Effects of a matrix metalloproteinase inhibitor on learning and memory function and hippocampal myelin-related proteins in epileptic model rats
10.3760/cma.j.cn371468-20250121-00031
- VernacularTitle:基质金属蛋白酶抑制剂对癫痫模型大鼠学习记忆及海马髓鞘相关蛋白的影响
- Author:
Yang XIAO
1
;
Yanan ZHAO
Author Information
1. 复旦大学附属中山医院神经内科，上海 200032
- Publication Type:Journal Article
- Keywords:
Epilepsy;
Cognitive function;
Myelin sheath;
Blood-brain barrier;
Matrix metalloproteinase;
Rat
- From:
Chinese Journal of Behavioral Medicine and Brain Science
2025;34(6):481-487
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the effects of a matrix metalloproteinase(MMP) inhibitor (ilomastat, GM6001) on learning and memory function and hippocampal myelin-related proteins in epileptic model rats.Methods:Thirty 8-week-old male SPF Sprague-Dawley rats were randomly divided into control group, intervention control group, short-term model group, long-term model group and long-term intervention group, with 6 rats in each group.The lithium-pilocarpine method was used to induce status epilepticus (SE). SE was terminated respectively by intraperitoneal injection of diazepam(10 mg/kg) at 15 min in short-term model group and at 30 min both in the long-term model group and long-term intervention group. Rats in intervention control group and long-term intervention group were treated with GM6001 (20 μg/kg) via tail vein injection. Morris water maze test was used to assess the learning and memory function and the blood-brain barrier permeability was evaluated by Evans blue (EB) staining. The levels of serum MMP, the hippocampal myelin basic protein (MBP) and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) were measured by ELISA and Western blot.Statistical analysis was performed by SPSS 21.0 software, with repeated measures ANOVA for Morris water maze data and one-way ANOVA with LSD post hoc test for other comparisons.Results:(1) In the water maze test, the interaction between the time and group on the latencies reached to the platform showed no significance among the 5 groups of rats ( F=0.430, P=0.970). The main effects of time and group on latencies were both significant among the 5 groups( F=144.521, 12.819, both P<0.001).From the second day to the fifth day, the latencies reached to the platform of rats in the long-term model group were significantly higher than those in the control group and in the long-term intervention group (both P<0.05). There were statistically significant differences in the latency of the first time reached the platform, the duration in the target quadrant, the frequency of crossing the platform and the distance to the platform among the 5 groups ( F=7.008, 7.306, 15.704, 11.559, all P<0.05). In the long-term intervention group, the latency of the first time reached the platform ((13.71±4.41) s) and the distance to the platform ((60.37±8.59) cm) were significantly lower than those in the long-term model group ((23.52±5.34) s, (73.06±12.01) cm) (both P<0.05), and the duration in the target quadrant ((10.93±2.99) s) and the frequency of crossing the platform (2.00(1.75, 2.75)times) were significantly higher than those of the long-term model group ((6.04±4.33) s, 1.00(0, 1.00)times) (both P<0.05).(2) The hippocampal EB fluorescence intensity and the serum levels of MMP-2 and MMP-9 were significantly different among the 5 groups ( F=15.249, 7.951, 33.299, all P<0.001). The EB fluorescence intensity of the long-term model group ((0.18±0.03) /100 μm 2) was significantly higher than that in control group ((0.09±0.02) /100 μm 2) and the long-term intervention group ((0.12±0.04) /100 μm 2) (both P<0.05). The serum MMP-2 and MMP-9 levels in the long-term model group ((10.91±1.36) ng/mL, (10.96±1.28) ng/mL) were significantly higher than those of the control group ((7.89±1.04) ng/mL, (4.20±1.48) ng/mL) and the long-term intervention group ((6.49±1.12) ng/mL, (8.06±0.91) ng/mL) (all P<0.05). (3) The expression levels of hippocampal MBP and CNPase were significantly different among the 5 groups ( F=8.757, 4.116, both P<0.05). The expression levels of MBP and CNPase in long-term model group ((1.00±0.19), (0.93±0.21)) were significantly lower than those in the control group ((1.57±0.27), (1.36±0.22)) and the long-term intervention group ((1.45±0.19), (1.23±0.26)) (all P<0.05). Conclusion:The MMP inhibitor GM6001 can ameliorate learning and memory deficits in epileptic model rats, potentially by reducing blood-brain barrier permeability and alleviating hippocampal myelin damage.
