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In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption

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Abstract

Background

Excessive alcohol consumption is a global health burden and requires a better understanding of its neurobiology. A lower density of brain microtubules is found in alcohol-related human brain disease postmortem and in rodent models of chronic alcohol consumption. Here, we report in vivo imaging studies of microtubules in brain using our recently reported Positron Emission Tomography (PET) tracer, [11C]MPC-6827, in chronic alcohol-consuming adult male C57BL/6 J mice and control mice.

Methods

In vivo PET imaging studies of [11C]MPC-6827 (3.7  ±  0.8 MBq) were performed in two groups of adult male mice: (1) water-consuming control mice (n  =  4) and (2) mice that consumed 20% alcohol (w/v) for 4 months using the intermittent 2-bottle choice procedure that has been shown to lead to signs of alcohol dependence. Dynamic 63 min PET images were acquired using a microPET Inveon system (Siemens, Germany). PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain, prefrontal cortex (PFC), liver and heart was measured and plotted as %ID/g over time (0–63 min) to generate time-activity curves (TACs).

Results

In general, a trend for lower binding of [11C]MPC-6827 in the whole brain and PFC of mice in the chronic alcohol group was found compared with control group. No group difference in radiotracer binding was found in the peripheral organs such as liver and heart.

Conclusions

This pilot study indicates a trend of loss of microtubule binding in whole brain and prefrontal cortex of chronic alcohol administered mice brain compared to control mice, but no loss in heart or liver. These results indicate the potential of [11C]MPC-6827 as a PET ligand for further in vivo imaging investigations of AUD in human.

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Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AUD:

Alcohol use disorder

BBB:

Blood brain barrier

IA:

Intermittent access

ID/g:

Injected dose/gram

MBq:

Mega becquerel

MT:

Microtubule

PET:

Positron emission tomography

PFC:

Prefrontal cortex

PTM:

Post-translational modifications

TAC:

Time-activity curves

SEM:

Standard error of the mean

SUV:

Standardized uptake values

W/v:

Weight per volume

References

  1. https://www.samhsa.gov/data/sites/default/files/cbhsqreports/NSDUHNationalFindingsReport2018/NSDUHNationalFindingsReport2018.pdf.

  2. Barve S, Chen S-Y, Kirpich I, Watson WH, McClain C. Development prevention, and treatment of alcohol-induced organ injury: the role of nutrition. Alcohol Res. 2017;38(2):289–302.

    PubMed  PubMed Central  Google Scholar 

  3. Scheideler JK, Klein WMP. Awareness of the link between alcohol consumption and cancer across the world: a review. Cancer Epidemiol Biomarkers Prev. 2018;27(4):429–37.

    Article  Google Scholar 

  4. Sabia S, Fayosse A, Dumurgier J, Dugravot A, Akbaraly T, Britton A, Kivimaki M, Singh MA. Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. BMJ. 2018;362:k2927.

    Article  Google Scholar 

  5. Ray LA, Bujarski S, Grodin E, Hartwell E, Green R, Venegas A, Lim AC, Gillis A, Miotto K. State-of-the-art behavioral and pharmacological treatments for Alcohol Use Disorder. Am J Drug Alcohol Abuse. 2019;45(2):124–40.

    Article  Google Scholar 

  6. Cannella N, Ubaldi M, Masi A, Bramucci M, Roberto M, Bifone A, Ciccocioppo R. Building better strategies to develop new medications in Alcohol Use Disorder: learning from past success and failure to shape a brighter future. Neurosci Biobehav Rev. 2019;103:384–98.

    Article  Google Scholar 

  7. Williams EC, Matson TE, Harris AHS. Strategies to increase implementation of pharmacotherapy for alcohol use disorders: a structured review of care delivery and implementation interventions. Addict Sci Clin Pract. 2019;14:6.

    Article  Google Scholar 

  8. Erdozain AM, Morentin B, Bedford L, King E, Tooth D, Brewer C, et al. Alcohol-related brain damage in humans. PLoS ONE. 2014;9(4):e93586.

    Article  Google Scholar 

  9. Labisso WL, Raulin A-C, Nwidu LL, Kocon A, Wayne D, Erdozain AM, et al. The loss of alpha- and beta-tubulin proteins are a pathological hallmark of chronic alcohol consumption and natural brain ageing. Brain Sci. 2018;8(9):175.

    Article  CAS  Google Scholar 

  10. Smith KJ, Butler TR, Prendergast MA. Ethanol impairs microtubule formation via interactions at a microtubule associated protein-sensitive site. Alcohol. 2013;47(7):539–43.

    Article  CAS  Google Scholar 

  11. Enculescu C, Kerr ED, Benjamin YKY, Schenk G, Fortes MRS, Schulz BL. Proteomics reveals profound metabolic changes in the alcohol use disorder brain. ACS Chem Neurosci. 2019;10(5):2364.

    Article  CAS  Google Scholar 

  12. Shepard BD, Tuma PL. Alcohol-induced alterations of the hepatocyte cytoskeleton. World J Gastroenterol. 2010;16(11):1358–65.

