Biphasic action of the histamine precursor l -histidine in the rat kindling model of epilepsy

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Neuroscience Letters 204 (1996) 205-208

HHROSClENC[ LETTERS

Biphasic action of the histamine precursor L-histidine in the rat kindling model of epilepsy Yuji Wada*, Jun Shiraishi, Mitsuhiko Nakamura, Yoshifumi Koshino Department of Neuropsychiatry, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920, Japan Received 4 December 1995; revised version received 8 January 1996; accepted 8 January 1996

Abstract

The effects of the histamine precursor, L-histidine, were examined in the rat kindling model of epilepsy. The intraperitoneal (i.p.) administration of 800 mg/kg L-histidine significantly prolonged the latency to the onset of bilateral forelimb clonus of previously kindled seizures from the amygdala (AM), with no significant effect observed in the behavioral seizure stage or afterdischarge duration. In contrast, daily administration of L-histidine at the same dose prior to each electrical stimulation to the AM significantly facilitated both behavioral and electrographic seizure development of kindling. The present results indicate that although L-histidine can suppress secondary generalization of AM-kindled seizures, it possesses a facilitatory effect on the acquisition of kindling epileptogenesis, suggesting a biphasic action of histamine in kindling.

Keywords: Kindling; Histamine; L-Histidine; Epilepsy; Amygdala; Rats

Histamine is a potent bioactive substance, and the histaminergic system is involved in various biobehavioral phenomena, including energy metabolism, hormone secretion, arousal state and pain sensation [ 18] as well as in thermoregulation [3]. Histamine has also been suggested to participate in the mechanisms regulating seizure activity in humans, and antihistaminergic drugs are reported to induce convulsions in children [6,13,19,20]. In a recent study with positron emission tomography (PET), Iinuma et al. [4] reported an increased histamine H1 receptor binding in epileptic foci and surrounding regions in epileptic patients. Although recent studies provide evidence that the histaminergic system plays an important role in acute experimental models of generalized seizures in rodents (i.e. maximal electroshock induced and chemically induced seizures) [12,16,21,22], no studies have investigated the effect of this neurotransmitter in partial seizure models. Kindling, a chronic experimental model of human complex partial seizures, refers to the phenomenon in which periodic focal application of initially subconvulsive electrical stimulation leads to the progressive intensification of seizures, culminating in a generalized * Corresponding author. Tel.: +81 762 628151, ext. 3722; fax: +81 762 344254.

convulsion [7,10,11]. To further elucidate the role of the central histaminergic system in epilepsy, we examined the action of L-histidine, a precursor of histamine, against: (1) previously kindled seizures and (2) kindling seizure development from the rat amygdala (AM). Male Wistar rats, weighing 280-320 g at surgery, were used. Under sodium pentobarbital anesthesia (50 mg/kg, i.p.), a tripolar electrode was stereotaxically implanted into the left AM, according to the atlas of Paxinos and Watson [8]: A, -2.8; L, 5.0; V, 8.5 (in mm), from the bregma. The AM electrode (0.1 m m in diameter, nichrome wire, insulated except for the tip) was used for electrical stimulation and EEG recording, and a skull screw served as a reference electrode. Throughout the experiment, animals were housed individually and had free access to food and water. One week after surgery, electrical stimulation to the AM was performed once daily with a 2-s train of biphasic constant current, 60-Hz, sine wave pulses. The stimulus intensity was initially set at 10/~A peak-to-peak, and was subsequently increased by 10-ktA steps each day until an afterdischarge (AD) was elicited. The intensity that first produced AD was designated as the AD threshold, and was used for daily stimulation. We assessed the behavioral seizure stage using a modification of Racine's clas-

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Yuji Wada et al. / Neuroscience Letters 204 (1996) 205-208

Table 1 Effects of L-histidine of fully kindled seizures from the rat amygdala Drug

Seizure stage

ADD(s)

Bilateral forelimb clonus Latency (s)

Saline L-Histidine 200 mg/kg 800 mg/kg

Duration (s)

