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In This Article
   Abstract
   Introduction
   Materials and Me...
   Results
   Discussion
   Acknowledgment
   References
   Article Figures

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RESEARCH ARTICLE
Year : 2009  |  Volume : 41  |  Issue : 1  |  Page : 15-18
 

Reversal of pentylenetetrazole-induced seizure activity in mice by nickel chloride


Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India

Date of Submission07-May-2008
Date of Decision10-Jul-2008
Date of Acceptance20-Jan-2009

Correspondence Address:
Nirmal Singh
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.48885

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 ╗ Abstract 

Objective: The present study was designed to investigate the anticonvulsant potential of nickel which is shown to selectively block t-type calcium channels by using nickel choride on pentylenetetrazole (80 mg/kg) induced seizure activity model in mice.
Materials and Methods: Seizures were assessed in terms of onset of Straub's tail phenomenon and onset of jerky movements of the whole body, convulsions, and death. Sodium valproate served as a standard control in the present study.
Results: Nickel chloride (5 mg/kg i.p. and 10 mg/kg i.p.) attenuated pentylenetetrazole-induced seizure activity in mice, as reflected by a significant increase in the onset time of Straub's tail phenomenon and onset of jerky movements of the whole body, convulsions, and death. High dose of nickel chloride showed more pronounced anticonvulsant action than sodium valproate.
Conclusions: The anticonvulsant action of nickel chloride was noticeable in this study. However, further studies are required to elucidate its full anticonvulsant potential.


Keywords: Nickel, pentylenetetrazole, seizure


How to cite this article:
Rehni AK, Singh N. Reversal of pentylenetetrazole-induced seizure activity in mice by nickel chloride. Indian J Pharmacol 2009;41:15-8

How to cite this URL:
Rehni AK, Singh N. Reversal of pentylenetetrazole-induced seizure activity in mice by nickel chloride. Indian J Pharmacol [serial online] 2009 [cited 2020 Nov 27];41:15-8. Available from: https://www.ijp-online.com/text.asp?2009/41/1/15/48885



 ╗ Introduction Top


Molecular cloning studies have revealed that heterogeneity of t-type Ca 2+ currents in native tissues arises from the three isoforms of Cav3 channels: Cav3.1, Cav3.2, and Cav3.3. [1] From pharmacological analysis of the recombinant t-type channels, low concentrations (<50 ÁM) of nickel were found to selectively block the Cav3.2 over the other isoforms. [1] Nickel has been used to selectively block t-type currents in a number of cell types, such as sinoatrial nodal cells [1],[2] and sensory neurons. [3] However, t-type currents in various neuronal cells require much higher doses of nickel to be blocked. [3],[4] Pharmacological studies have shown that low-voltage-activated t-type Ca 2+ channels are involved in the genesis of absence seizures. [5],[6] Drugs that act by inhibiting neuronal t-type calcium currents like sodium valproate have potential activity against absence seizure. [7],[8] Therefore, the present study was designed to evaluate the anticonvulsant potential of nickel, by using nickel chloride on pentylenetetrazole-induced seizure activity in mice.


 ╗ Materials and Methods Top


Male inbred BALB/C mice - each weighing 25 ▒ 2 g, maintained on standard laboratory diet (Kisan Feeds Ltd., Mumbai, India), and having free access to tap water - were employed in the present study. They were housed in the departmental animal house and were exposed to 12-hour light-dark cycle. The protocol of study was approved by animal ethics committee of the department and the experiments were carried out as per the guidelines of committee for the purpose of control and supervision of experiments on animals (CPCSEA), Ministry of Environment and Forest Government of India.

Induction of seizures

Seizure activity was induced in wakeful mouse using an intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). Time of appearance of Straub's tail andonset of jerky movements of the whole body, and convulsions were recorded as a measure of the severity of experimental epileptic activity elicited by the administration of the drug. [9] Mortality percentage of animals post pentylenetetrazole administration in various treatment groups was recorded and the data were employed to evaluate ED 50 value of nickel chloride as well as sodium valproate.

Experimental protocol

In the present study, five groups were employed and each group comprised 10 animals.

