains unclear. Neuroprotective approach to the prevention, treatment, or management of methylphenidate-induced oxidative stress, inflammation, and mitochondrial dysfunction through a novel neuroprotective agent is continuously superior to any other therapeutic strategy.[8],[9] The explanation, introduction, and development of a potent novel neuroprotective agent is therefore necessary.[10],[11] Studies have shown the possible neuroprotective and antiinflammatory efficacy of cannabinoid compounds and their derivatives such as cannabidiol (CBD) and delta 9 tetrahydrocannabinol against various neurodegenerative diseases and disorders over the past few years.[9],[12],[13],[14] According to some previous studies, cannabinoid derivative by direct activation of Nrf2/ARE or by inhibition of Keap1, a Nrf2 repressor protein, exerts its antioxidant and antiinflammatory effects and also induces mitochondrial biogenesis, but the specific role of Nrf2/ARE in the neuroprotective function of cannabinoid compounds was not entirely understood.[15],[16] The function of Nrf2 signaling pathways in mediating the protective and beneficial effects of cannabinoids on cardiovascular, musculoskeletal, gastro-hepatic, and other systems was also demonstrated in many previous studies,[17],[18] but its clear role in brain function and the role of Nrf2 signaling pathways in the mediation of cannabinoid-derived neuroprotection remains unclear and seems to require further assessment. According to the aforementioned literature on the neurotoxicity properties of methylphenidate and cannabinoid neuroprotective effects, we may assume that the use of cannabinoids in methylphenidate-dependent subject will produce antioxidant and antiinflammatory effects and cause mitochondrial biogenesis and neuroprotection in methylphenidate-induced neural cell degeneration; also, based on the role of Nrf2/ARE signaling pathways in antioxidant and antiinflammatory processes, it appears that methylphenidate can cause neurodegeneration by activation of Keap1 or direct inhibition of the Nrf2/ARE pathway. Cannabinoid derived by direct activation of the Nof2/ARE signaling pathways or their repressor, Keap1, is also expected to be capable of managing the sequel to methylphenidate abuses such as oxidative stress, inflammation, and neurodegeneration, but this claim requires molecular assessment in both experimental and human studies [Figure 1].
Figure 1: Possible inhibitory activity of cannabinoid derivatives such as cannabidiol (CBD) and delta 9 tetrahydrocannabinol (9 THC) against methylphenidate—oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Methylphenidate has been suggested to induce oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction through activation of Keap1 or direct inhibition of the Nrf2/ARE pathway. Cannabinoid derivative by direct activation of Nrf2/ARE signaling pathways or by inhibition of their repressor, Keap1, can control the sequel of methylphenidate abuse, such as oxidative stress, inflammation, and neurodegeneration, and can cause neuroprotection against methylphenidate-induced neurodegeneration. MPH: Methylphenidate, CBD: Cannabidiol, 9 THC: Delta 9 tetrahydrocannabinol, Nrf-2: Nuclear erythroid 2-related factor 2, Keap1: Kelch ECH associating protein 1, ARE: Antioxidant response element, TNF-α: Tumor necrosis factor, IL-6: Interleukin-6, IL-1β: Interleukin-1β, SOD: Superoxide dismutases, GPx: Glutathione peroxidase, GR: Glutathione reductase, CAT: Catalase

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  References Top

1.
Motaghinejad M, Motevalian M, Shabab B. Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats. Neurosci Lett 2016;619:106-13.  Back to cited text no. 1
    
2.
Coelho-Santos V, Cardoso FL, Leitão RA, Fontes-Ribeiro CA, Silva AP. Impact of developmental exposure to methylphenidate on rat brain's immune privilege and behavior: Control versus ADHD model. Brain Behav Immun 2018;68:169-82.  Back to cited text no. 2
    
3.
Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2015:CD009885. doi: 10.1002/14651858.CD009885.pub2.  Back to cited text no. 3
    
4.
Tu W, Wang H, Li S, Liu Q, Sha H. The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis 2019;10:637-51.  Back to cited text no. 4
    
5.
Petri S, Körner S, Kiaei M. Nrf2/ARE signaling pathway: Key mediator in oxidative stress and potential therapeutic target in ALS. Neurol Res Int 2012;2012:878030.  Back to cited text no. 5
    
6.
Zhang L, Yang J, Wu S, Jin C, Lu X, Hu X, et al. Activation of Nrf2/ARE signaling pathway attenuates lanthanum chloride induced injuries in primary rat astrocytes. Metallomics 2017;9:1120-31.  Back to cited text no. 6
    
7.
Ramon-Duaso C, Gener T, Consegal M, Fernández-Avilés C, Gallego JJ, Castarlenas L, et al. Methylphenidate attenuates the cognitive and mood alterations observed in Mbnl2 knockout mice and reduces microglia overexpression. Cereb Cortex 2019;29:2978-97.  Back to cited text no. 7
    
8.
Dang D-K, Shin E-J, Mai A-T, Jang C-G, Nah S-Y, Jeong JH, et al. Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice. Free Radic Biol Med 2017;108:204-224.  Back to cited text no. 8
    
9.
Kendall DA, Yudowski GA. Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Front Cell Neurosci 2017;10:294.  Back to cited text no. 9
    
10.
Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M. Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. Biomed Pharmacother 2017;87:721-40.  Back to cited text no. 10
    
11.
Liu Q-R, Canseco-Alba A, Zhang H-Y, Tagliaferro P, Chung M, Dennis E, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep 2017;7:17410.  Back to cited text no. 11
    
12.
Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 2016;112:119-27.  Back to cited text no. 12
    
13.
Borges R, da Silva A. Cannabidiol as an antioxidant. Handbook of Cannabis and Related Pathologies. Elsevier; 2017. e122-30.  Back to cited text no. 13
    
14.
Mori MA, Meyer E, Soares LM, Milani H, Guimarães FS, de Oliveira RMW. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia. Prog Neuropsychopharmacol Biol Psychiatry 2017;75:94-105.  Back to cited text no. 14
    
15.
Li X, Han D, Wang Y, Fan M, Li X, Cao F. GW27-e1152 activation of cannabinoid receptor II-CB2 ameliorates cardiac fibrosis after myocardial infarction via Nrf2-mediated inhibition of TGFβ-1/Smad3 pathway. J Am Coll Cardiol 2016;68:C42.  Back to cited text no. 15
    
16.
Casares L, García V, Garrido-Rodríguez M, Millán E, Collado JA, García-Martín A, et al. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol 2020;28:101321.  Back to cited text no. 16
    
17.
Li X, Han D, Tian Z, Gao B, Fan M, Li C, et al. Activation of cannabinoid receptor type II by AM1241 ameliorates myocardial fibrosis via Nrf2-mediated inhibition of TGF-β1/Smad3 pathway in myocardial infarction mice. Cell Physiol Biochem 2016;39:1521-36.  Back to cited text no. 17
    
18.
Zhang M, Zhang M, Wang L, Yu T, Jiang S, Jiang P, et al. Activation of cannabinoid type 2 receptor protects skeletal muscle from ischemia-reperfusion injury partly via Nrf2 signaling. Life Sci 2019;230:55-67.  Back to cited text no. 18
    


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