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Improvement Effects of Apigenin in Temporal Lobe Epilepsy

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Improvement Effects of Apigenin in Temporal Lobe Epilepsy Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir Evaluation of the neuroprotective, anticonvulsant, and cognition- improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway Paria Hashemi 1, Javad Fahanik Babaei 2, Somaye Vazifekhah 1, Farnaz Nikbakht 3* 1 Department of Physiology, School of Medicine and Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran 2 Physiology Research Centre, Iran University of Medical Sciences, Tehran, Iran 3 Cellular and Molecular Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran A R T I C L E I N F O A B S T R A C T Article type: Objective(s): Original article the use of antiepileptic drugs includes their side effects on learning and memory. Herbal medicine Article history: Cognitive deficit is a common problem in epilepsy. A major concern emergent from Received: Aug 3, 2018 Accepted: Jan 22, 2019 iscognition considered in epilepsy. a complementary and alternative therapy in epilepsy. Apigenin is a safe flavone with Materialsantioxidant and properties. Methods: ForHowever, evaluating there the is anticonvulsant little information effect about of apigenin the beneficial in the kainite effect temporal of apigenin epilepsy on Keywords: model, apigenin was orally administered at 50 mg/kg for six days. Reference and working memory were examined via the Morris water maze and Y-maze task spontaneously. Results: P<0.01) and restored ApigeninCognition P AnticonvulsantCytochrome c number ofResults living showedneurons that in the apigenin hilus (P had<0.001). significant Immunohistochemical anticonvulsant activity analysis ( showed that apigenin Neuroprotection <0.01), suggesting an inhibitory role in the intrinsic apoptotic Temporal lobe epilepsy the memory-deficit induced by kainic acidP ( <0.05). Furthermore, apigenin significantly increased the pathway. Conclusion:reduced the Theserelease results of cytochrome suggest that c ( apigenin restores memory impairment via anticonvulsant and neuroprotective activity. ►Please cite this article as: Hashemi P, Fahanik Babaei J, Vazifekhah S, Nikbakht F. Evaluation of the neuroprotective, anticonvulsant, and cognition-improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway. Iran J Basic Med Sci 2019; 22:752-758. doi: 10.22038/ ijbms.2019.33892.8064 Introduction neurodegeneration, almost all available antiepileptic Epilepsy is one of the most common and chronic neurological diseases. It manifests itself by recurring, drugsbeen unsuccessful (AEDs) worsen in controlling memory andimpairment reducing epileptic(9, 10). Recentseizures studies in drug-resistant have shown patients that AEDs but have have also not led only to unprovokedepilepsy, is recognizedseizures that as havethe mostno clear frequent prognosis form (1). of Temporal lobe epilepsy (TLE), Partial a type evidence of partial indicates or focal need to replace these with other alternatives. Recently, that memory impairment is one of the main complaints undesirablescholars have side focused effects (9).on Therefore,medical herbs,there is especiallyan urgent acquired epilepsy in adults (2). of patients with TLE; it is caused by hippocampal flavonoids,many fruits onand neurodegenerative vegetables, with chamomile disorders, and including celery sclerosis (3). Hippocampal sclerosis is characterizedSome studies epilepsy (11). Apigenin, a natural flavone, is abundant in byhave the suggested loss of neurons, that there specifically is a clear ininteraction the CA1/CA3 between and particular interest because of its anxiolytic, sedative, thememory hilus lossareas and of theneurodegeneration hippocampus (4). in the temporal beingneuroprotective, the highest anticonvulsive,sources (12). Apigenin and antidepressant has received prolonged seizures lead to progressive hippocampal cortex,neuronal amygdala, death, whichand hippocampus is accompanied (5, 6). by Apparently, memory propertiescancer properties (13). Apigenin of apigenin can arealso due ameliorate to the induction memory dysfunction linked to Alzheimer’s disease (14). The anti- Mitochondrial dysfunction after prolonged seizure 17). However, in pathological conditions, apigenin acts dysfunctionis the other (7). cause of neuronal cell death. One of the of apoptosis through different apoptotic pathways (15- mitochondrial dysfunction manifestations during suggesting the protective role of apigenin in cognition epilepsy is opening of the mitochondrial permeability asimprovement an anti-apoptotic through agent amelioration (18, 19). There of mitochondria are no data transition pore and release of cytochrome c into the cytosol. Cytochrome c is the key protein that