Dipeptidyl peptidase-4 inhibitor ameliorates status epilepticus seizures and cognitive disturbances in a rat model of temporal lobe epilepsy

Document Type: Research Paper


1 Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran


Background and Objective: In temporal lobe epilepsy (TLE), recurrent seizures accompany with cognitive deficit. In some patients, the current medications cannot provide satisfactory control of seizures, therefore new drugs that act through different mechanisms are required. In the present study, the useful effect of dipeptidyl peptidase-4 inhibitor was evaluated in experimental model of temporal lobe epilepsy in male rats.
Materials and Methods: In this study, the effects of administration of dipeptidyl peptidase-4 inhibitor, linagliptin, on seizures score according to Racine’s scores and learning and memory impairment induced by intrahippocampal injection of kainic acid (4 g) using Y-maze and passive avoidance test were studied in rats. Linagliptin thirty minutes before kainic acid injection was administrated intracerebroventricularly.
Results: In this study, the kainic acid-induced recurrent seizures, reduced alternation level in Y-maze test (p<0.001) and lowered step through latency (STL) in the passive avoidance test (p<0.001). Administration of linagliptin to epileptic rats reduced the score of status epilepticus seizures (p<0.001), increased alternation score (p<0.05) and learning capability in the passive avoidance test (p<0.05). The difference between the effect of valproic acid and linagliptin on STL and Racine’s scores was significant (p<0.05-p<0.01).
Conclusion: The obtained data indicate that linagliptin in kainate rats mitigates seizure severity and develops short-term memory.


  1. Goffin K, Nissinen J, Van Laere K, Pitka¨nen A. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat. Experimental Neurology 2007; 205: 501–505.
  2. Robert SF, Boas WE, Blume W, Elger C , Genton P, Lee P and al. Epileptic Seizures and Epilepsy: Definitions Proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy. Epilepsia 2005; 46(4):470-472.
  3. D'Ambrosio R, Eastman CL, Fattore C, Perucca E. Novel Frontiers in Epilepsy Treatments: Preventing Epileptogenesis by Targeting Inflammation. Expert review of Neurotherapeutics 2013; 13(6): 615–625.
  4. Pro B, Dang NH. CD26/dipeptidyl peptidase IV and its role in cancer. Histology&Histopathology 2004; 19: 1345-1351.
  5. Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regulatory Peptides 2006; 137(3):147-55.
  6. Blázquez E ,Velázquez E, Hurtado-Carneiro V, Miguel Ruiz-Albusac J. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and alzheimer’s disease. Frontiers in Endocrinology 2014; 5:161.
  7. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalography and Clinical Neurophysiology 1972; 32: 295–299.
  8. Rasoolijazi H, Joghataie MT, Roghani M, Nobakht M.The beneficial effect of (-)-epigallocatechin-3-gallate in an experimental model of Alzheimer’s disease in rat: A behavioral analysis. Iran Biomedical Journal 2007; 11(4): 237–243.
  9. Roghani M, Baluchnejadmojarad T. Chronic epigallocatechin-gallate improves aortic reactivity of diabetic rats: Underlying mechanisms. Vascular Pharmacology 2009; 51(2–3): 84–89.
  10. Kornelius E, Lin C, Chang H, Li H, Huang W,Yang Y, et al. DPP-4 Inhibitor Linagliptin Attenuates Ab-induced Cytotoxicity through Activation of AMPK in Neuronal Cells. CNS Neuroscience & Therapeutics 2015; 21(7): 549–557.
  11. Darsalia VOlverling ALarsson MMansouri SNathanson D, Nystrom T, et al. Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice. Regulatory Peptides2014; 190191: 25-31.
  12. Puchałowicz K, Tarnowski M, Baranowska-Bosiacka I, Chlubek D, Dziedziejko V. P2X and P2Y Receptors Role in the Pathophysiology of theNervous System. International Journal of Molecular Sciences 2014; 15: 23672-23704.
  13. Wang ZFan YXu JLi LHeng DHan S, et al. Transcriptome Analysis of the Hippocampus in Novel Rat Model of Febrile Seizures. PLOS ONE 2014; 9(4): e95237.
  14. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nature Medicine 2003; 9(9): 1173-9.
  15. Li LYang GLi QTan XLiu HTang Y, et al. Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels. Diabetes, Obesity & Metabolism 2008; 10: 921–930.
  16. Gault VA, HölscherC. GLP-1agonists facilitate hippocampal LTP and re- verse the impairment of LTP induced by beta-amyloid. European Journal of Pharmacology 2008; 587 (1–3): 112–11710.
  17. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes.  International Journal of Clinical Practice  2006; 60(11):1454-70.
  18. Boland CLDegeeter MNuzum DSTzefos M. Evaluating second-line treatment options for type 2 diabetes: Focus on secondary effects of GLP-1 agonists and DPP-4 inhibitors. The Annals of Pharmacotherapy 2013; 47: 490–505.
  19. Jain SSharma B. Neuroprotective effect of selective DPP-4inhibitor in experimental vascular dementia. Physiology & Behavior 2015; 152(Pt A):182-93.