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Protective effects of fructose 1,6-diphosphate on learning, memory and emotional behavior impairment in rats with febrile seizures
Protective effects of fructose 1,6-diphosphate on learning, memory and emotional behavior impairment in rats with febrile seizures
Abstract :
ã€Objective】 To investigate the learning and memory and emotional behavioral loss of febrile seizures in rats with fructose21, 62diphosphate (FDP).
The protective effect of harm.
ã€Methods】 Thirty 21-day-old male Sprague-Dawley rats were randomly divided into FDP intervention group (FD), so-dium chloride solutin cont rol group (NS) and febrile seizure group (febrile seizure group). FS). The febrile seizure model was established by water bath method; the FD group was intraperitoneally injected with FDP 25 mg/100 g rat body weight 30 min before convulsion; the NS group was intraperitoneally injected with the same volume of 0.99% sodium chloride solution; the FS group was not interfered. The changes of memory and emotional behavior were observed in each group in the passive avoidance test (PAT), Morris water maze (MWM) and open field test (OFT).
[Results] FDP can prolong the memory latency in PAT in convulsive rats [341.16 ±97.44) s in the FD group, (227.62 ±92.19) s in the NS group, and 213 in the FS group. 66 ± 90. 70) s , P < 0. 01 ] , the number of errors decreased (1. 84 ± 1.27 in the FD group, 4. 97 ± 1.18 in the NS group, and 5. 06 ± 1 in the FS group) 38 , P < 0.011; In OFT, FDP can enhance the excitability of rats with recurrent seizures (FD score is 65. 41 ± 8.02, NS group is 46. 22 ± 7.97, FS group) 48.81 ± 7.69, P < 0.01), to improve the adaptability of rats to unfamiliar environments (the number of hind limbs standing in the FD group was 36. 29 ± 5. 06, and the NS group was 18. 72 ± 4). 71, FS group was 20. 06 ± 4.96, P <0.01. It improved the nervousness of the rats (the number of feces in the FD group was 5.62 ± 2.76, and that in the NS group was 10. 79 ± 2). 91, FS group was 11.43 ± 3. 01, P < 0.01. In MWM, the escaping latency of rats in FD group was shortened and the search strategy improved.
ã€Conclusion】 Fructose 1,6-diphosphate can improve the learning and memory and emotional behavior of rats with recurrent seizures, and has protective effects on convulsive brain function damage.
Keywords : 　 Fructose 1,6-diphosphate (FDP); febrile seizures; learning and memory; behavior; Morris water maze
Febrile seizures (FS) are common pediatric emergencies and have the potential to cause varying degrees of brain damage. Animal experiments have confirmed that repeated febrile seizures can lead to abnormal learning and memory dysfunction and neuronal, organelle and synaptic pathological changes in rats [1~2]. The authors pre-injected fructose 1,6-diphosphate fructose (f ruc-tose21,6-diphosphate, FDP) into the rats with recurrent febrile seizures to investigate the learning, memory and emotional behavioral damage of febrile seizures in rats. Whether it has a protective effect.
1 objects and methods
1. 1 30 male SD rats of 21 days old (provided by Experimental Animal Center of Xi'an Jiaotong University School of Medicine) with a body mass of (50 ± 5) g; they were divided into fructose intervention group by random number method. FD), saline control group (sodium chloride solution cont rol, NS) and febrile seizure group (FS), the number of rats in each group were 10; each group was kept in a standard environment and fed freely.
1. 2 methods
1. 2. 1 Model establishment A heated convulsion rat model was established using the modified hot bath method [1]. Rats in the FD group were intraperitoneally injected with 2.5 mg of FDP solution (FDP from Hainan) at a dose of 25 mg/100 g (ie 1 ml / 100 g) of rat body weight 30 min before each induction of febrile seizures. Tianwang International Pharmaceutical Co., Ltd. provided the batch number); while the NS group was intraperitoneally injected with the same volume (1 ml/100 g rat body weight) of 0.9% sodium chloride solution; no intervention was given in the FS group.
