| Background:Epilepsy is a common neurological disorder characterized by repeated seizures caused by excessive discharge of neurons, which makes the patients suffer a lot. With the incidence of5%o-7%o, it is estimated that there are90million epileptic patients worldwide, and6.1to9.1million epileptic patients in China. In addition to experiencing seizures, many people with epilepsy experience cognitive problems, and the most common cognitive problem is memory impairment. For example, a paper published in pediatrics in2012, reported that children with epilepsy were more likely to experience mental health and developmental comorbidities, and more likely to access mental health treatment and special education services. Temporal lobe epilepsy, one of the most common types of adult epilepsy, usually lead to severe memory problem, which causes more disabilities than seizures themselves. As a result, memory impairment has a huge negative influence on both the society and the family of epileptic patients. However, the mechanisms of memory impairment induced by epilepsy remain unclear, and we have no effective therapeutic drugs or other treatment for this condition, so far. In addition, most antiepileptic drugs also cause negative effective on cognition. So, investigation on mechanisms of memory impairment induced by epilepsy has both theoretical and clinical significance. The histaminergic neuron system seems to be involved in various physiological and behavioral functions through H1, H2and H3receptors including sleep-wake cycles, emotion, appetite control, locomotor activity, stress behavior, neuroendocrine functions, learning and memory. Our previous study suggested that the histaminergic function was decreased by pentylenetetrazole (PTZ)-kindled seizures, and enhancement of the histaminergic function could ameliorate the memory impairment.Objective:The present study planned to investigate whether PTZ-kindling epilepsy could lead to spatial memory acquirement in rats, to analyse the features of spatial memory acquirement impairment induced by PTZ-kindling epilepsy, to investigate whether PTZ-kindling epilepsy could give rise to decrease of brain histamine level, to analyse the spatiotemporal features of brain histamine level changes induced by PTZ-kindling epilepsy, and in the end, to investigate whether histamine could improve spatial memory acquirement impairment in PTZ-kindling epilepsy rats.Methods:A subconvulsive dose of PTZ (35mg/kg) was intraperitoneally injected every48h in rats to induce chemical kindling until fully kindled. To measure the spatial memory acquirement, rats (24h,1w,2w, and3w after fully PTZ-kindled) were trained at Morris water maze. The histamine content of brain was measured spectrofluorometrically,24h,1w,2w, and3w after fully PTZ-kindled. After getting the time-dependent spatial memory acquirement impairment pattern, we investigate the effects of histamine on spatial memory acquirement impairment induced by PTZ-kindling epilepsy using histidine (the precursor of histamine,200mg/kg,500mg/kg and1000mg/kg)1week after fully kindled. Morris water maze was used to measure the spatial memory acquirement1w after fully kindled. Histamine related drugs were intraperitoneally injected once a training day, half an hour before the first trial. The scheme included:histidine (0mg/kg)+histamine H1receptor antagonist pyrilamine (0mg/kg), histidine (1000mg/kg)+histamine H1receptor antagonist pyrilamine (0mg/kg), histidine (1000mg/kg)+histamine H1receptor antagonist pyrilamine (4mg/kg), histidine (1000mg/kg)+histamine H1receptor antagonist pyrilamine (10mg/kg) and histidine (1000mg/kg)+histamine H1receptor antagonist pyrilamine (20mg/kg). Histidine (0mg/kg)+histamine H2receptor antagonist zolantidine (0mg/kg), histidine (1000mg/kg)+histamine H2receptor antagonist zolantidine (4mg/kg), histidine (1000mg/kg)+histamine H2receptor antagonist zolantidine (10mg/kg) and histidine (1000mg/kg)+histamine H2receptor antagonist zolantidine (20mg/kg). After trained in Morris water maze for3dyas, some rats were sacrificed by decapitation, and brains were quickly removed. Hippocampus was dissected from the brain on ice. The phospho protein kinase A (p-PKA) and phospho cAMP-response element binding protein (p-CREB) levels of hippocampus were measured by western blot.Results:Spatial memory acquirement was markedly impaired at24h,1w and2w after fully kindled. The spatial memory acquirement recovered at the third week after fully kindled. The histamine levels of hippocampus, thalamus and hypothalamus decreased significantly at24h,1w and2w after fully kindled, which were elevated to histamine levels of control group at3w after fully kindled. Intraperitoneal injection of histidine, the precursor of histamine, ameliorated the spatial memory acquirement deficit induced by PTZ-kindling epilepsy in a dose-dependent manner. Histidine ameliorated spatial memory acquirement impairment in PTZ-kindling epilepsy rats in a dose-dependent manner. Escape latency significantly decreased by histidine (1000mg/kg) at training day2and training day3, when it was compared to the escape latency of control group. Histamine H2receptor antagonist zolantidine reversed the ameliorative effects of histidine in a dose-dependent manner. However, histamine H1receptor antagonist pyrilamine have no significant influence on the ameliorative effects of histidine, even at a dose of20mg/kg. After trained in Morris water maze for3days, p-PKA and p-CREB level of hippocampus decreased in PTZ-kindling epilepsy rats, which were reversed by histidine in a dose-dependent manner.Conclusion:Partterns of spatial memory acquirement deficit and brain histamine decrease in PTZ-kindling epilepsy rats were both time-dependent, and the time was consistent with each other. This suggests that insufficiency of brain histamine is possibly involved in spatial memory impairment of PTZ-kindling epilepsy rats. Enhancing of brain histamine function improved spatial memory acquirement deficit in PTZ-kindling epilepsy rats. Enhancement of histaminergic function can ameliorate the spatial memory acquirement impairment induced by PTZ-kindling epilepsy in rats. Drugs which can enhance brain histamine function are potential for treating memory problem induced by epilepsy. |
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