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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2018; 64(2): 12-18

The protease-activated receptor 1 inhibition during epileptogenesis does not alter behavioral excitability in rats

O.O. Lunko1, R.I. Bogovyk1, M.P. Fedoriuk1, G.S. Semenets2, E.V. Isaeva1,2

  1. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
  2. Taras Shevchenko National University of Kyiv, Ukraine


Antiepileptic drugs can induce both positive and adverse psychotropic effects, therefore evaluation of the behavioral effects of potential antiepileptic treatment early in the screening process is essential. Recently, we have shown that antagonist of protease-activated receptor 1 (PAR1), a major thrombin receptor in CNS, exhibits antiepileptogenic effect in the experimental model of temporal lobe epilepsy (TLE) reducing animal mortality, decreasing cell loss in hippocampal CA1 pyramidal region and probability of spontaneous recurrent seizures. PAR1 inhibition also improves contextual and cued fear learning and restores the control level of anxiety-related behavior in rats experiencing status epilepticus (SE). The aim of the present study was to determine the effect of PAR1 inhibition on the behavioral excitability of rats after SE. The experimental model of TLE was induced using intraperitoneal injections of lithium and pilocarpine. After that rats were treated with PAR1 inhibitor, SCH79797, for ten consecutive days. A battery of behavioral tests (approach-test, pick-up test, and touch-response test) was used for evaluation of behavioral hyperexcitability. We have found that SE induced different signs of the disturbance of behavior in response to sensory stimuli in pick-up test (average score of the test was 3.1 ± 0.6 in control animals and 5.2 ± 0.1 in animals with SE) and touch-response test (average score was 2.6 ± 0.6 and 5.7 ± 0.4 in rats without and with SE respectively). PAR1 inhibition did not affect the behavioral excitability of experimental rats. There was no significant difference between experimental groups in approach-test. Our results suggest the PAR1-independent development of disturbances of sensorimotor reactions during epileptogenesis in the current experimental model of TLE.

Keywords: protease-activated receptor type 1; SCH79797; lithium-pilocarpine model; status epilepticus; behavioral hyperexcitability.


