A STUDY OF POSSIBLE PROTECTION BY NEFIRACETAM ON ESLICARBAZEPINE INDUCED MEMORY IMPAIRMENT IN TEMPORAL LOBE EPILEPSYHTML Full Text
A STUDY OF POSSIBLE PROTECTION BY NEFIRACETAM ON ESLICARBAZEPINE INDUCED MEMORY IMPAIRMENT IN TEMPORAL LOBE EPILEPSY
Bipul Ray, K. L. Krishna *, T. Madesh, Vineetha Francis and J. M. Asher
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagar, Mysuru - 570015, Karnataka, India.
ABSTRACT: Memory impairment (MI) is commonly seen in epilepsy and is at times aggravated by antiepileptic therapy. Recent studies reported that co-administration of nootropic agent with an antiepileptic drug (AED) might decrease the MI. This study was designed to evaluate MI activity of Eslicarbazepine (ESL) in temporal lobe epilepsy (TLE) and to assess the protective effect of Nefiracetam (NEF) which is a racetam group nootropic. MI activity was evaluated by radial arm maze (RAM) on lithium-pilocarpine induced TLE in Wistar Albino Rats. Antiepileptic activity of ESL was also assessed in the absence and presence of NEF. ESL treated a group of animals had increased errors in RAM, compared to the control group which indicated the presence of MI. The extent of MI was decreased when given a half dose of ESL. ESL aggravated the MI in epileptic rats which was very much similar to phenytoin, a standard more than the control group. Co-administration of NEF reversed the MI induced by ESL significantly. It was also observed that NEF treated animals have shown activity as that of the normal group of animals, demonstrating that NEF ameliorates MI in TLE. The anticonvulsant activity was found to be synergized due to the co-administration of NEF when compared to control, and ESL alone treated animals. The combination of a reduced dose of ESL and Nefiracetam was very potent compared to ESL and Phenytoin alone. The reduced dose of ESL and NEF showed a very synergistic effect as nootropic without altering the Anti-epileptic activity.
Memory, Eslicarbazepine, Temporal lobe epilepsy, Lithium-pilocarpine, Nefiracetam, Radial Arm Maze
INTRODUCTION: Epilepsy is a neurological disorder where the recurrent seizure occurs due to the abnormal electrical firing 1, 2. These seizures occur as episodes which can vary from brief and almost undetectable to a long period of vigorous shaking. The main cause of epilepsy is not cleared although some may develop epilepsy due to brain injury, stroke, tumor, drugs, genetic mutations, etc. Memory impairment is one of the major problems associated with epilepsy. Moreover, temporal lobe deals with memory storage and encoding.
The abnormal functions of the neurotransmitter of the brain lead to the stress, tiredness in the brain which causes a lapse in memory. Moreover, antiepileptic therapy induces memory impairment especially in the case of TLE 3, 4. When AEDs are administered like all the other drugs, AEDs do have adverse effects. At high dose sedation, unsteadiness, slurring, of speech has been observed. Other side effects include nausea, rash, dysplasia, memory impairment. The side effects occur at the starting of treatment and may become less troublesome in most of the cases, but there is offset in the improvement of patient’s cognition.
MATERIALS AND METHODS:
Animals: Wistar rats of either sex (200-250 g) procured from Biogen Laboratory Animal Facility, was used for the study which was carried out during the year 2016-17.
The animals were housed in polypropylene cages at 23-27 °C with a natural light-dark cycle. The rats were fed on a standard pellet diet and water ad libitum.
The animals were allowed to acclimatize to laboratory conditions for a week before the start of the experiment. Groups of 8 rats were used in all sets of experiments except the normal group (6 rats). All the experiments were by the approval number 201/2016 of Institutional Animal Ethics Committee (IAEC) of JSS College of Pharmacy, Mysuru.
Drugs Procurement: Eslicarbazepine (ESL) and Diazepam injections were procured from JSS Hospital, Mysuru, and Pilocarpine, Lithium chloride, Nefiracetam were procured from Sigma Aldrich.