5

53.1 _+12.6

3.6 ± 0.9

26.6 ± 2.3

5 5

55.7 ± 9.0 66.1 ± 12.1

4.0 _+1.0 10.5±2.5"*

25.8 ± 3.5 22.4_+2.8

Values are means + SEM (n = 10). ADD, afterdischarge duration. **P < 0.01 compared with saline and 200 mg/kg L-histidine (Scheffe's test). sification [10]: stage 0, no response; stage 1, rhythmic mouth and facial movement; stage 2, rhythmic head nodding; stage 3, forelimb clonus; stage 4, rearing and bilateral forelimb clonus; stage 5, rearing and falling. In experiment 1, drug effects on previously kindled seizures were tested in 10 rats after stage 5 generalized seizures reliably provoked on 3 consecutive days at the intensity o f the generalized seizure triggering threshold (GST). The G S T was determined in each rat by application of trains that were decreased in intensity at 10-~A steps once daily. Each rat underwent 3 drug tests, including a saline-control trial, separated by 7 days. The rats received an i.p. injection of either 0.9% saline (4 ml/kg) or L-histidine hydrochloride (Research Biochemicals Inc., 200 or 800 mg/kg), 30 rain prior to electrical stimulation at the previously determined GST. L-Histidine was dissolved in warm sterile saline and was freshly prepared prior to each injection. The order o f treatments was counter-balanced among the animals. In experiment 2, drug effects on kindling development were tested in 21 rats. Following a 1-week postsurgical period, they were subjected to kindling stimulation without drug treatment, and the A D threshold was determined in each rat as described above (day 1). The rats were then divided into 2 groups, the saline-control group and the Lhistidine group, matched for the A D threshold and A D duration (Table 2). F r o m the second day, the rats received i.p. administration of L-histidine 800 mg/kg ( n = 10) or saline 4 ml/kg (n = 11) once per day, 30 min prior to each

electrical stimulation at the intensity o f the A D threshold. This procedure was continued until an animal displayed 3 consecutive stage 5 generalized seizures. Upon completion of these experiments, the rats were deeply anesthetized with pentobarbital, after which their brains were perfused, removed, serially sectioned, and stained for histological examination. All electrode tips were localized in the intended structure. Data in experiment 1 were evaluated by Friedman's analysis of variance (ANOVA), followed by Scheffe's multiple comparisons procedure. Data in experiment 2 were evaluated by M a n n - W h i t n e y U-test. Statistical significance was defined as P < 0.05. Table 1 shows the effects of L-histidine on previously AM-kindled seizures. Stage 5 seizures were elicited in all rats receiving saline and L-histidine treatments, and no significant changes were found in the duration of either A D (¢2= 0.667, d.f. = 2, P = 0.717, F r i e d m a n ' s test) or bilateral forelimb clonus (Z2 = 1.135, d.f. = 2, P = 0.567). The i.p. administration of L-histidine significantly affected the latency to the onset o f bilateral forelimb clonus ((2 = 11.72, d.f. = 2, P = 0.0028), and post-hoc analysis by Scheffe's test showed that 800 mg/kg L-histidine significantly increased this seizure parameter compared to saline control and 200 mg/kg L-histidine (P < 0.01). The effects of L-histidine on kindling development are shown in Table 2. Daily treatment with 800 mg/kg Lhistidine caused a significant reduction in the number o f A M stimulations needed to produce the first stage 5 seizure (U = 85, P < 0.05). No significant group differences were found, however, in either A D duration o f the first stage 5 seizure or GST. Fig. 1 shows the comparative pattern of kindling development between the L-histidine and saline groups. Treatment with 800 mg/kg L-histidine significantly facilitated the behavioral seizure stage from day 3 to day 10 (Fig. 1A). L-Histidine also facilitated the progressive lengthening of the A D duration, and significant group differences were found from day 2 to day 6 and on day 10 (Fig. 1B). There have been several studies showing the inhibitory action of histamine in acute experimental models of generalized seizures. Yokoyama et al. [22] showed that the i.p. injection of L-histidine at the dose (800 mg/kg) used in the present study decreased the duration of the clonic

Table 2 Seizure parameters of kindling development in rats receiving daily treatment with saline or 800 mg/kg L-histidine Drug

Saline L-Histidine

n

11 10

ADT (uA)

53.7 _ 4.9 57.8 _ 8.5

First response

First stage 5 seizure

GST Q~A)

ADD (s)

No. of stimulations

ADD (s)

5.6 ± 1.6 6.2 _+1.3

12.3 ± 1.1 8.7 ± 0.8*

40.3 ___6.1 44.9 +_5.5

35.0 ± 5.9 37.5 + 9.2

Values are means - SEM. ADT, afterdischarge threshold; ADD, afterdischarge duration; GST, generalized seizure triggering threshold. *P < 0.05 compared with saline-treated group (Mann-Whitney U-test).

