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Histidine Enhances Carbamazepine Action Against Seizures and Improves Spatial Memory Deficits Induced by Chronic Transauricular Kindling in Rats1

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Histidine Enhances Carbamazepine Action Against Seizures and Improves Spatial Memory Deficits Induced by Chronic Transauricular Kindling in Rats1 Acta Pharmacologica Sinica 2005 Nov; 26 (11): 1297–1302 Full-length article Histidine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in rats1 Qing LI2,3, Chun-lei JIN2, Li-sha XU2, Zheng-bin ZHU-GE 2, Li-xia YANG2, Lu-ying LIU2, Zhong CHEN2,4 2Department of Pharmacology, Zhejiang University, Hangzhou 310031, China; 3Department of Physiology, Zhejiang Medical College, Hangzhou 310053, China Key words Abstract histidine; carbamazepine; memory disorders; Aim: To investigate whether histidine can enhance the anticonvulsant efficacy of transauricular kindled seizures; epilepsy carbamazepine (CBZ) and simultaneously improve the spatial memory impairment 1 Project supported by the National Natural induced by transauricular kindled seizures in Sprague-Dawley rats. Methods: Science Foundation of China (No 30371638, Chronic transauricular kindling was induced by repeated application of initially 30472013), Natural Science Foundation of subconvulsive electrical stimulation through ear-clip electrodes once every 24 h Zhejiang Province (No R303779), Scientific Research Foundations of Zhejiang Province until the occurrence of 3 consecutive clonic-tonic seizures. An 8-arm radial maze (No 2004C34002) and the Scientific (4 arms baited) was used to measure spatial memory, and histamine and γ-amino- Foundation of the Department of Education butyric acid levels were measured by high performance liquid chromatography of Zhejiang Province (No 20040284). 4 Correspondence to Prof Zhong CHEN. (HPLC). Results: Chronic transauricular kindling produced a significant impair- Phn/Fax 86-571-8721-7446. ment of spatial memory and a marked decrease in histamine content in the hypotha- E-mail [email protected] lamus, the brainstem, and the hippocampus. Injection of histidine (1000 mg/kg or 1500 mg/kg, ip) significantly inhibited transauricular kindled seizures. Injection of Received 2005-07-05 Accepted 2005-08-22 histidine at lower doses (200 mg/kg or 500 mg/kg, ip) had no appreciable anticon- vulsant effect when administered alone, whereas it significantly potentiated the doi: 10.1111/j.1745-7254.2005.00220 protective effects of CBZ against kindled seizures. CBZ had no ameliorative effect on memory deficit, but, in contrast, histidine (200 mg/kg or 500 mg/kg, ip) alone or co-administered with CBZ significantly ameliorated the memory deficits induced by the seizures. Conclusion: Chronic transauricular kindling is a very useful animal model for evaluating memory deficits associated with epilepsy, and histi- dine has both a potentiate effect on the anticonvulsant efficacy of CBZ and an ameliorative effect on the spatial memory deficits induced in this model. Histidine at a specific dosage range might serve as a beneficial adjuvant for the clinical treatment of epilepsy, especially when accompanied by impaired spatial memory. press seizures and ameliorate the concomitant cognitive Introduction impairment. Epilepsy is frequently accompanied by impairments in Brain histamine levels might play an important role in the various cognitive functions. More than 45% of epileptics regulation of seizure susceptibility. Injection of histidine ip, have psychological or social problems with behavioral mani- a precursor of histamine, and metoprine, a histamine festations and are completely or partly disabled[1]. Although N-methyltransferase inhibitor, or icv injection of histamine, the causes of cognitive impairment in patients with epilepsy inhibited seizures induced by pentylenetetrazol, maximal elec- have not yet been completely elucidated, 3 factors are troshock (MES) or amygdaloid kindling in mice or rats[3–6], proposed: the underlying etiology of the epilepsy, the ef- whereas α-fluoromethylhistidine, a selective and irrevers- fects of seizures themselves, and the side-effects of ible histidine decarboxylase inhibitor, increases the duration antiepileptic drugs (AEDs) at therapeutic doses[2]. There is of clonic convulsions induced by MES in mice[3] and causes a need for drugs or adjuvants that can simultaneously sup- severe seizure development in pentylenetetrazol-induced ©2005 CPS and SIMM 1297 Li Q et al Acta Pharmacologica Sinica ISSN 1671-4083 kindling[7]. In contrast, the involvement of histamine in learn- whereas re-entry into arms where the pellet had already been ing and memory processes has also been well documented. eaten was considered as a working memory error (WME). Histamine significantly ameliorates memory deficits induced Rats continued training until reaching a criterion of less than by aging, dorsal hippocampal lesions, scopolamine and 1 error per trial for 5 consecutive trials. Memory retrieval MK-801, as determined in rats using passive and active avoid- was tested in the same maze. ance tasks and the 8-arm radial