| Epilepsy is a heterogeneous symptom complex which is a chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. According to WHO, 50 million persons worldwide, and 3 million in China have the diseases. Medications just control the symptoms but fail to change the basic process of pathophysiology, since the exact mechanisms of epilepsy remain unclear. Excessive excitability, over-synchronized discharges and the imbalance between excitation and inhibition of cerebral neurons may contribute to seizures. Histamine, a biogenic amine, is an important neurotransmitter or neuromodulator in the mammalian central nervous system. Histamine neurons are exclusively located in the tuberomammillary nucleus of the posterior hypothalamus receiving input mainly from the limbic system and projects efferent nerve fibers to almostall parts of the brain. Histamine seems to be involved in various physiological and behavioral functions including sleep-wake cycles, emotion, appetite control, locomotor activity, stress behavior, neuroendocrine, learning and memory through its specific receptors. It has been suggested that histamine regulates seizure susceptibility as an endogenous substance. In present study, we investigated the effects of endogenous histamine on the seizure development of pentylenetetrazole (PTZ)-kindling, PTZ-kindled seizures and amnesia induced by PTZ-kindling in rats.1. Effects of endogenous histamine on seizure development of PTZ-kindling in ratsObjective: To investigate whether or not endogenous histamine can inhibit seizure development of PTZ-kindling and PTZ-kindled seizures in rats. Methods: To induce chemical kindling, a subconvulsive dose of PTZ (35 mg/kg) was intraperitoneally (ip) injected every 48 h in rats. In the process of development of PTZ-kindling, histamine-related drugs were used before every injection of PTZ. When the rats had a seizure stage of 4 after three consecutive injections, it was defined as fully kindled, and then test the effects of histamine-related drugs on PTZ-kindled seizures. both on development of PTZ-kindling and PTZ-kindled seizures, behaviorchanges were recorded for 30 min after injection of PTZ. The histamine content of brain was measured spectrofluorometrically. Results: An ip injection with histidine (200 and 500 mg/kg), the precursor of histamine, 1 h before PTZ treatment significantly inhibited the development of PTZ-kindling, presenting prolonged latency for myoclonic jerks (LTMJ) and clonic generalized seizures (LCGS) and depressed seizure stages in a dose-dependent manner. The protective action of histidine (500 mg/kg) was significantly reversed by FMH ( 5 and 10 g, icv), an irreversible histidine decarboxylase inhibitor. FMH (20 g, icv) alone accelerated the seizure development of PTZ-induced kindling. On PTZ-kindled seizures, an ip injection with histidine (100, 200, 500 and 1000 mg/kg) significantly delayed the seizure stage in a dose-dependent manner. The protection induced by histidine (500 mg/kg) on PTZ-kindled seizures was reversed by a-FMH (5, 10 and 20 g, icv) or pyrilamine (1,2 and 5 mg/kg, ip), a histamine H1 receptor antagonist, respectively but not by zolantidine (2, 5 and 10 mg/kg, ip), a histamine H2 receptor antagonist, even at a dose of 10 mg/kg. An intracerebroventricular (icv) injection with clobenpropit (5 and 10 g), a representative histamine H3 receptor antagonist, 30 min before PTZ treatment marked inhibited the development of PTZ-kindling. The protective action of clobenpropit (20 g) on the development of PTZ-kindling was significantly reversed by both immepip (2 g, icv), a histamine H3 receptor agonist, and a-FMH (10 g, icv), respectively. OnPTZ-kindled seizures, an icv injection with clobenpropit (2, 5, 10 and 20 g) significantly delayed the seizure stage and prolonged LTMJ and LCGS in a dose-dependent manner. The protective action induced by clobenpropit (20 g) o...
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