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Effect of chronic epilepsy on spatial memory regeneration in rats
Effect of chronic epilepsy on spatial memory regeneration in rats
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[Abstract] Objective: To investigate the effect of chronic epilepsy on spatial memory regeneration in rats, and to detect the effects of histamine precursor histidine and cholinesterase inhibitor TA K2147 on epilepsy-induced memory impairment.
METHODS: After successful training in the radial eight-arm (four-arm food) maze, rats were injected intraperitoneally with subacne dose (35 mgökg) of pentylenetetrazol every other day until complete ignition. After complete ignition, the reproduction process of memory is measured in the same labyrinth.
RESULTS: From 1st to 18th day after complete ignition, the number of errors in the radial maze was significantly higher than that in the control group, and remained in a relatively balanced state. After 31 days, it was consistent with the control group. TA K2147 dose-dependently improved epilepsy-induced spatial memory reproducibility, including reference memory and working memory. Histidine dose-dependently improved reference memory without affecting working memory.
Conclusion: Pentylenetetrazol-induced epilepsy can lead to a decrease in spatial memory regeneration in rats, which may be related to the decrease of cholinergic nerve and histaminergic activity caused by epilepsy.
[Key words] epilepsy/chemical induction, radial maze, memory impairment, cholinesterase inhibitor/pharmacology, histidine/pharmacology
The harm caused by epilepsy is not only the seizure itself, but also the mental retardation caused by recurrent epileptic seizures. It has been reported that 45% of patients with epilepsy have behavioral disorders such as memory disorders, and 10% to 20% of children with epilepsy need special education [1]. Therefore, it is more urgent to study the mechanism of learning and memory impairment caused by epilepsy and to screen drugs for treating such learning and memory disorders. Pentylenetetrazol (PTZ) is a central stimulant. Repeated use of sub-convulsant doses of pentylenetetrazol can reduce the convulsion threshold of animals and eventually cause "ignition." The pentylenetetrazol ignition model is a chronic epilepsy model that is often used to study the pathogenesis of epilepsy and the effects of antiepileptic drugs and is one of the most commonly used epilepsy models [2, 3]. Radial eight-arm (four-arm food) is a classic method for measuring spatial memory in animals. It can simultaneously detect reference memory and working memory (wo rk ing m emo ry). To this end, this experiment used a radial maze to determine the spatial memory recurrence of pentylenetetrazol-ignited rats, to study the relationship and mechanism of epilepsy and learning and memory, and to preliminarily evaluate two compounds that are believed to improve memory impairment, TAK2147 and histamine. Acid, providing clues for memory impairment in patients with epilepsy.
1 Materials and methods
1.1 Animals and grouped SD rats 50 males, weighing 220-300g (provided by Experimental Animal Center of Zhejiang University Medical College), clean grade, certificate number: 2229601018. SD rats were randomly divided into PTZ-ignited group (n=40) and control group (n=10), and they were grouped in groups, freely influent, and given 12 hours of light per day (lighting time: 8:00 to 20:00) . Rat diets were restricted prior to the eight-arm maze test to maintain body weight between 80% and 85% of free-fed body weight. Behavioral observations were performed from 10:00 to 17:00.
1.2 Maze training uses a radial eight-arm (four-arm food) maze. The central area of ​​the labyrinth is 30 cm in diameter, and extends eight arms (50 cm × 12 cm, surrounded by a wall of 4.5 cm) at equal angles and equal lengths. The entire labyrinth is 40 cm above the ground. Rats were acclimated in the maze for 2 days before training, once a day. Three to four rats were placed in the maze at the same time, free to move and ingest food for 10 min. After the adaptation, perform one training per day. In each training, only four of the eight arms were placed with food (arms 3, 5, 6 and 8 respectively), which was maintained throughout the experiment. The rat is placed in the central area of ​​the maze. At this time, the door is closed for 15 s around the central area. The rat can choose to enter any arm to ingest food. The rat enters the arm with food and takes the food for 1 correct selection, otherwise it is the wrong choice. Record the number of times the parameter was selected incorrectly. Re-entering the food arm is called working memory error (w rk ing m emo ry er ro r, WM E), and entering the food arm is called reference memory error (reference m emo ry er ro r, RM E). The number of total error selections for 5 consecutive trainings is 1 or less, and the training is considered successful.
1. After the pentylenetetrazol ignition model maze training was successful, the rats in the pentylenetetrazol-ignited group were intraperitoneally injected with PTZ35mgökg for 48h once, and the non-ignition group was intraperitoneally injected with the same volume of normal saline. After each injection, the rats were individually placed in a clear glass cage and observed for 30 min of behavioral changes. The severity of seizures was graded according to the literature [2,3]: 0 = no response; 1 = ear and facial tics, including blinking, moving, rhythmic chewing; 2 = myoclonus, but no erect; 3 = myoclonus , both forelimbs lifted; 4 = sideways fell to the ground; 5 = back to the ground, body tonic - clonic attack or death. If the animal has a grade of 4 or 5 after 3 consecutive injections of PTZ, it is considered to be completely ignited. The reproduction process of memory was started 24 hours after the rat was completely ignited, and the reference object and the food arm were consistent with the training process.
