Abstract
R-phenylpiracetam (R-PhP, (4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide) is an optical isomer of phenotropil, a clinically-used nootropic drug that improves physical condition and cognition. Recently, R-PhP was shown to bind to the dopamine transporter (DAT). Since growing evidence suggests that dysfunction of the dopaminergic system is associated with persistent neuroinflammation, the aim of this study was to determine whether R-PhP, an inhibitor of DAT, has neuroprotective and anti-inflammatory effects in male mice. The pharmacokinetic profiles of R-PhP in mouse plasma and its bioavailability in brain tissue were assessed. To study possible molecular mechanisms involved in the anti-inflammatory activity of R-PhP, target profiling was performed using radioligand binding and enzymatic activity assays. To clarify the neuroprotective and anti-inflammatory effects of R-PhP, we used a lipopolysaccharide (LPS)-induced endotoxaemia model characterized by reduced body temperature and overexpression of inflammatory genes in the brain. In addition, the antinociceptive and anti-inflammatory effects of R-PhP were tested using carrageenan-induced paw oedema and formalin-induced paw-licking tests. R-PhP (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (ip) and peroral (po) injections. The maximal concentration of R-PhP in the brain tissues was 28 µg/g and 18 µg/g tissue after ip and po administration, respectively. In radioligand binding assays, DAT was the only significant molecular target found for R-PhP. A single ip injection of R-PhP significantly attenuated the LPS-induced body temperature reduction and the overexpression of inflammatory genes, such as tumour necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β) and inducible nitric oxide synthase (iNOS). Seven-day po pretreatment with R-PhP dose-dependently reduced paw oedema and the antinociceptive response, as shown by the carrageenan-induced paw oedema test. In addition, R-PhP decreased the nociceptive response during the inflammatory phase in the formalin-induced paw-licking test. Our study showed that R-PhP possesses neuroprotective and anti-inflammatory effects, demonstrating the potential of DAT inhibitors as effective therapeutics.
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Abbreviations
- ANOVA:
-
Analysis of variance
- DA:
-
Dopamine
- DAT:
-
Dopamine transporter
- iNOS:
-
Inducible nitric oxide synthase
- IL-1β:
-
Interleukin 1 beta
- Ip:
-
Intraperitoneal
- LPS:
-
Lipopolysaccharide
- PCR:
-
Polymerase chain reaction
- Po:
-
Peroral
- R-PhP:
-
R-Phenylpiracetam [(4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide]
- SEM:
-
Standard error of the mean
- S-PhP:
-
S-Phenylpiracetam
- TNF-α:
-
Tumour necrosis factor-α
- UPLC⁄MS⁄MS:
-
Ultra-performance liquid chromatography–tandem mass spectrometry
References
Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, Quintero-Fabián S, Pavón L (2016) Immunomodulatory effects mediated by dopamine. J Immunol Res 2016:3160486
Berk M, Dodd S, Kauer-Sant’Anna M, Malhi GS, Bourin M, Kapczinski F, Norman T (2007) Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand 116:41–49. https://doi.org/10.1111/j.1600-0447.2007.01058.x
Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M, Schwaninger M, McEwen B, Kirschbaum C, Nawroth PP (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 100:1920–1925. https://doi.org/10.1073/pnas.0438019100
Capuron L, Miller AH (2004) Cytokines and psychopathology: lessons from interferon-α. Biol Psychiatry 56:819–824. https://doi.org/10.1016/J.BIOPSYCH.2004.02.009
Felger JC, Miller AH (2012) Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 33:315–327. https://doi.org/10.1016/j.yfrne.2012.09.003
Frenois F, Moreau M, O’Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531. https://doi.org/10.1016/J.PSYNEUEN.2007.03.005
Giros B, Caron MG (1993) Molecular characterization of the dopamine transporter. Trends Pharmacol Sci 14:43–49. https://doi.org/10.1016/0165-6147(93)90029-J
Gustafsson H, Flood K, Berge O-G, Brodin E, Olgart L, Stiller C-O (2003) Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Exp Neurol 182:427–434. https://doi.org/10.1016/S0014-4886(03)00097-9
Hajhashemi V, Sadeghi H, Minaiyan M, Movahedian A, Talebi A (2010) The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats. Clinics 65:1183–1187. https://doi.org/10.1590/S1807-59322010001100022
Hara K, Haranishi Y, Kataoka K, Takahashi Y, Terada T, Nakamura M, Sata T (2014) Chlorogenic acid administered intrathecally alleviates mechanical and cold hyperalgesia in a rat neuropathic pain model. Eur J Pharmacol 723:459–464
Horn AS (1990) Dopamine uptake: a review of progress in the last decade. Prog Neurobiol 34:387–400. https://doi.org/10.1016/0301-0082(90)90033-D
Kilic F, Aydin S, Yildirim C, Donertas B, Oner S, Kaygisiz B (2018) Effects of gabapentin on carrageenan-induced inflammation, acute phase reactants and gastric mucus secretion in rats. Eur J Ther. https://doi.org/10.5152/EurJTher.2018.543
