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CC BY-NC-ND 4.0 · International Journal of Epilepsy 2016; 03(02): 068-074
DOI: 10.1016/j.ijep.2016.10.001
Research paper
Thieme Medical and Scientific Publishers Private Ltd.

To evaluate the anti-kindling effect of allopregnanolone alone and its interaction with sodium valporate in pentylenetetrazole induced kindling model

Puja Kumari
a   Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
,
Lekha Saha
a   Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
,
Sheekha Vijayanti
a   Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
,
Alka Bhatia
b   Department of Experimental Medicine & Biotechnology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
,
Dibyajyoti Banerjee
b   Department of Experimental Medicine & Biotechnology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
,
Amitava Chakrabarti
a   Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
› Author Affiliations
Further Information

Publication History

Received: 18 January 2016

Accepted: 04 October 2016

Publication Date:
06 May 2018 (online)

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Abstract

Background and purpose Studies in the animal models of epilepsy have suggested the anti-seizure effects of neuroactive steroids and its derivatives in kainic acid and pilocarpine induced limbic seizures and status epilepticus in mice, but no such studies have been reported in the published literature on the role of allopregnanolone in chemical kindling model and its interaction with sodium valproate. The purpose of this study was to evaluate the interaction between sodium valproate and allopregnanolone in pentylenetetrazole induced kindling model in rats.

Methods In a PTZ kindled Wistar rat model, sodium valproate and allopregnanolone were administered 30 min before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The parameters measured were latency to develop kindling and incidence of kindling, histopathological study of hippocampus, hippocampal anti-oxidant parameters and hippocampal DNA fragmentation studies.

Results In this study, the combination of low dose of allopregnanolone with low dose of sodium valproate showed a similar beneficial effect to that of a higher dose of sodium valproate in significantly reducing the number of kindled animals (0/8) as compare to PTZ control group (5/8) as well as the seizure scores and the histopathological scores. The combination significantly reduces oxidative stress by significantly decreasing the MDA levels, and increasing the SOD levels and GSH levels in the hippocampus of rats as compared to PTZ control group. So all these data suggest the antiepileptic effect of the combination and confers the synergistic interaction between the allopregnanolone and sodium valproate.

Conclusions It can be concluded that by choosing this combination the dose of sodium valproate can be reduced and thereby reduces the incidence of adverse effects caused by sodium valproate and hence proves to be a useful combination clinically. This study has lead the basis to further investigate the various combinations of neurosteroids and valproate in the process of epileptogenesis with better side effect profile.