1.4 The drug pentylenetetrazol and histidine were purchased from Sigm a, and TA K2147 was supplied by Takeda Pharmaceutical Co., Ltd. All drugs are dissolved in normal saline. Histidine and TA K2147 were injected intraperitoneally 2 h and 30 m before the memory test, respectively.
1.5 Statistical analysis The data were analyzed by Sigm a Stat 1. 01 (W indows 95 1992, Co rp , U SA ) statistical software. The data are expressed in xq±s. Comparison between groups was performed by ANOVA and Dunnet t's test.
2 results
2.1 After 1d, 7d, 11d, 16d and 18d after complete ignition, RME are: 215±015, 218±015, 218±015, 218±017 and 219±016 respectively; WME are: 116±014, 118 respectively ±015, 210±016, 119±016, and 118±015, significantly increased compared with the control group (P<0105), and maintained in a relatively balanced state, suitable for testing drug effects. After 18 days, the above indicators began to decline, and remained basically unchanged from the non-ignition group at 31d. For 23d and 31d after complete ignition, the RME decreased to 210±016 and 113±016, respectively, and the WME decreased to 018±013 and 015±014, respectively. The RME and WM E of the control group were maintained between 111±016～113±015 and 012±012～013±012, respectively.
2.2 The effect of TAK2147 on memory reproduction was measured 1 to 18 days after complete ignition. TA K2147 dose-dependently reduced RM E. As shown in Table 1, TA K2147 at 013 m gö kg significantly reduced both RM E and WM E (P < 0105), and TA K2147 at 011 m gö kg also significantly reduced RM E (P < 0105).
2.3 The effect of histidine on memory reproduction was measured 1 to 18 days after complete ignition. Histidine (1 000 m gö kg) significantly reduced RM E (P < 0105) without affecting WM E.
3 Discussion
This experiment found that pentylenetetrazol ignited significantly increased the number of false selections (including RM E and WM E) in the trained eight-arm maze, and remained relatively stable within 1 to 18 days after complete ignition. status. There are many studies on the learning and memory of epileptic rats, and the electro-ignition model is rare. Compared with the electric ignition model, the pentylenetetrazol chemical ignition model has the advantages of convenient production, high success rate, and no damage to brain tissue structure. In addition, pentylenetetrazol is an antagonist of the GABAA receptor, which itself has no significant effect on memory. The results of this experiment indicate that rat pentylenetetrazol igniting is promising as a model for studying epilepsy-induced learning and memory impairment, and is used to evaluate and screen for drugs for the treatment of epilepsy-induced cognitive dysfunction. Acetylcholine is essential for learning acquisition and memory retention. Ser ra et al reported that pentylenetetrazol ignited reduced the acetylcholine content in the hippocampus of free-living rats to 52% of the control group, and maintained this level for 4 weeks, and returned to the control level 30 days after the pentylenetetrazol injection was stopped [7]. . Our behavioral results are temporally consistent with the biochemical results of Ser ra, suggesting that chronic epilepsy-induced memory impairment may be associated with decreased acetylcholine levels in the brain. TAK2147 is a more selective cholinesterase inhibitor that activates the brain's cholinergic nerves. We found that the role of TA K2147 may be that it improves the acetylcholine function of hippocampus caused by ignition, thereby improving the spatial memory reproducibility disorder induced by pentylenetetrazol ignition in rats.
In addition, histamine in the brain is also thought to improve learning and memory. The action of histamine is related to the activation of histamine H1 receptor and activated cholinergic nerve in the brain [8]. Although there is no report on the relationship between pentylenetetrazol igniting and histamine content in the brain, it has been reported that amygdala is stimulated to complete ignition, and the histamine content in the brain decreases 1 week after stopping electrical stimulation, and returns to pre-ignition level after 1 month [ 9 ]. Histamine precursor histidine can increase histamine content in the brain. Histidine may activate histamine H1 receptor and ö or activate cholinergic nerve by increasing histamine content in the brain, improving the memory reproduction disorder induced by pentylenetetrazol ignition in rats. We have reported that histamine can inhibit the formation of pentylenetetrazol-induced epilepsy and the process of seizure after ignition. Therefore, histamine-related drugs may become better antiepileptic drugs or adjuvant drugs for the treatment of epilepsy. And interestingly, histidine only improved the reference memory and had no effect on working memory. This result further confirmed our previous results, that is, the separation of endogenous histamine from reference memory and working memory. . In summary, rat pentylenetetrazol igniting caused spatial memory reproducibility, which may be related to the decrease of cholinergic nerve and histaminergic activity caused by ignition. The specific mechanism needs further discussion. Our findings provide a new way of thinking and clues to the relationship between epilepsy and cognitive function and the evaluation of drug therapy for epilepsy-induced memory impairment.