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Association Between the Endocannabinoid System-Related Gene Variants and Epilepsy

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Abstract

The endocannabinoid system (ECS) is an intricate network consisting of receptors, enzymes, and endogenous ligands that play a pivotal role in various neurological processes. It has been implicated in the pathophysiology of several neurological disorders, including epilepsy. Extensive research has demonstrated the involvement of genetic factors in influencing the susceptibility to and progression of epilepsy. In this study, we focused on investigating the connection between genetic variations in genes related to the ECS and the occurrence of epilepsy. Some ECS-related gene variants were selected and genotyping was performed using the polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) technique. Interestingly, CNR1 rs12720071 genotype (OR 16.33, 95% CI 1.8–149; p = 0.001) showed an association with generalized epilepsy and MGLL rs604300 genotype (OR 2, 95% CI 1.1–3.4; p = 0.013) demonstrated a relationship with females diagnosed with focal epilepsy. So, studying CNR1, MGLL, and their genetic variations provides insights into the role of the endocannabinoid system in health and diseases. Moreover, they hold the potential to pave the way for the development of novel therapeutic approaches specifically targeting them.

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Data Availability

The data supporting the findings of this study is available upon request from the corresponding author.

References

  1. Lu HC, Mackie K (2021) Review of the endocannabinoid system. Biol Psychiatry Cogn Neurosci Neuroimaging 6:607–615

    PubMed  Google Scholar 

  2. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    Article  CAS  PubMed  Google Scholar 

  3. Atwood BK, Mackie K (2010) CNR2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 160:467–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Busquets-Garcia A, Bains J, Marsicano G (2018) CB(1) Receptor signaling in the brain: extracting specificity from ubiquity. Neuropsychopharmacology 43:4–20

    Article  CAS  PubMed  Google Scholar 

  5. Demuth DG, Molleman A (2006) Cannabinoid signalling. Life Sci 78:549–563

    Article  CAS  PubMed  Google Scholar 

  6. J. E. W. H. O. h. w. w. i. n.-r. f.-s. d. e. World Health Organization.

  7. Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367:3353–3363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao Q, Yang F, Wang H (2021) CNR2R induces a protective response against epileptic seizures through ERK and p38 signaling pathways. Int J Neurosci 131:735–744

    Article  CAS  PubMed  Google Scholar 

  9. Blair RE, Deshpande LS, Sombati S, Falenski KW, Martin BR, DeLorenzo RJ (2006) Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther 317:1072–1078

    Article  CAS  PubMed  Google Scholar 

  10. Amini M, Saboory E, Derafshpour L, Fakhari A, Wu JC, Bruggeman R, Asgharzadeh F, Ahmadalipour A (2020) The impact of sleep deprivation on sexual behaviors and FAAH expression in the prefrontal cortex of male rats. Neurosci Lett 735:135254

    Article  CAS  PubMed  Google Scholar 

  11. Mobed A, Kohansal F, Ahmadalipour A, Hasanzadeh M, Zargari F (2022) Correction: bioconjugation of 2-arachidonoyl glycerol (2-AG) biotinylated antibody with gold nano-flowers toward immunosensing of 2-AG in human plasma samples: a novel immuno-platform for the screening of immunomodulation and neuroprotection using biosensing. Anal Methods 14:4029

    Article  PubMed  Google Scholar 

  12. von Ruden EL, Bogdanovic RM, Wotjak CT, Potschka H (2015) Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice. Neurobiol Dis 77:238–245

    Article  Google Scholar 

  13. Sugaya Y, Yamazaki M, Uchigashima M, Kobayashi K, Watanabe M, Sakimura K, Kano M (2016) Crucial roles of the endocannabinoid 2-arachidonoylglycerol in the suppression of epileptic seizures. Cell Rep 16:1405–1415

    Article  CAS  PubMed  Google Scholar 

  14. Monteleone P, Bifulco M, Maina G, Tortorella A, Gazzerro P, Proto MC, Di Filippo C, Monteleone F, Canestrelli B, Buonerba G, Bogetto F, Maj M (2010) Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacol Res 61:400–404

    Article  CAS  PubMed  Google Scholar 

  15. Si P, Liu S, Tong D, Cheng M, Wang L, Cheng X (2018) Association of polymorphisms of NAPE-PLD and FAAH genes with schizophrenia in Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 35:215–218

    PubMed  Google Scholar 

  16. Ahmadalipour A, Mehdizadeh Fanid L, Zeinalzadeh N, Alizadeh M, Vaezi H, Hassanpour Aydinlou Z, Noorazar SG (2020) The first evidence of an association between a polymorphism in the endocannabinoid-degrading enzyme FAAH (FAAH rs2295633) with attention deficit hyperactivity disorder. Genomics 112:1330–1334

    Article  CAS  PubMed  Google Scholar 

  17. Anvar LH, Alejafar A, Moosavi SE, Charsouei S, Zeynalzadeh N, Fanid LM, Emamalizadeh B, Aydinlou ZH, Vaezi H, Kashefi A, Tomaz C, Nikanfar M, Ahmadalipour A (2023) The study of rs324420 (C385A) polymorphism of the FAAH gene of the endocannabinoid system in patients with epilepsy and ADHD. Epilepsy Res 192:107100

    Article  CAS  PubMed  Google Scholar 

  18. Hosseinzadeh Anvar L, Ahmadalipour A (2023) Fatty acid amide hydrolase C385A polymorphism affects susceptibility to various diseases. BioFactors 49:62–78