1. 2. 2 Passive avoidance test (PAT) SFK-I type dark proof test box (made in Japan) is divided into two parts: open and dark, with small doors communicating with each other; avoiding dark habits makes rats instinctively choose to enter the darkroom Rats entering the darkroom were immediately subjected to an electric shock (3 mA, 50 Hz) and passively escaped to a safe bright room. 5 minutes without entering the dark room is considered to have completed the study, recording the number of times the rat erroneously entered the dark room before completing the study, mainly reflecting the ability of the rat to learn recently; after 24 hours, it was returned to the bright room again, and the rats were recorded by the bright room. The time to enter the dark room is the memory latency, which mainly reflects the ability of the rat to remember in the near future.
1. 2. 3 open field test (OFT) 60 cm × 60 cm × 60 cm The top of the topless wooden box is divided into 36 small squares. The rats are placed in the central square and recorded within 5 minutes. The number of grids through which the rat was active, the number of hind limbs standing, and the number of grains discharged from the feces. The scoring criteria are: 1/2 of the rats above the body enters the adjacent square with a score of 1 point, and the hind limbs stand for 1 point, which is the total score. The study believes that the number of grids reflects the excitability of the animals; the number of hind limbs standing represents the ability of the rats to adapt to the unfamiliar environment; the number of grains discharged from the feces indicates the degree of tension in the rats [3].
1. 2. 4 Morris water maze (MWM) test The Morris water maze consists of a circular pool (130 cm in diameter, 50 cm high), a camera and an operational analysis system. The circular water surface is divided into four quadrants by two imaginary vertical lines through the center of the circle. The rats were allowed to swim freely for 2 min in the pool the day before the test to familiarize themselves with the environment. For a total of 4.5 d, a circular transparent platform (10 cm in diameter and 28 cm in height) was placed in the middle water of a quadrant. The platform was hidden at 2 cm below the surface of the water and the water temperature was maintained at around 24 °C. Each experiment was carried out 4 times in the morning and afternoon. Each rat was randomly inserted into the water from the midpoint of each quadrant. The rats tried to escape the flood after entering the water. When the platform was found, they stayed on the platform. The image acquisition system automatically Record the incubation period of the rat to find the platform. If the platform is still not found in 120 seconds, the operator will take the rats to the platform for 4 seconds and the incubation period as 120 seconds. The mean of the scores of 4 times in each rat and in the afternoon was analyzed as a time period value (I2 IX). The strategies of rats searching for platforms are divided into linear, trending, random and edge [1]. From the perspective of the efficiency of the search platform, the order of the four strategies is linear, trending, random, and edge.
1. 3 Statistical processing Measurement data are expressed as mean ± standard deviation ( . x ± s ). The SPSS 10. 0 statistical software was used for variance analysis, q- test and χ2 test according to the nature of the data. The MWM test was carried out with software analysis for variance analysis. The test level was α=0.05.
2 results
2. 1 Changes in learning and memory in PAT In the FD group, the number of errors was the lowest in the FD group, which was significantly different from the NS and FS groups ( q = 6.63, 6.29; P < 0.01). After 24 h, the memory latency of the FD group was the longest, which was significantly different from the NS and FS groups ( q = 5.76, 6. 03; P < 0.01). It indicates that FDP has a protective effect on the recent learning and memory impairment caused by recurrent febrile seizures. See Table 1.
2. 2 Changes in emotional behavior in OFT The FD group had the highest score in the penetrating score, the most hind leg standing, and the least number of fecal pellets discharged in 5 min; the FD group was in the NS and FS groups in the trellis score ( q) = 4. 89 , 4. 63 ; P < 0. 01) , the number of hindlimb standing ( q = 5. 38 , 5. 07 ; P < 0.01) and the number of discharged feces ( q = 5. 81 , 5. 64 ; P < 0. 01) The difference is significant, suggesting that FDP can improve the abnormal behavior of rats caused by repeated seizures. See Table 1.
2. Changes in spatial learning ability in 3 MWM trials The ability of FD rats to find hidden platforms in the Morris water maze was improved, and the escape latency was significantly shortened. The analysis of variance showed that the FD group had significant escape latencies with the NS and FS groups. Statistical difference ( F = 133. 19, P < 0.01). see picture 1 .
