Effects Of Histamine On Spatial Memory Deficits Induced By Epilepsy In Rats

Epilepsy is the most common neurological disorder after stroke, with a 0.5% prevalence, and a 2-3% life time risk of being given a diagnosis of epilepsy. Patients with epilepsy may experience a range of neurological, psychological, and behavioral problems, in addition to the immediate disabling effects of the seizures themselves. More than 45% of epileptics have psychological or social problems with behavioral manifestations and are completely or partly disabled. And more and more evidences showed that antiepileptic drugs medication might contribute to deterioration in normal learning and memory processes. For example, phenytoin, phenobarbital and valproate are indicated to adversely affect cognition in patients with epilepsy. However, there is contradictory theory about the interaction between epilepsy and cognitive activity. So there is a need for drugs or adjuvants that can simultaneously suppress seizures and ameliorate the concomitant cognitive impairment. Therefore the purposes of the present study were to investigate the effects of acute MES and chronic transauricular kindled seizures on learning and memory abilities and the possible mechanism of learning and memory abilities in Sprague-Dawley rats. Then we investigated the effects of histamine against seizures and memory deficits induced by chronic transauricular kindling in rats.1 Effects of acute maximal electroshock and chronic transauricular kindled seizures on learning and memory abilities in Sprague-Dawley ratsAim: To investigate the effects of acute maximal electroshock (MES) and chronic transauricular kindled seizures on learning and memory abilities in Sprague-Dawley rats as evaluated by 8-arm radial maze. METHODS: Acute MES was produced by giving MES (150 mA for 0.2 s) through earclip electrodes. Chronic transauricular kindling was induced by repeated application of initially subconvulsive electrical stimulation (40mA, 0.2s) through ear-clip electrodes once every 24 h until the occurrence of 3 consecutive clonic-tonic seizures. An 8-arm radial maze (4 arms baited) was used to measure spatial learning and memory abilities in rats. A passive avoidance test was used to measure memory retention ability. Histamine, GABA and Glutamate was measured by high-performance liquid chromatography (HPLC). Morphological change of neurons and astrocytes were examined by HE staining and glial fibtillary acidic protein (GFAP) staining, respectively. RESULTS: In the acquisition process, an acute MES impaired reference memory but not working memory. On the other hand, chronic transauricular kindled seizures impaired both working and reference memory in retrieval memory process, which remained in a steady state for approximately 3 weeks after fully kindled. Chronic transauricular kindled seizures also impaired passive-avoidance test memory retention in rats. The damaged neurons (CA1 region) were observed 24 h after the end of kindling in the chronic transauricular kindled rats, correlating with an increase in the GFAP-immumoreactivity and hypertrophy of astrocytes. Compaired with control rats, acute MES significantly increased the GABA content of hippocampus. However, chronic transauricular kindling produced a significant decrease in the histamine content of the hippocampus. CONCLUSIONS: These results indicate that an acute MES and chronic transauricular kindled seizures produced different effects on learning behavior, in which acute MES impaired learning ability due to increasing GABA content of hippocampus, chronic transauricular kindled seizures impaired retrieval memory mainly due to a pathological damage of hippocampal CAl neuron and a decrease of histaminergic activity in the hippocampus. The chronic transauricular kindling may be a very useful animal model for evaluating memory deficits associated with epilepsy.2 Histamine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in ratsAim: To investigate whether histamine can enhance the anticonvulsant efficacy of carbamazepine (CBZ) and simultaneously improve the spatial memory impairment induced by transauricular kindled seizures in Sprague-Dawley rats. Methods: Chronic transauricular kindling was induced by repeated application of initially subconvulsive electrical stimulation through ear-clip electrodes once every 24 h until the occurrence of3 consecutive clonic-tonic seizures. An 8-arm radial maze (4 arms baited) was used to measure spatial memory, and histamine and GABA levels were measured by high performance liquid chromatography (HPLC). Results: Chronic transauricular kindling produced a significant impairment of spatial memory and a marked decrease in histamine content in the hypothalamus, the brain stem, and the hippocampus. Injection of histidine (1000 mg/kg or 1500 mg/kg, i.p.) significantly inhibited transauricular kindled seizures. Injection of histidine at lower doses (200 mg/kg or 500 mg/kg, i.p.) had no appreciable anticonvulsant effect when administered alone, whereas it significantly potentiated the 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 histidine 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.