Methods: In-vivo Activities:
Lithium-Pilocarpine Model: 5, 6 In this model, the cholinomimetic convulsing pilocarpine is used to induce a status epilepticus, which is followed by hippocampal damage and development of spontaneous recurrent seizure. Pilocarpine (30mg/ kg i.p.) was administered in combination with lithium chloride (3 mmol s.c.), which reduces the Pilocarpine dose and mortality. Temporal lobe Epilepsy (TLE) was induced by administration of Pilocarpine 30 mg/kg intra-peritoneal on every 7th Day of treatment and Lithium chloride was given 24 h before pilocarpine administration to minimize the mortality rate. The memory impairment activity was assessed on 8th, 15th, 22nd and 29th day by radial arm maze and the Anti-epileptic activity was assessed on every 7th day for the entire treatment period.
TABLE 1: GROUPING, TREATMENT, AND EVALUATION
|Group||No. of Animals||Treatment||Evaluation|
|Normal||6||Vehicle (0.5% Na-CMC p.o.) was administered for 29 days||Antiepileptic activity on every 7th day followed by memory impairment on every 8th day|
|Control||8||Vehicle (0.5% Na CMC) p.o. daily as suspension in vehicle for 29 days + Pilocarpine on every 7th day||--do--|
|Phenytoin||8||Phenytoin (25mg/kg) p.o. daily as a suspension in the vehicle for 29 days + Pilocarpine on every 7th day||--do--|
|ESL ND||8||ESL (40mg/kg) p.o. daily as suspension in vehicle for 29 days + Pilocarpine on every 7th day||--do--|
|ESL RD||8||ESL (20mg/kg p.o.) daily as a suspension in the vehicle for 29 days. + Pilocarpine on every 7th day||--do--|
|ESL ND + NEF||8||ESL (40 mg/kg p.o.) and NEF administration for 29 days + Pilocarpine on every 7th day||--do--|
|ESL RD + NEF||8||ESL 20 mg/kg p.o. and NEF administration for 29 days + Pilocarpine on every 7th day||--do--|
|NEF||8||10 mg/kg p.o. administration for 29 days + Pilocarpine on every 7th day||--do--|
ESL- Eslicarbazepine, NEF- Nefiracetam, ND-Normal Dose, RD-Reduced dose
TABLE 2: TREATMENT SCHEDULE AND EVALUATION
|Day 1-5||Animals were trained for RAM test|
|Day 6-34||Animals were treated with regular treatment as shown in Table 1. TLE will be induced by Pilocarpine; Memory impairment activity was measured on every 8th day and antiepileptic activity on every 7th Day.|
Racine Scale to Measure Temporal Lobe Epilepsy: 7-9
- No response
- Myoclonic jerks of the head and head bobbing.
- Bilateral activity of the whole body.
- Rearing of limbs.
- Generalized tonic-clonic activity and loss of posture.
The control group was given Diazepam 10 mg/kg i.p. to stop the TLE at stage 4 of the Racine scale to save the life of the animal as they were not treated by any drug.
Radial Arm Maze: 10, 11 8-Arm radial maze. For rats, the central platform has to be ≥45 cm in diameter to accommodate the animal and allow it to turn easily between arms. A wall, 25 cm high, surrounds the central platform. The arms are 87 cm long and 10 cm wide, radiating from the central platform at equal angles. Each arm has a 5-mm-deep hole 1 cm from the end, which is used as a food cup, and each arm is separated from the center. A LED light was used to create aversion. The first entry to any arm is counted as exploration, and the repeated entry to the baited arm is working, and non-baited arm is Reference error.
RESULTS AND DISCUSSION:
MEAN ± SEM, n = 8, p≤0.05, a-significant when compared to Normal, b-significant when compared to control, c-significant when compared to phenytoin (PHT), d-significant when compared to Eslicarbazepine (ESL)
FIG. 3: ANTI-EPILEPTIC ACTIVITY
MEAN ± SEM, n = 8, p≤0.05, a-significant when compared to Control, b-significant when compared to phenytoin(PHT), c-significant when compared to Eslicarbazepine (ESL)
DISCUSSION: Working memory & Reference memory was assessed in radial arm maze as per Table 1, the ESL induced groups showed more memory impairment than the control group, and the ESL reduced dose group was seen to have less memory impairment, but it has less anti-epileptic activity than ESL normal dose. The combination of ESL & Nefiracetam which reduces the memory impairment significantly than ESL but not as compared to ESL reduce dose & NEF combination.
ESL Reduced dose & NEF combination was seen to have a synergistic effect of reducing memory impairment without altering its anti-epileptic activity.