Yuji Wada et al. / Neuroscience Letters 204 (1996) 205-208

5-

4-

N= 2-

0

A I

I

I

I

i

1

I

I

!

I

Number of stimulations

B

100~ . 80.=_o 60~40r~ •< 20i

i

I

I

/

I

s

I

I

i

1

I

I

I

10

!

I

I

1S

Number of stimulations Fig. 1 Effects of saline ( A ) and 800 mg/kg L-histidine ( 0 ) on the development of amygdala kindling. (A) Behavioral seizure stage; (B) AD duration. Data represent means + SEM. Seizure stages graded as in text. *P < 0.05, **P < 0.01 compared with saline control (Mann-Whitney U-test).

phase of maximal electroshock convulsions in mice, in association with a significant increase in brain histamine levels. Scherkl et al. [12] also reported that L-histidine elevated the threshold for eliciting pentylenetetrazolinduced convulsions in mice. Moreover, Tuomisto and Tacke [16] found an inhibition of tonic hindlimb extension of electroshock seizures in rats following the administration of metoprine, which elevates brain histamine levels by inhibiting histamine-N-methyltransferase. The present study showed that although L-histidine did not suppress the generalized portion of kindled seizures, it significantly prolonged the latency to the onset of bilateral forelimb clonus, suggesting that histamine has an inhibitory effect on the secondary generalization of kindled seizures. In contrast to the suppressive action of L-histidine against previously kindled seizures, this compound significantly reduced the number of AM stimulations required to reach the first stage 5 seizure. In addition, it significantly facilitated both behavioral and electrographic aspects of seizures during the course of kindling, suggesting that histamine possesses a facilitatory effect on the acquisition of kindling epileptogenesis. The present results are consistent with the view that different neuronal mechanisms exist between the developmental process of

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kindling and the expression of previously kindled seizures [7,11]. In the present study, L-histidine significantly increased the AD duration, but not the behavioral seizure stage, in the second kindling trial (i.e. the first drug trial). Considering that the AD duration is generally thought to be the principal factor in determining kindling development [9], it is possible that L-histidine primarily accelerates the electrographic seizure response, which may lead to a facilitation in the acquisition of kindling epileptogenesis. Kostopoulos et al. [5] showed that brief exposure of hippocampal slices to histamine produces a longlasting enhancement of population spikes in genetically epileptic mutant mice. Furthermore, it has recently been shown that histamine potentiates N-methyl-D-aspartate (NMDA) receptor-mediated currents in acutely isolated hippocampal neurons [17]. Similarly, Bekkers [1] reported the enhancement by histamine of NMDA-mediated synaptic transmission in hippocampal cultures. In their study using rat hippocampal slices, Brown et al. [2] have reported that histamine can facilitate the induction of long-term potentiation, which has been suggested to be involved in the mechanisms of kindling development [14,15], most likely by acting directly on NMDA receptors. NMDA receptors are known to play a critical role in the acquisition of kindling epileptogenesis, but not in the expression of kindled seizures [7]. It is possible therefore that the facilitatory effect of L-histidine on AM kindling development is mediated, at least in part, by the action on NMDA receptors. In summary, the present study demonstrates that Lhistidine can suppress kindled seizure generalization, whereas it accelerates the development of kindling, suggesting a biphasic action of histamine in the kindling model. There have been clinical case reports showing that centrally acting antihistaminergic agents induce seizures in healthy pre-school age children [6,13,19] and a 5-yearold boy with epilepsy [20]. Yokoyama et al. [21] showed that histamine HI-antagonists increased the duration of electroshock-induced convulsions in 21- and 30-day-old mice, but not in 42-day-old mice. Further studies are needed, therefore, to examine the age-related differences of L-histidine effects in the kindling model. Since previous studies have shown that the role of the histaminergic system in generalized seizure models differs depending on the histamine receptor subtype [12,22], drugs which act selectively on the specific receptor subtype should be used to further clarify the histaminergic mechanisms in kindling. This study was supported in part by grants from the Ministry of Health and Welfare of Japan. [I] Bekkers, J.M., Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus, Science 261 (1993) 104-106. [2] Brown, R.E., Fedorov, N.B., Haas, H.L. and Reymann, G., His-

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[3]

[4]

[5]

[6] [7] [8] [9]

[10]

[I1]

[12]

[13]

Yuji Wada et al. / Neuroscience Letters 204 (1996) 205-208

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