maze[8–12]. It is proposed that Chronic transauricular kindling After successful train- histamine and histaminergic compounds might be useful ing in the radial maze, each rat in the experimental group was adjuncts for conventional AEDs, with dual advantages: one given 1 subconvulsive electrical stimulation daily via ear- for enhancement of the anticonvulsant efficacy of AEDs, clip electrodes (40 mA, 0.2 s, Hugo Saches type 221) until and the other for improvement of the memory deficits occur- fully kindled. Animals in the sham group had the electrodes ring with epilepsy. applied, but no current was delivered. Each rat was placed The objectives of the present study were to further clarify separately under a glass funnel, and the appearance of clonic- whether histidine can both enhance the anticonvulsant effi- tonic seizures was recorded. When rats exhibited clonic- cacy of AEDs and ameliorate the spatial memory impairment tonic seizures after each of 3 consecutive stimulations, they induced by seizures. The chronic transauricular kindling were regarded as fully kindled and used for the drug study. procedure was used in rats as a new animal model of epilepsy, The endpoint of efficacy was taken as the inhibition of tonic and an 8-arm (4 arms baited) radial maze paradigm was used hindlimb extension (HLE). The number of animals showing to evaluate spatial memory and differentiate between short- complete abolition of tonic HLE was expressed as percent term and long-term memory. protection. Measurements of brain histamine and γ-aminobutyric acid (GABA) content Materials and methods Sample preparation Rats were sacrificed by decapita- Animals All experiments were carried out in accordance tion. The brain was quickly removed, placed on an ice-cold with the National Institutes of Health Guide for the Care and stainless steel plate, and dissected into the cortex, hippo- Use of Laboratory Animals. Male Sprague-Dawley rats (220– campus, brainstem and hypothalamus according to the meth- 270 g, Grade II, Certificate No 22-9601018, Experimental Ani- ods of Glowinski and Iversen[14]. The brain tissues were mal Center, Zhejiang University) were maintained in an air- stored at -80 ºC until assayed. The tissue was homogenized conditioned room at 22−26 °C and 40%–70% humidity, and in 3% perchloric acid containing 5 mmol/L disodium EDTA housed in individual cages with a 12-h light-dark cycle (lights and 5-hydro-Nω-methyltryptamine in a Polytron homogenizer on from 8:00 to 20:00). Animals were given free access to (Kinematica) at the maximum setting for 20 s in an ice bath. water and kept at 80%–85% of their free feeding body weight The homogenate was centrifuged at 15 000×g at 4 ºC for throughout the radial-arm maze experiments. Experiments 20 min. Then, the supernatant was removed and filtered with were carried out each day between 10:00 and 17:00. a 0.22 µm polyvinylidene difluoride membrane. Radial-arm maze training The apparatus used is de- Chromatographic conditions Tissue samples were ana- scribed in our previous reports[9,10,13]. The rats were familiar- lyzed by high performance liquid chromatography (HPLC) ized with the radial maze once per day for 2 d prior to training. combined with electrochemical detection using a technique Food pellets (45 mg each, Bio-Serv) were scattered over the developed in our laboratory for the simultaneous and sensi- entire maze surface, and 3 or 4 rats were simultaneously tive analysis of histamine and GABA. The system consisted placed in the maze and allowed to explore and take food of a model 582 pump, a model 540 autosampler and a 4-chan- freely for 10 min. After adaptation, all rats were trained with nel CoulArray electrochemical detector. The HPLC was con- 1 trial per day. In each trial, only 4 arms (3, 5, 6, and 8) were trolled and the data acquired and analyzed using CoulArray baited, and the sequence was never changed throughout software. All of the above equipment was obtained from the experiment. One rat was placed on the center platform ESA. After reacting with the derivate o-phthalaldehyde, that was closed off by a door. After 15 s, the door was analytes were separated on a 3 µm, 3 mm×50 mm Capcell Pak opened and the rat was allowed to make an arm choice to MG C18 column from Shiseido. A 2-component gradient elu- obtain food pellets until all 4 pellets had been eaten or 5 min tion system was used, with component A of the mobile phase had elapsed. The number of entries into unbaited arms was being 100 mmol/L Na2HPO4, 13% acetonitrile, and 22% regarded as the total error (TE). The number of entries into methanol, pH 6.8, and component B being similar to A except never-baited arm was taken as reference memory error (RME), with 5.6% acetonitrile and 9.4% methanol. The gradient elu- 1298 Http://www.chinaphar.com Li Q et al tion profile was as follows: 0–3.5 min, isocratic 100% B; 3.5– 20 min, linear ramp to 0% B; 20–22 min, isocratic 0% B; 22– 23 min, linear ramp to 100% B; 23–30 min, isocratic 100% B. Flow rate was set to 0.75 mL/min. The first cell was set at +250 mV, whereas the second cell was set at +350 mV.
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