CONCLUSION: In major drawback of anti-epileptic treatment is memory impairment especially in temporal lobe epilepsy because temporal lobe is the major part which deals with the memory encoding and storage. The study aimed to treat epilepsy and reduce the memory impairment induced by ESL. The memory impairment was seen more in ESL treated group compared to control as AEDs aggravates more memory impairment. The ESL half doses also reduce memory impairment but not as compared to the control group. The combination of Nefiracetam, which is a nootropic with ESL reduces memory impairment but not as compared ESL reduced dose & Nefiracetam combination.
The combination of ESL reduced the dose and NEF was seen to have a synergistic effect of reducing the memory impairment without altering the anti-epileptic effect in lithium-pilocarpine induced TLE in rats model.
ACKNOWLEDGEMENT: The authors sincerely thank Principal, JSS College of Pharmacy, Mysuru, for his support and encouragement. Our gratitude goes to JSS Academy of Higher Education & Research, Mysuru, for providing all the necessary facilities.
CONFLICT OF INTEREST: The authors declared no conflict of interest.
- Martinez-Chavez SM, Rivero-Angeles ME, Garay-Jimenez LI and Ruiz-Ledesma EF: Cognitive radio system for interference reduction in BANETs focused on epilepsy diagnosis. Computer Networks 2018; 134: 1-22.
- Zhu Q, Naegele JR and Chung S: Cortical GABAergic Interneuron/Progenitor transplantation as a novel therapy for intractable epilepsy. Frontiers in Cellular Neuroscience 2018; 12: 167.
- Park CH, Choi YS, Jung AR, Chung HK, Kim HJ and Yoo JH: Seizure Control and Memory Impairment Are Related to Disrupted Brain Functional Integration in Temporal Lobe Epilepsy. The Journal of Neuropsychiatry and Clinical Neurosciences 2017; 29(4): 343-50.
- Zhao F, Kang H, You Li, Rastogi P, Venkatesh D and Chandra M: Neuropsychological deficits in temporal lobe epilepsy: A comprehensive review. Annals of Indian Academy of Neurology 2014; 17(4): 374-82.
- Faure J-B, Akimana G, Carneiro JEM, Cosquer B, Ferrandon A and Geiger K: A comprehensive behavioral evaluation in the lithium-pilocarpine model in rats: effects of carisbamate administration during status epilepticus. Epilepsia 2013; 54(7): 1203-13.
- Ran X, Xiang J, Song PP, Jiang L, Liu BK and Hu Y: Effects of gap junction’s blockers on fast ripples and connexin in rat hippocampi after status epilepticus. Epilepsy Research 2018; 146: 28-35.
- Phelan KD, Shwe UT, Williams DK, Greenfield LJ and Zheng F: Pilocarpine-induced Status Epilepticus in Mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale. Epilepsy Research 2015; 117: 90-6.
- Huang C, Chi X, Li R, Hu X, Xu H and Li J.: Inhibition of P2X7 Receptor Ameliorates Nuclear Factor-Kappa B mediated neuroinflammation induced by status epilepticus in rat hippocampus. Journal of Molecular Neuroscience 2017; 63(2): 173-84.
- Haritov E: Synergic effects of doxycycline and celecoxib in a pilocarpine model of experimental epilepsy in rats. Comptes rendus de l Academie bulgare des sciences 2016; 69(2): 203-10.
- Aher YD, Subramaniyan S, Shanmugasundaram B, Sase A, Saroja SR and Holy M: A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System. Frontiers in Behavioral Neuroscience 2010; 10: 20.
- Penley SC, Gaudet CM and Threlkeld SW: Use of an Eight-arm Radial Water Maze to Assess Working and Reference Memory Following Neonatal Brain Injury. Journal of Visualized Experiments 2013; 82: 50940.
How to cite this article:
Ray B, Krishna KL, Madesh T, Francis V and Asher JM: A study of possible protection by nefiracetam on eslicarbazepine induced memory impairment in temporal lobe epilepsy. Int J Pharm Sci & Res 2019; 10(5): 2236-39. doi: 10.13040/IJPSR.0975-8232.10(5).2236-39.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
B. Ray, K. L. Krishna *, T. Madesh, V. Francis and J. M. Asher
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, India.
17 August 2018
02 November 2018
09 November 2018
01 May 2019