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412. https://doi.org/10.1371/journal.pbio.1000412
Kim S, Park JH, Myung SW, Lho DS (1999) Determination of carphedon in human urine by solid-phase microextraction using capillary gas chromatography with nitrogen-phosphorus detection. Analyst 124(11):1559–1562
Kovalchuk VV, Skoromets AA, Kovalchuk IV, Stoianova EG, Vysotskaia ML, Melikhova EV, Iliaǐnen EV (2010) Efficacy of phenotropil in the rehabilitation of stroke patients. Zh Nevrol Psikhiatr Im Korsakova 110:38–40
Li N, Li C, Han R, Wang Y, Yang M, Wang H, Tian J (2019) LPM580098, a novel triple reuptake inhibitor of serotonin, noradrenaline, and dopamine attenuates neuropathic Pain. Front Pharmacol 14:10–53. https://doi.org/10.3389/fphar.2019.00053
Lin Y, Morrow TJ, Kiritsy-Roy JA, Terry LC, Casey KL (1989) Cocaine: evidence for supraspinal, dopamine-mediated, non-opiate analgesia. Brain Res 479(2):306–312
Mackie P, Lebowitz J, Saadatpour L, Nickoloff E, Gaskill P, Khoshbouei H (2018) The dopamine transporter: an unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s disease. Brain Behav Immun 70:21–35. https://doi.org/10.1016/j.bbi.2018.03.020
Malykh AG, Sadaie MR (2010) Piracetam and piracetam-like drugs. Drugs 70:287–312. https://doi.org/10.2165/11319230-000000000-00000
McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL (2010) Editorial: Guidelines for reporting experiments involving animals: The ARRIVE guidelines. Br J Pharmacol. https://doi.org/10.1111/j.1476-5381.2010.00873.x
Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. https://doi.org/10.1038/nri.2015.5
Miller AH, Haroon E, Raison CL, Felger JC (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297–306. https://doi.org/10.1002/da.22084
Morón JA, Zakharova I, Ferrer JV, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang JB, Javitch JA, Galli A, Shippenberg TS (2003) Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. J Neurosci 23(24):8480–8488
Posadas I, Bucci M, Roviezzo F, Rossi A, Parente L, Sautebin L, Cirino G (2004) Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br J Pharmacol 142:331–338. https://doi.org/10.1038/sj.bjp.0705650
Samotrueva MA, Tyurenkov IN, Teplyi DL, Serezhnikova TK, Khlebtsova EB (2011) Psychoimmunomodulatory effect of phenotropil in animals with immune stress. Bull Exp Biol Med 151:51–54. https://doi.org/10.1007/s10517-011-1257-4
Savchenko A, Zakharova NS, Stepanov IN (2005) The phenotropil treatment of the consequences of brain organic lesions. Zh Nevrol Psikhiatr Korsakova 105(12):22–26
Sawynok J, Esser MJ, Reid AR (2001) Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 26:21–29
Sazonov DV, Ryabukhina OV, Bulatova EV et al (2006) Use of phenotropil in complex treatment of multiple sclerosis [in Russian]. Nervnye Bolezni 4:18–21
Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (2014) The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats. Int J Neuropsychopharmacol 17:2045–2056. https://doi.org/10.1017/S1461145714000996
Taylor NE, Pei J, Zhang J, Vlasov KY, Davis T, Taylor E, Weng FJ, Van Dort CJ, Solt K, Brown EN (2019) The role of glutamatergic and dopaminergic neurons in the periaqueductal gray/dorsal raphe: separating analgesia and anxiety. eNeuro. https://doi.org/10.1523/eneuro.0018-18.2019
Tyurenkov IN, Samotrueva MA, Tsibizova AA, Yasenyavskaya AL (2015) Phenotropil as modulator of cytokine level under conditions of experimental immunopathology. Eksp Klin Farmakol. 78:15–17. https://doi.org/10.30906/0869-2092-2015-78-12-15-17
Zvejniece L, Svalbe B, Veinberg G, Grinberga S, Vorona M, Kalvinsh I, Dambrova M (2011) Investigation into stereoselective pharmacological activity of phenotropil. Basic Clin Pharmacol Toxicol 109:407–412. https://doi.org/10.1111/j.1742-7843.2011.00742.x
Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, Kalvinsh I, Dambrova M (2015) R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects. Pharmacol Biochem Behav 137:23–29. https://doi.org/10.1016/J.PBB.2015.07.014
Zvejniece L, Svalbe B, Vavers E, Makrecka-Kuka M, Makarova E, Liepins V, Kalvinsh I, Liepinsh E, Dambrova M (2017) S-phenylpiracetam, a selective DAT inhibitor, reduces body weight gain without influencing locomotor activity. Pharmacol Biochem Behav 160:21–29. https://doi.org/10.1016/j.pbb.2017.07.009
Acknowledgements
This work was in part founded by the Latvian Institute of Organic Synthesis internal grant. We thank JSC Olainfarm for providing target profiling data for R-phenylpiracetam.
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This work was in part founded by the Latvian Institute of Organic Synthesis internal grant.
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Zvejniece, L., Zvejniece, B., Videja, M. et al. Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice. Inflammopharmacol 28, 1283–1292 (2020). https://doi.org/10.1007/s10787-020-00705-7
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DOI: https://doi.org/10.1007/s10787-020-00705-7