  • Group-I (pentylenetetrazole-treated control group): Mice were administered pentylenetetrazole (80 mg/kg, i.p.).
  • Group-II (vehicle + pentylenetetrazole-treated control group): Mice were administered vehicle (10 ml/kg, i.p.) 30 min prior to the injection of pentylenetetrazole (80 mg/kg, i.p.).
  • Group-III (sodium valproate + pentylenetetrazole-treated standard control group): Animals were administered sodium valproate (150 mg/kg, i.p.) 30 min prior to the injection of pentylenetetrazole (80 mg/kg, i.p.).
  • Group-IV (low-dose nickel + pentylenetetrazole treatment group): Mice were administered nickel chloride (5 mg/kg, i.p.) 30 min prior to the injection of pentylenetetrazole (80 mg/kg, i.p.).
  • Group-V (High-dose nickel + pentylenetetrazole treatment group): Animals were administered nickel chloride (10 mg/kg, i.p.) 30 min prior to the injection of pentylenetetrazole (80 mg/kg, i.p.)


Drugs and chemicals

Pentylenetetrazole (Sigma, St. Louis, USA), sodium valproate (Sun Pharma, Mumbai, India), and nickel chloride (Central Drugs House (P) Ltd., New Delhi, India) were dissolved in normal saline. All drug solutions were freshly prepared before use.

Statistical analysis

Data obtained from the study were statistically analyzed using one-way ANOVA followed by Tukey's multiple range test as post-hoc analysis. Statistical analysis for the results of mortality was done using chi-square test. A value of P < 0.05 was considered to be statistically significant.


 ╗ Results Top


The ED 50 values, calculated based on the percentage mortality of animals post pentylenetetrazole administration in various treatment groups, were 2.28 mg/kg and 53 mg/kg for nickel chloride and sodium valproate, respectively.

Effect of pentylenetetrazole, sodium valproate, and nickel chloride on the onset time Straub's tail phenomenon

Although vehicle did not have any effect, prior administration of sodium valproate (150 mg/kg, i.p.) significantly ( P < 0.05) attenuated pentylenetetrazole-induced seizure activity in mice in terms of onset time of Straub's tail phenomenon. Prior administration of nickel chloride (5 mg/kg i.p. and 10 mg/kg i.p.) also significantly ( P < 0.05 and P < 0.01) attenuated pentylenetetrazole-induced seizure activity in mice measured in terms of onset time of Straub's tail phenomenon. However, the extent of delay in the onset time of Straub's tail phenomenon induced by the high-dose nickel chloride (group V) was found to be significantly more marked ( P < 0.01) than by sodium valproate ( P < 0.05) [Figure 1].

Effect of pentylenetetrazole, sodium valproate, and nickel chloride on onset time of jerky movements of the whole body

Although vehicle did not have any effect, prior administration of sodium valproate (150 mg/kg, i.p.) significantly prevented pentylenetetrazole-induced seizure activity in mice in terms of onset time of jerky movements of the whole body. Prior administration of nickel chloride (5 mg/kg i.p. and 10 mg/kg i.p.) also significantly ( P < 0.05 and P < 0.01) attenuated pentylenetetrazole-induced seizure activity in mice measured in terms of onset time of jerky movements of the whole body. However, the extent of delay in the onset time of jerky movements of the whole body induced by the high-dose nickel chloride (group V) was found to be significantly more noticeable ( P < 0.01) than by sodium valproate ( P < 0.05) [Figure 2].

Effect of pentylenetetrazole, sodium valproate, and nickel chloride on onset time of convulsions

Although vehicle did not have any effect, prior administration of sodium valproate (150 mg/kg, i.p.) significantly decreased pentylenetetrazole-induced seizure activity in mice in terms of onset time of convulsions. Prior administration of nickel chloride (5 mg/kg i.p. and 10 mg/kg i.p.) also significantly attenuated pentylenetetrazole-induced seizure activity in mice measured in terms of onset time of convulsions. Moreover, the extent of delay in the onset time of convulsions induced by the high-dose nickel chloride ( P < 0.01) treatment group was found to be significantly more pronounced than by sodium valproate ( P < 0.05) [Figure 3].

Effect of pentylenetetrazole, sodium valproate, and nickel chloride on percentage mortality in mice

Administration of pentylenetetrazole induced a significant increase ( P < 0.05) in percentage mortality of mice. Although vehicle did not have any effect, prior administration of sodium valproate (150 mg/kg, i.p.) as well as nickel chloride (5 mg/kg i.p. and 10 mg/kg i.p.) significantly ( P < 0.05) reversed the mortality rate [Figure 4].


