| Epilepsy is a serious chronic neurological disease, which is characterized by recurrent abnormal discharge of cerebral neurons and transient disfunction of brain. The clinical symptoms include a variety of abnormities in motor, sense, conscious state, vegetative nervous and psychology. According to WHO, 50 million persons worldwide, and 3 million in China have suffered from the diseases. The exact pathogenesis of epilepsy remains largely unclear. Excessive excitability, over-synchronized discharges and the imbalance between excitation and inhibition of cerebral neurons may contribute to seizures. With the currently available antiepileptic durgs, the disease in about 80% patients who have no serious injuries in the brain, especially those with less frequence of seizures and noramal interictal EEGs, are well controlled. Bycontrast, about 20% epileptic patients can't get effective therapies using those drugs. This epilepsy is called drug-resistance or intractable epilepsy. Moreover, long application of those antiepileptic drugs often results in some adverse responses in psychological, neurological, splanchnic and skin system. Thus, developing new safe and effective antiepileptic drugs is urgently expected.Histamine, a biogenic amine, is an important neurotransmitter or neuromodulator in the mammalian central nervous system. Brain histaminergic system seems to be involved in various physiological and behavioral functions including sleep-wake cycles, appetite control, neuroendocrine, learning and memory through its specific receptors. The studies from others and our laboratory have also reported that brain histamine may be involved in the epileptogenesis and regulate seizure susceptibility as an endogenous anticonvulsant substance. Recently, our group further found that increasing brain histamine levels (e.g. i.p. injection of histdine;i.c.v. injection of histamine or H3 receptor antagonist clobenpropit) markedly delays pentylenetetrazol-induced seizure development, while knock out of histamine HI receptor or histidine decarboxylase genes accelerates pentylenetetrazol-induced seizure development in mice. These evidences indicate that histaminergic system exerts an antiepileptic effect in the brain. Moreover, it is proposed that certain histaminergic drugs may be used as new anticonvulsants in clinic infuture.In the present study, we firstly investigated the effects of carnosine ((3-alanyl-L-histidine), the precursor of histidine, on amygdaloid-kindled seizure in rats, and the role of tuberomammillary nucleus (TM, the only seat of histaminergic neurons in the brain) in postictal seizure protection in rats. Through simultaneously examing both drug pharmacological mechanism and animal endogenous physiological response in epilepsy, we expect to specially elucidate the relation between brain histamine and epilepsy. Now, we have found that carnosine regulated brain histaminergic function and significantly inhibited amygdaloid kindled seizures in rats through two different (direct and indirect) mechanisms of activating brain histamine HI receptor. Additionally, bilateral lesions of the TM E2 region induced a significant attenuation of postictal seizure protection in rats, which may be mediated by lesion-induced reduction of brain histaminergic activation. Moreover, brain GABAergic and glycinergic systems may be also involved in the regulative mechanisms of TM E2 region lesions-induced inhibition of postictal seizure protection. Furthermore, this study suggests that carnosine may be an endogenous anticonvulsant factor in the brain and could be used as a new antiepileptic drug in the future;and the TM may function as an inhibitory neural substrate during the intermittent MES procedure and may be responsible for the initiation of a postictal refractory state in epileptic patients. In conclusion, our study notonly develops the knowledgies about the relations between brain histamine and epilepsy, but also provides necessary theories for the development of histaminergic antiepileptic drugs, especially the medical use of carnsine in future.1. Mechanism of carnosine on amygdaloid kindled seizures in ratsThe effects of carnosine ((3-alanyl-L-histidine) on amygdaloid kindled seizures were investigated in rats. Intraperitoneal injection of carnosine (500, 1000, 1500 mg/kg, i.p.) significantly decreased seizure stage, afterdischarge duration and generalized seizure duration, and significantly prolonged generalized seizure latency of amygdaloid kindled seizures, in a dose-dependent, and time-related manner. The protective effect of carnosine (1500 mg/kg) was completely antagonized by histamine HI-antagonists pyrilamine (2, 5 mg/kg, i.p.) and diphenhydramine (5, 10 mg/kg, i.p.), but not by histamine H2-antagonist zolantidine even at a high dose of 10 mg/kg. Carnosine (1500 mg/kg, i.p.) caused a significant increase of carnosine and histidine levels in the hypothalamus, thalamus, hippocampus, amygdala and cortex, as well as histamine levels in the hippocampus and amygdala. Intracerebroventricular injection of ot-fluoromethylhistidine (50 |ig, i.c.v.), a selective and irreversible histidine decarboxylase inhibitor, only partially reversed the inhibition of amygdaloid kindled seizures induced by carnosine. In addition, carnosinesignificantly decreased glutamate contents in the amygdala and hippocampus. These results indicate that camosine could protect against amygdaloid kindled seizures in rats, and its action may be due to the activation of histamine postsynaptic HI-receptors via two different mechanisms, one being carnosine's direct action, and the other, being indirectly mediated by histaminergic pathway. The study suggests that carnosine may be an endogenous anticonvulsant factor in the brain and could be used as a new antiepileptic drug in the future.2. Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in ratsPostictal seizure protection (PSP) is an endogenous anticonvulsant phenomenon that follows an epileptic seizure and inhibits the induction of further seizures. The tuberomammillary nucleus (TM), located in the posterior hypothalamus, consists of five subregions and is the sole seat of histaminergic neurons in the brain. To determine whether the TM is involved in PSP in rats we tested the effects of bilateral electrolytic lesions of the TM E2-region on intermittent maximal electroshock (MES)-induced seizures. In sham-operated rats, intermittent MES resulted in PSP, with a progressive decrease in both seizure pattern score and duration of tonic fore- and hindlimb extension with each successive seizure. The TM E2-region lesions significantly weakened PSP. Furthermore,intracerebroventricular injection of 100 |ig cc-fluoromethylhistidine, a selective and irreversible histidine decarboxylase inhibitor, adequately mimicked the TM E2-region lesion-induced attenuation of PSP. On the other hand, neurochemical studies revealed that the TM E2-region lesions markedly decreased basal histamine levels in the cortex, hippocampus, brainstem and hypothalamus, but had no significant effect on basal glutamate and GAB A levels. Moreover, intermittent MES induced a significant and persistent decrease of brain histamine levels in the cortex, brainstem, hippocampus and hypothalamus in both sham-operated and lesioned rats. These results indicate that partial destruction of TM can result in attenuation of PSP which is possibly due to a lesion-induced reduction of histaminergic activity. Additionally, the TM may function as an inhibitory neural substrate during the intermittent MES procedure and be involved in the mechanisms of PSP. |
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