    Article  CAS  PubMed  Google Scholar 

  19. Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T, Watanabe Y, Takahashi M, Someya T, Ujike H, Iwata N, Ozaki N, Onaivi ES, Kunugi H, Sasaki T, Itokawa M, Arai M, Niizato K, Iritani S, Naka I, Ohashi J, Kakita A, Takahashi H, Nawa H, Arinami T (2010) Brain cannabinoid CNR2 receptor in schizophrenia. Biol Psychiatry 67:974–982

    Article  CAS  PubMed  Google Scholar 

  20. Carey CE, Agrawal A, Zhang B, Conley ED, Degenhardt L, Heath AC, Li D, Lynskey MT, Martin NG, Montgomery GW, Wang T, Bierut LJ, Hariri AR, Nelson EC, Bogdan R (2015) Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: evidence from an endocannabinoid system-level analysis. J Abnorm Psychol 124:860–877

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ferretjans R, de Souza RP, Panizzutti B, Ferrari P, Mantovani L, de Campos-Carli SM, Santos RR, Guimaraes FC, Teixeira AL, Gama CS, Salgado JV (2022) Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls. Braz J Psychiatry 44:26–34

    Article  PubMed  Google Scholar 

  22. Tong D, He S, Wang L, Jin L, Si P, Cheng X (2013) Association of single-nucleotide polymorphisms in the cannabinoid receptor 2 gene with schizophrenia in the Han Chinese population. J Mol Neurosci 51:454–460

    Article  CAS  PubMed  Google Scholar 

  23. Ishiguro H, Higuchi S, Arinami T, Onaivi ES (2018) Association between alcoholism and the gene encoding the endocannabinoid synthesizing enzyme diacylglycerol lipase alpha in the Japanese population. Alcohol 68:59–62

    Article  CAS  PubMed  Google Scholar 

  24. Peiro AM, Garcia-Gutierrez MS, Planelles B, Femenia T, Mingote C, Jimenez-Trevino L, Martinez-Barrondo S, Garcia-Portilla MP, Saiz PA, Bobes J, Manzanares J (2020) Association of cannabinoid receptor genes (CNR1 and CNR2) polymorphisms and panic disorder. Anxiety Stress Coping 33:256–265

    Article  PubMed  Google Scholar 

  25. Navarrete F, Garcia-Gutierrez MS, Gasparyan A, Navarro D, Lopez-Picon F, Morcuende A, Femenia T, Manzanares J (2022) Biomarkers of the endocannabinoid system in substance use disorders. Biomolecules 12

  26. h. f. g. c.-F. b. Genoox.

  27. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978–1980

    Article  CAS  PubMed  Google Scholar 

  28. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP (2017) Epilepsy-associated genes. Seizure 44:11–20

    Article  CAS  PubMed  Google Scholar 

  29. Prasad DK, Satyanarayana U, Munshi A (2013) Genetics of idiopathic generalized epilepsy: an overview. Neurol India 61:572–577

    Article  CAS  PubMed  Google Scholar 

  30. Rubino T, Parolaro D (2011) Sexually dimorphic effects of cannabinoid compounds on emotion and cognition. Front Behav Neurosci 5:64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guennoun R (2020) Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci 21:5271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jameson JL, De Groot LJ, de Kretser DM, Giudice LC, Grossman AB, Melmed S, Potts Jr. JT and Weir GC (Eds.) (2016) Endocrinology: adult & pediatric. (7th ed.) Elsevier

  33. Reddy DS, Thompson W, Calderara G (2021) Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis. Neurosci Lett 750:135753

    Article  CAS  PubMed  Google Scholar 

  34. Dalic L, Cook MJ (2016) Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat 12:2605–2616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Makowska M, Smolarz B, Brys M, Forma E, Romanowicz H (2021) An association between the rs1799853 and rs1057910 polymorphisms of CYP2C9, the rs4244285 polymorphism of CYP2C19 and the prevalence rates of drug-resistant epilepsy in children. Int J Neurosci 131:1147–1154

    Article  CAS  PubMed  Google Scholar 

  36. Seven M, Batar B, Unal S, Yesil G, Yuksel A, Guven M (2014) The effect of genetic polymorphisms of cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on drug-resistant epilepsy in Turkish children. Mol Diagn Ther 18:229–236

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate all participants of this project and Tabriz University of Medical Sciences for financial support of the project.

Funding

The research reported in this publication was supported by Tabriz University of Medical Sciences.

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Author notes

  1. Leila Hosseinzadeh Anvar and Seyyed Ebrahim Moosavi equally contributed to this work.

Authors and Affiliations

  1. Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Leila Hosseinzadeh Anvar & Ali Ahmadalipour

  2. Department of Neurology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Seyyed Ebrahim Moosavi, Saeid Charsouei & Masoud Nikanfar

  3. Department of Animal Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Narges Zeinalzadeh

  4. Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Ali Ahmadalipour

Authors
  1. Leila Hosseinzadeh Anvar
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  2. Seyyed Ebrahim Moosavi
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  3. Saeid Charsouei
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  4. Narges Zeinalzadeh
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  5. Masoud Nikanfar
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Contributions

LHA: methodology, experimental design, data collection, writing and editing the draft. EM: data collection, experimental design. SC: conceptualization study, funding acquisition, data collection. NZ: methodology, review and editing. MN: supervision, review and editing, AA: supervision, data collection, review and editing of the draft.

Corresponding authors

Correspondence to Saeid Charsouei or Ali Ahmadalipour.

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Ethics Approval

The study was approved by the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1400.535).

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Patients and controls who participated signed an informed consent form approved by the local ethics committee.

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Not applicable as no personal information will be published.

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The authors declare no competing interests.

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Hosseinzadeh Anvar, L., Moosavi, S.E., Charsouei, S. et al. Association Between the Endocannabinoid System-Related Gene Variants and Epilepsy. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04132-5

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