  1. Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: A population-based analysis. Epilepsia. 2007; 48:2336-44. CrossRef  
  2. Isaev DS, Lushnikova IV, Lunko OO, Zapukhliak O, Maximyuk OP, Romanov AK, Skibo GG, Tian C, Holmes GL, Isaeva EV. Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis. Neurobiol Dis. 2015; 78:68-76. CrossRef PubMed PubMedCentral
  4. Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol. 2010; 160:191-203. CrossRef PubMed PubMedCentral
  6. Bourgognon J-M, Schiavon E, Salah-Uddin H, et al. Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala. Mol Psychiatry. 2013; 18:1136-45. CrossRef PubMed PubMedCentral
  8. Isaeva E, Hernan A, Isaev D, Holmes GL. Thrombin facilitates seizures through activation of persistent sodium current. Ann Neurol. 2012; 72:192-8. CrossRef PubMed PubMedCentral
  10. Lunko OO, Isaev DS, Krishtal OO, Isaeva EV. Thrombin modulates persistent sodium current in CA1 pyramidal neurons of young and adult rat hippocampus. Fiziol Zh. 2015; 61:5-10. CrossRef PubMed
  12. Lee CJ, Mannaioni G, Yuan H, Woo DH, Gingrich MB, Traynelis SF. Astrocytic control of synaptic NMDA receptors. J Physiol. 2007; 581:1057-81. CrossRef PubMed PubMedCentral
  14. Maggio N, Cavaliere C, Papa M, Blatt I, Chapman J, Segal M. Thrombin regulation of synaptic transmission: Implications for seizure onset. Neurobiol Dis. 2013; 50:171-8. CrossRef PubMed
  16. Almonte AG, Qadri LH, Sultan FA, Watson JA, Mount DJ, Rumbaugh G, Sweatt JD. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. J Neurochem. 2013; 124:109-22. CrossRef PubMed PubMedCentral
  18. Almonte AG, Hamill CE, Chhatwal JP, Wingo TS, Barber JA, Lyuboslavsky PN, David Sweatt J, Ressler KJ, White DA, Traynelis SF. Learning and memory deficits in mice lacking protease activated receptor-1. Neurobiol Learn Mem. 2007; 88:295-304. CrossRef PubMed PubMedCentral
  20. Striggow F, Riek M, Breder J, Henrich-Noack P, Reymann KG, Reiser G. The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc Natl Acad Sci. 2000; 97:2264-9. CrossRef PubMed PubMedCentral
  22. Olson EE, Lyuboslavsky P, Traynelis SF, McKeon RJ. PAR-1 Deficiency Protects Against Neuronal Damage and Neurologic Deficits After Unilateral Cerebral Hypoxia/ Ischemia. J Cereb Blood Flow Metab. 2004; 24:964-71. CrossRef PubMed
  24. Yan J, Manaenko A, Chen S, Klebe D, Ma Q, Caner B, Fujii M, Zhou C, Zhang JH. Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage. Stroke. 2013; 44:1410-7. CrossRef PubMed PubMedCentral
  26. Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: Deleterious or protective? J Neurochem. 2003; 84:3-9. CrossRef PubMed
  28. Glien M, Brandt C, Potschka H, Voigt H, Ebert U, Löscher W. Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy. Epilepsy Res. 2001; 46:111-9. CrossRef  
  29. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation: II. Motor Seizure. Electroencephalogr Clin Neurophysiol. 1972; 32:295-9. CrossRef  
  30. Brandt C, Gastens AM, Sun M zhen, Hausknecht M, Löscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology. 2006; 51:789-804. CrossRef PubMed
  32. Brandt C, Glien M, Gastens AM, Fedrowitz M, Bethmann K, Volk HA, Potschka H, Löscher W. Prophylactic treatment with levetiracetam after status epilepticus: Lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats. Neuropharmacol. 2007; 53:207-21. CrossRef PubMed
  34. Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol. 2010; 224:219-33. CrossRef PubMed
  36. Rice AC, Floyd CL, Lyeth BG, Hamm RJ, DeLorenzo RJ. Status epilepticus causes long-term NMDA receptordependent behavioral changes and cognitive deficits. Epilepsia. 1998; 39:1148-57. CrossRef PubMed
  38. Bröer S, Löscher W. Novel combinations of phenotypic biomarkers predict development of epilepsy in the lithium-pilocarpine model of temporal lobe epilepsy in rats. Epilepsy Behav. 2015; 53:98-107. CrossRef PubMed
  40. Bogovyk R, Lunko O, Fedoriuk M, Isaev D, Krishtal O, Holmes GL, Isaeva E. Effects of protease-activated receptor 1 inhibition on anxiety and fear following status epilepticus. Epilepsy Behav. 2017; 67:66-9. CrossRef PubMed
  42. Brandt C, Nozadze M, Heuchert N, Rattka M, Löscher W. Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy. J Neurosci. 2010; 30:8602-12. CrossRef PubMed
  44. Brandt C, Rankovic V, Töllner K, Klee R, Bröer S, Löscher W. Refinement of a model of acquired epilepsy for identification and validation of biomarkers of epileptogenesis in rats. Epilepsy Behav. 2016; 61:120-31. CrossRef PubMed
  46. Huang X, McMahon J, Huang Y. Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy. Neurosci. 2012; 215:90-7. CrossRef PubMed PubMedCentral
  48. Schauwecker PE. Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus. Neurobiol Dis. 2012; 45:297-304. CrossRef PubMed PubMedCentral
  50. Brandt C, Bankstahl M, Töllner K, Klee R, Löscher W. The pilocarpine model of temporal lobe epilepsy: Marked  intrastrain differences in female Sprague-Dawley rats and the effect of estrous cycle. Epilepsy Behav. 2016; 61:141-52. CrossRef PubMed
  52. Lekic T, Klebe D, McBride DW, Manaenko A, Rolland WB, Flores JJ, Altay O, Tang J, Zhang JH. ProteaseActivated Receptor 1 and 4 Signal Inhibition Reduces Preterm Neonatal Hemorrhagic Brain Injury. Stroke. 2015; 46:1710-3. CrossRef PubMed PubMedCentral
  54. Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 2010; 40:193-9. CrossRef PubMed PubMedCentral

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