 ╗ Discussion Top


The administration of pentylenetetrazole in the present study induced Straub's tail phenomenon, followed by jerky movements of the whole body, and convulsions in pentylenetetrazole-treated control group animals along with an increase in the percentage mortality of mice. Pentylenetetrazole is a chemoconvulsant, which induces seizures by the inhibition of GABAA receptors and is widely accepted experimental model for absence seizure. [7],[8] These observations are in line with the previous findings. [9] Administration of sodium valproate markedly attenuated pentylenetetrazole-induced seizure activity in mice observed in terms of onset time of Straub's tail, jerky movements of the whole body, as well as convulsions . In addition, there was a significant decrease in percentage mortality of animals. Sodium valproate has been shown to be an effective agent in ameliorating the symptoms of generalized absence epilepsy via blockade of voltage dependent t-type calcium channels. [10-11] Thus, our results are in consonance with previous reports and sodium valproate served as a standard control in the present study.

Nickel chloride inhibited in a significant manner, pentylenetetrazole-induced seizures as assessed in terms of time of appearance of Straub's tail and onset of jerky movements of whole body and convulsions. Moreover, there was a significant reduction in percentage mortality of mice. Molecular cloning studies have revealed that heterogeneity of t-type Ca 2+ currents in native tissues arises from the three isoforms of Cav3 channels: Cav3.1, Cav3.2, and Cav3.3. [1] From pharmacological analysis of the recombinant t-type channels, low concentrations (<50 ÁM) of nickel were found to selectively block the Cav3.2 over the other isoforms. [1],[2],[3],[4] The Cav3.2 isoform of t-type calcium channels is widely distributed in the CNS and have been shown to be involved in mediating the effect of nickel. [12] Therefore, it may be suggested that nickel-induced blockade of T-type calcium channels may be involved in the reduction of seizures elicited by pentylenetetrazole. However, what accounted for more pronounced effect of nickel than sodium valproate remains to be elucidated. Nevertheless, further studies are required to unearth full potential of nickel chloride as an anticonvulsant.


 ╗ Acknowledgment Top


The authors are grateful to Dr. N. K. Talwar, Punjab Veterinary Vaccine Institute, Punjab Agriculture University, Ludhiana for animal facilities.

 
 ╗ References Top

1.Kang HW, Park JY, Jeong SW, Kim JA, Moon HJ, Reyes EP, et al. A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels. J Biol Chem 2006;281:4823-30.  Back to cited text no. 1    
2.Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol (Lond) 1988;395:233-53.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Todorovic SM, Lingle CJ. Pharmacological properties of T-type Ca 21 current in adult rat sensory neurons: Effects of anticonvul-sant and anesthetic agents. J Neurophysiol 1998;79:240-52.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Huguenard JR. Low threshold calcium currents in central nervous system neurons. Annu Rev Physiol 1996;58:329-48.   Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.van Luijtelaar G, Wiaderna D, Elants C, Scheenen W. Opposite effects of T- and L-type Ca 2+ channels blockers in generalized absence epilepsy. Eur J Pharmacol 2000;406:381-9.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Porcello DM, Smith SD, Huguenard JR. Actions of U-92032, a T-type Ca 2+ channel antagonist, support a functional linkage between I(T) and slow intrathalamic rhythms. J Neurophysiol 2003;89:177-85.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Loscher W, Honack D, Fassbender CP, Nolting B. The role of technical,biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs, III: Pentylenetetrazole seizure models. Epilepsy Res 1991;8:171-89.  Back to cited text no. 7    
8.Starzl TE, Niemer WT, Dell M, Forgrave PR. Cortical and subcortical electrical activity in experimental sezures induced by metrazole. J Neuropath Exp Neurol 1953;12:262-76.  Back to cited text no. 8  [PUBMED]  
9.Bastian JW, Krause WE, Ridlon SA, Ercoli N. CNS drug specificity as detrmined by the mouse intravenous pentylenetetrazole technique. J Pharmacol Exp Ther 1959;127:75-80.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Kelly KM, Gross RA, Macdonald RL. Valproic acid selectivity reduces the lowthreshold (T) calcium current in rat nodose neurons. Neurosci Lett 1990;116:233-8.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Mclean MJ, Mcdonald RL. Sodium valporate, but not ethosuximide, produces use- and voltage- dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986;237:1001-1.  Back to cited text no. 11    
12.Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss D. Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 1999;19:1895-911.  Back to cited text no. 12    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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