    Article  CAS  Google Scholar 

  13. Piano MR, Phillips SA. Alcoholic cardiomyopathy: pathophysiologic insights. Cardiovasc Toxicol. 2014;14(4):291–308.

    Article  CAS  Google Scholar 

  14. Kumar JSD, Solingapuram SKK, Prabhakaran J, Oufkir HR, Ramanathan G, Whitlow CT, et al. Radiosynthesis and In vivo evaluation of [11C]MPC-6827, the first brain penetrant microtubule PET ligand. J Med Chem. 2018;61(5):2118–23.

    Article  CAS  Google Scholar 

  15. Kumar JSD, Prabhakaran J, Damuka N, Hines JW, Norman S, Meghana DM, et al. In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands. Bioorg Med Chem Let. 2010;30(2):126785.

    Article  Google Scholar 

  16. Kumar JSD, Prabhakaran J, Kim J, Castrillon J, Molotkov A, Dileep H, et al. In vivo evaluation of microtubule PET ligand [11C]MPC-6827 in animal models of neurodegenerative disorders. J Nucl Med. 2019;60:1301 (s1).

    Article  Google Scholar 

  17. Hwa LS, Chu A, Levinson SA, Kayyali TM, DeBold JF, Miczek KA. Persistent escalation of alcohol drinking in C57Bl/6J mice with intermittent access to 20% ethanol. Alcohol Clin Exp Res. 2011;35(11):1938.

    Article  Google Scholar 

  18. Salling MC, Skelly MJ, Avegno E, Regan S, Zeric T, Nichols E, Harrison NL. Alcohol consumption during adolescence in a mouse model of binge drinking alters the intrinsic excitability and function of the prefrontal cortex through a reduction in the hyperpolarization-activated cation current. J Neurosci. 2018;38(27):6207–22.

    Article  CAS  Google Scholar 

  19. Lindell SG, Schwandt ML, Suomi SJ, Rice KC, Heilig M, Barr CS. Intermittent access to ethanol induces escalated alcohol consumption in primates. J Addict Behav Ther Rehabil. 2017;6(1):163.

    PubMed  PubMed Central  Google Scholar 

  20. Laere KV, Ceccarini J. How acute and chronic alcohol consumption modulate multiple neurotransmitter systems: a review of clinical PET neuroimaging. J Alcohol Drug Depend. 2018;6:2.

    Article  Google Scholar 

  21. Wiers CE, Cabrera E, Skarda E, Volkow ND, Wang G-J. PET imaging for addiction medicine: from neural mechanisms to clinical considerations. Prog Brain Res. 2016;224:175.

    Article  Google Scholar 

  22. Solingapuram Sai KK, Hurley RA, Dodda M, Taber KH. Positron emission tomography: updates on imaging of addiction. J Neuropsychiatry Clin Neurosci. 2019;31:4.

    Article  Google Scholar 

  23. Smith SL, Jennett RB, Sorrell MF, Tuma DJ. Acetaldehyde sub-stoichiometrically inhibits bovine neurotubulin polymerization. J Clin Investig. 1989;84:337.

    Article  CAS  Google Scholar 

  24. Skultetyova L, Ustinova K, Kutil Z, Novakova Z, Pavlicek J, Mikesova J, et al. Human histone deacetylase 6 shows strong preference for tubulin dimers over assembled microtubules. Sci Rep. 2017;7:11547.

    Article  Google Scholar 

  25. Kasibhatla S, Baichwal V, Cai SX, Roth B, Skvortsova I, Skvortsov S, et al. MPC-6827: a small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps. Cancer Res. 2007;67(12):5865–71.

    Article  CAS  Google Scholar 

  26. Yan W, Yang T, Yang J, Wang T, Yu Y, Wang Y, et al. SKLB060 reversibly binds to colchicine site of tubulin and possesses efficacy in multidrug-resistant cell lines. Cell Physiol Biochem. 2018;47:489–504.

    Article  CAS  Google Scholar 

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Funding

This work was Funded by NCATS UL1TR001873 (Reilly) Irving Institute/CTSA Translational Therapeutics Accelerator.

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Authors and Affiliations

  1. Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, Manhattan, NY, USA

    J. S. Dileep Kumar, Jaya Prabhakaran & Akiva Mintz

  2. Feinstein Institutes for Medical Research, North Shore University Hospital, Manhasset, New York, USA

    J. S. Dileep Kumar

  3. Department of Radiology, Columbia University Medical Center, Manhattan, NY, USA

    Andrei Molotkov, Patrick Carberry, John Castrillon & Akiva Mintz

  4. Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Michael C. Salling

  5. Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

    Jaya Prabhakaran

Authors
  1. J. S. Dileep Kumar
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  2. Andrei Molotkov
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  3. Michael C. Salling
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  4. Patrick Carberry
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  5. Jaya Prabhakaran
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  7. Akiva Mintz
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Contributions

JSDK conceived the idea. JSDK, MCS, and AM designed the experiments. JSDK, MCS, AM, PC, JP, and JC performed the experiments. JSDK, AM, and MCS performed all analyses. JSDK, AM, MCS, and AM analyzed and interpret the data. JSDK drafted the manuscript. The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript.

Corresponding author

Correspondence to J. S. Dileep Kumar.

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The authors declare no conflicts of interest.

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Dileep Kumar, J.S., Molotkov, A., Salling, M.C. et al. In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption. Pharmacol. Rep 74, 241–247 (2022). https://doi.org/10.1007/s43440-021-00311-6

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  • DOI: https://doi.org/10.1007/s43440-021-00311-6

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