can trigger to investigate the protective role of apigenin in cognition dysfunctionand memory in impairments TLE. Therefore, induced this studyby kainic was aciddesigned with emphasis on the possible involvement of mitochondrial mitochondrial cell death (8). Apart from seizures per se and vast hippocampal *Corresponding author: Farnaz Nikbakht. Cellular and Molecular Research Center, School of Medicine, Iran University of Medical Sciences, Tehra, Iran. Tel: +98-21- 86704546; Email: [email protected] Protective effects of apigenin in temporal lobe epilepsy Hashemi et al. Seizure intensity was measured according to a cell death pathway. Additionally, we examined the Stage 0: immobility; stage 1: rigid posture, eye Materialsanticonvulsant and effect Methods of apigenin in the rat model of TLE. modifiedblinking, Racine’sand /or scale mild values: facial clonus; stage 2: head Animals bobbing and multiple facial clonus; stage 3: myoclonic from the Experimental Studies Centre, Iran University forelimbs with rearing; and stage 5: generalized tonic- of MaleMedical Wistar Sciences, rats (200–250 Tehran, g)Iran. were The obtained animals (n=44) were jerksclonic in convulsions. the forelimbs; stage 4: clonic convulsions in the kept under the following standard conditions: 12 hr Training in the spatial version of the Morris water maze task light/dark50% with free cycle availability (lights on of from food 7:00and waterAM to throughout 7:00 PM), commonly accepted behavioral tests for assessing the environmental temperature 22±2 °C, and humidity 40– spatialMorris learning water and maze memory (MWM) capabilities is one ofof rodents.the most In were compiled according to Guidelines for the Care and the study. All experimental protocols and procedures MWM was a circular black tank the present study, MWM was conducted five days after Useapproved of Laboratory by the Ethics Animals and as Research stipulated Committee by the National of Iran induction of TLE in rats. Institute of Health (NIH). In addition, this study was (100 cm in diameter and 75 cm in height). It was placed in a dim room with visual cues. Theconstantly tank was filledlocated to ExperimentalUniversity of Medical procedure Sciences (Tehran, Iran) in 2016. a1.5 depth cm beneathof 40 cm the with water water surface (21±1 °C).in one A hidden of the blackpool The rats were randomly divided into 4 groups as platformquadrants. (10 The cm task in consisted diameter) of 2was stages: the acquisition follows: control-vehicle group, apigenin-treated sham phase for spatial learning assessment, and the probe group, kainic acid group, and apigenin-treated kainic test and retention retrieval of memory. The acquisition in which the rats were given four trials per session acid group. For induction of TLE in rats, they were phaseper day was with performed the platform during in a constantfive subsequent place. In days,each first anesthetized by the intraperitoneal (IP) injection session and between each trial, an interval of 20 sec was of ketamine (100 mg/kg) and xylazine (20 mg/kg). observed. If the platform was not found within 60 sec, Animalsincision inwere the scalp,then positioned the left lateral and ventriclefixed on wasa stereotaxic targeted the rat was forced into the platform and placed on it for apparatusat the anteroposterior (Stoelting, USA).position, After in aaccordance midline sagittalto the an additional 20 sec. During each trial session, the total platform was recorded using a video camera-based stereotaxic atlas, as follows: 1 mm; lateral; –1.5 mm from time (latency time) and movement to find the hidden bregma, and 3.5 mm ventral from the dura. An amount hours after the acquisition phase, the probe trial session of 1.8 μl of sterile normal saline solution containing 0.5 EthoVisionwas performed System in (Noldus,which the Netherlands). platform was Twenty-four removed μg of kainic acid was microinjected unilaterally into the from the pool and the rat was allowed to swim for 60 leftin lateraldistilled ventricle. water, Aftercontaining 5 min, the 5% needle sodium-carboxyl was removed sec to search for it. the target to minimize the drug withdrawn. Apigenin was dissolved quadrant, time spent in the target quadrant, and the total number of crossingsThe latency into theof first target entry quadrant to were methylcellulose (CMC-Na) and was administered orally recorded. at a dose of 50 mg/kg/day once a day five days before Behavioralsurgery till one testing day afterward (Figure 1). Y-maze spontaneous alternation performance Anticonvulsant activity of apigenin against kainite- This test was conducted 2 days after the MWM task. induced seizures To evaluate spatial working memory, we recorded In kainite-induced convulsion, the intensity of the spontaneous alternation behavior
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