Keywords

Allopregnanolone - PTZ kindling - Sodium valproate - Combination - Side effects
 

  • References

  • 1 Morimoto K, Fasnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol 73 (01) 2004; 1-60
    CrossrefPubMedGoogle Scholar
  • 2 Engel Jr J. Introduction to temporal lobe epilepsy. Epilepsy Res 26 (01) 1996; 141-150
    CrossrefPubMedGoogle Scholar
  • 3 Lowenstein DH. Seizures and epilepsy. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. 18th edition. 2008. McGraw-Hill; New York: 2498-2512 [Chapter-369. Section 2: Diseases of the Central Nervous System]
    Google Scholar
  • 4 Wang W, Wu Y, Zhang G. et al. Activation of Nrf2-ARE signal pathway protects the brain from damage induced by epileptic seizure. Brain Res 1544 2014; 54-61
    CrossrefPubMedGoogle Scholar
  • 5 Liou AKF, Clark RS, Henshall DC, Yin XM, Chen J. To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress activated signaling pathways and apoptotic pathways. Prog Neurobiol 69 (02) 2003; 103-142
    CrossrefPubMedGoogle Scholar
  • 6 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 342 2000; 314-319
    CrossrefPubMedGoogle Scholar
  • 7 Loscher W, Parnham MJ, Bruinvels J. Valproate – Milestones in Drug Therapy. 1999. Birkhauser; 8 [Table 1]
    Google Scholar
  • 8 McNamara JO. Pharmacotherapy of the epilepsies. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th edition. 2011. McGraw-Hill; New York: 583-607
    Google Scholar
  • 9 Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16 (10) 2002; 695-714
    CrossrefPubMedGoogle Scholar
  • 10 Kokate TG, Cohen AL, Karp E, Rogawski MA. Neuroactive steroids protect against pilocarpine and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology 35 1996; 1049-1056
    CrossrefPubMedGoogle Scholar
  • 11 Lonsdale D, Burnham WM. The anticulvulsant effects of allopregnanolone against amygdala-kindled seizures in female rats. Neurosci Lett 411 (02) 2007; 147-151
    CrossrefPubMedGoogle Scholar
  • 12 Biagini G, Longo D, Baldelli E. et al. Neurosteroids and epileptogenesis in the pilocarpine model: evidence for a relationship between P450scc induction and length of the latent period. Epilepsia 50 (01) 2009; 53-58
    PubMedGoogle Scholar
  • 13 Reddy DS, Mohan A. Development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors. J Neurosci 31 2011; 650-658
    CrossrefPubMedGoogle Scholar
  • 14 Patil CY, Jadhav SA, Doifode SM, Baig MS. Neuroactive steroids and their role in epilepsy. Int J Basic Clin Pharmacol 1 (03) 2012; 150-159
    CrossrefPubMedGoogle Scholar
  • 15 Racine RJ. Modification of seizure activity by electrical stimulation. I. After-discharge threshold. Electroencephalogr Clin Neurophysiol 32 (03) 1972; 269-279
    CrossrefPubMedGoogle Scholar
  • 16 Myung RJ, Petko M, Judkins AR. et al. Regional low-flow perfusion improves neurologic outcome compared with deep hypothermic circulatory arrest in neonatal piglets. J Thorac Cardiovasc Surg 127 (04) 2004; 1051-1057
    CrossrefPubMedGoogle Scholar
  • 17 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95 1979; 351-358
    CrossrefPubMedGoogle Scholar
  • 18 Kono Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186 (01) 1978; 189-195
    CrossrefPubMedGoogle Scholar
  • 19 Paglia DE, Velentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 7 (01) 1967; 158-169
    PubMedGoogle Scholar
  • 20 Sambrook J, Russell DW. Isolation of high-molecular-weight DNA from mammalian cells using proteinase K and phenol. CSH Protoc. 2006. 1 2006
    PubMedGoogle Scholar
  • 21 Hayashi M. Oxidative stress in developmental brain disorders. Neuropathology 29 2009; 1-8
    CrossrefPubMedGoogle Scholar
  • 22 Kumar A, Goyal R, Prakash A. Possible GABAergic mechanism in the protective effect of allopregnenolone against immobilization stress. Eur J Pharmacol 602 2009; 343-347
    CrossrefPubMedGoogle Scholar
  • 23 Kabuto H, Yokoi I, Ogawa N. Melatonin inhibits iron-induced epileptic discharges in rats by suppressing peroxidation. Epilepsia 39 1998; 237-243
    CrossrefPubMedGoogle Scholar
  • 24 Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim 303 2001; 19-24
    CrossrefPubMedGoogle Scholar
  • 25 Pollard H, Charriaut-Marlangue C, Cantagrel S. et al. Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 63 (01) 1994; 7-18
    CrossrefPubMedGoogle Scholar
  • 26 Weiss S, Cataltepe O, Cole AJ. Anatomical studies of DNA fragmentation in rat brain after systemic kainate administration. Neuroscience 74 1996; 541-551
    CrossrefPubMedGoogle Scholar
  • 27 Loscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16 (10) 2002; 669-694
    CrossrefPubMedGoogle Scholar
  • 28 Reddy DS, Rogawski MA. Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 6 2009; 392-401
    CrossrefPubMedGoogle Scholar
  • 29 Reddy DS, Rogawski MA. Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther 295 2000; 1241-1248
    PubMedGoogle Scholar