Biomed Res Int. 2016;2016:2794096.

Myoinositol Attenuates the Cell Loss and Biochemical Changes Induced by Kainic Acid Status Epilepticus.

Tsverava L1, Lordkipanidze T1,2, Lepsveridze E1, Nozadze M1,2, Kikvidze M1& Solomonia R1,2

1 Institute of Chemical Biology, Ilia State University, 3/5 K.Cholokashvili av., 0162 Tbilisi, Georgia

2 I.Beritashvili Centre of Experimental Biomedicine, 14 L.Gotua Str, Tbilisi 0160, Georgia

 

Abstract

Identification of compounds preventing or modifying the biochemical changes that underlie the epileptogenesis process and understanding the mechanism of their action are of great importance. We have previously shown that myoinositol (MI) daily treatment for 28 days prevents certain biochemical changes that are triggered by kainic acid (KA) induced status epilepticus (SE). However in these studies we have not detected any effects of MI on the first day after SE. In the present study we broadened our research and focused on other molecular and morphological changes at the early stages of SE induced by KA and effects of MI treatment on these changes. The increase in the amount of voltage-dependent anionic channel-1 (VDAC-1), cofilin, and caspase-3 activity was observed in the hippocampus of KA treated rats. Administration of MI 4 hours later after KA treatment abolishes these changes, whereas diazepam treatment by the same time schedule has no significant influence. The number of neuronal cells in CA1 and CA3 subfields of hippocampus is decreased after KA induced SE and MI posttreatment significantly attenuates this reduction. No significant changes are observed in the neocortex. Obtained results indicate that MI posttreatment after KA induced SE could successfully target the biochemical processes involved in apoptosis, reduces cell loss, and can be successfully used in the future for translational research.

PMID: 27642592; DOI:10.1155/2016/2794096

 

Supplement:

Epilepsy is a heterogeneous syndrome characterized by recurrent and spontaneous seizures. Currently available antiepileptic drugs suppress seizures but do not prevent or cure epilepsy. The treatment strategies that could interfere with epileptogenesis (process leading to epilepsy) or at least modify and weaken the natural course of the disease will be of great importance for epilepsy treatment.

We have previously shown that myo-inositol (MI) pretreatment significantly decreases the severity of seizures induced either by pentylentetrazolium or kainic acid (KA) [1,2]. In our following series of experiments status epilepticus (SE) was induced by KA and afterward started MI daily treatment. We have found out that MI treatment during 28 days after SE attenuates biochemical changes underlying the process of epileptogenesis, namely KA induce SE determines strong decrease in the amounts of GLUR1 subunit of AMPA-glutamate receptors, calcium-calmodulin dependent protein kinase II and gamma-2 subunit of GABA-A receptors in the hippocampus, that are nearly completely reversed by daily treatment of MI [3.4]. However we were not able to find any specific effects of MI 24hafter KA induced SE. Taking into account that KA induced SE increases mitochondrial dysfunction, and apoptosis in neurons of hippocampus in present study we have decided to focus on this area of biochemical processes and to elucidate further mechanisms of MI action.

KA induced SE 24h later is followed by increase in the amount of voltage dependent anionic channel -VDAC-1, cofilin and caspase-3 activity in the hippocampus of rats. Three times administration of MI during this period (4, 10 and 20 hours later after KA treatment) abolishes these changes. The number of neuronal cells in CA1 and CA3 subfields of hippocampus is decreased after KA induced SE and MI post-treatment significantly attenuates this reduction. The general target of MI action could be normalization of disturbed cellular condition mediated by its osmolyte properties. Another possibility could be that MI treatment acts though GABA-A receptors [5]. To evaluate this possibility we have included a group of animals treated with anti-convulsant and GABA-A receptor agonist Diazepam. Our results have shown that Diazepam treatment does not have any significant effect on studied molecular changes.

In conclusion we have demonstrated that at least some of biochemical changes triggered by KA induced SE could be significantly attenuated by MI post-treatment and this approach can be successfully used in the future for translational research.

 

References:

  1. Solomonia R, Nozadze M, Kuchiashvili N, Bolkvadze T, Kiladze M, Zhvania, M, Kiguradze T, Pkhakadze V (2007) “Effects of myo-Inositol on pentylentetrazol and kainic acid induced convulsions in rats,” Bulletin of Experimental Biology and Medicine, 143, 58-60.
  2. Nozadze M, Mikautadze E, Lepsveridze E, Mikeladze E, Kuchiashvili N, Kiguradze T, Kikvidze M, Solomonia R. (2011) “Anticonvulsant activities of myo-Inositol and scyllo-Inositol on pentylenetetrazol induced seizures,” Seizure:European Journal of Epilepsy, 20, pp. 173-176
  3. Solomonia R, E. Mikautadze E, Nozadze M, Kuchiashvili N, Lepsveridze E, Kiguradze T, (2010) “Myo-Inositol treatment prevents biochemical changes triggered by kainate-induced status epilepticus,” Neuroscience Letters, 468, 277-281.
  4. Solomonia R, Gogichaishvili N, Nozadze M, Lepsveridze E, Dzneladze D, Kiguradze T. (2013) “Myo-inositol treatment and GABA-A receptor subunit changes after kainate-induced status epilepticus,”. Cell. Mol. Neurobiol. 33, 119-127
  5. Solomonia R, Kuchiashvili N, Berulava A, Pkhakadze V, Trapaidze N, Zhvania M, Abesadze I, Kojima H, Dalakishvili N. (2004) “Purification and identification of components of the Aquilegia vulgaris extract fraction exhibiting anti-epileptic activity,” Journal of Biol. Physics and Chemistry, 4 185-192

 

 

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