In the Morris water maze test, the FD group searched the station with the highest frequency and percentage, while the edge strategy searched the station with the lowest frequency and percentage, indicating that the FD group search platform is the most efficient. The χ2 test showed significant statistical differences in the search strategy between the FD group and the other two groups (χ2 = 50.51, P < 0.005 ); the FD group was the same as the FS group (χ2 = 40.50, P <0. 005). There were also significant statistical differences between the NS group and the NS group (χ2 = 42.72, P < 0.005 ). The above results suggest that FDP can improve the spatial learning and memory impairment in rats caused by repeated seizures. See Table 2.
3 Discussion
A number of long-term follow-up studies have found that FS has a certain relationship with abnormal emotional behavior, learning difficulties, mental retardation, and temporal lobe epilepsy [4,5]. Animal experiments have shown that repeated FS can lead to different degrees of damage in the function of immature brain [1] (learning memory and emotional behavior) and morphological structure [2] (neurons, organelles). Research on FS brain injury interventions has received attention. In this study, pre-injection of FDP was performed on young rats with recurrent febrile seizures. FDP improved learning, memory and emotional behavior in rats with recurrent seizures, suggesting that FDP has protective effects on FS brain function damage.
3. 1 Clinical application and mechanism of FDP FDP is an important intermediate in glucose metabolism, which activates the rate-limiting enzymes in phosphoglycology, phosphofructokinase and pyruvate kinase, and accelerates the phosphoketene pyruvate. Pyruvate conversion increases intracellular energy. FDP interacts with cell membrane to change membrane ion permeability, which can effectively prevent "calcium overload" of smooth muscle cells, neurons, platelets, nerve cells and cardiomyocytes, and improve activation of Na + 2K+ pump. Active, prevent cell edema [6], with membrane stability, cell protection, antioxidant and improve oxygen metabolism. FDP has been widely used in the adjuvant treatment of myocardial damage, and it has also been applied to the treatment and research of liver, kidney and cerebrovascular diseases [7,8]. The neuroprotective mechanism of FDP is mainly [9～11]: 1FDP acts as a regulator of high-energy substances and glycolysis, and participates in cell metabolism to increase the amount of ATP produced by anaerobic metabolism of brain tissue; 2Improve ion pump energy and inhibit Ca2 + influx, stabilize intracellular Ca2+, maintain internal environment stability; 3 promote sugar anaerobic glycolysis, inhibit aerobic oxidation, thereby reducing the production of oxygen free radicals and harmful amino acids; 4 increase red blood cell 2,32 diphosphate glycerate The content of the red blood cell membrane is stabilized, and the utilization of oxygen by the anoxic tissue is increased. In addition, FDP reduces the expression of early gene protein mRNA in the brain after hypoxia, inhibiting apoptosis and neuronal necrosis [12]; FDP also has a role in improving and regulating the cellular signaling pathway [13].
3. 2 FDP protection against convulsive brain injury Repeated multiple febrile seizures, the brain is in hypoxia and relative ischemic state, more sensitive to hypoxic-ischemic hippocampus. Hypoxia caused by frequent seizures can cause pathological changes in mitochondria, swelling and even vacuolization, and ATP deficiency in cells, impairing the function of various channels that maintain intracellular and extracellular ion balance, especially ATP-dependent Ca2+ channels. Involved, the Ca2+ outflow is blocked and reverse inflow occurs. The calcium load caused by Ca2+ influx and the massive release of various excitatory amino acids and free radicals excited by it eventually lead to neuronal degeneration and necrosis; excitatory nerve The massive release under neurotransmitter stress and the weakening of synaptic contact function in hypoxic state increase the abnormal excitation discharge of neurons, which can also trigger the occurrence of convulsions and form a vicious circle [2]. FDP is an important energy substance that can reach the tissues and cells of the central nervous system through various biofilms and blood-brain barriers, providing ion pump activity and energy required for neuronal metabolism, ensuring the outflow of Ca2+ under normal conditions, preventing Ca2 + reverse influx; promote oxygen-carrying red blood cells release oxygen in hypoxic tissue, increase oxygen content in hypoxia, relieve hypoxia; increase glycerol diphosphate content in red blood cells, inhibit oxygen free radicals and histamine release effect. It is speculated that the comprehensive participation of the above mechanisms can reduce the damage of convulsive nerve cells and improve brain function such as learning and memory.