Curcumin alleviates orofacial allodynia and improves cognitive impairment via regulating hippocampal synaptic plasticity in a mouse model of trigeminal neuralgia

Abstract

Objective: Cognitive impairment, one of the most prevalent complications of trigeminal neuralgia, is troubling for patients and clinicians due to limited therapeutic options. Curcumin shows antinociception and neuroprotection pharmacologically, suggesting that it may have therapeutic effect on this complication. This study aimed to investigate whether curcumin alleviates orofacial allodynia and improves cognitive impairment by regulating hippocampal CA1 region synaptic plasticity in trigeminal neuralgia.

Methods: A mouse model of trigeminal neuralgia was established by partially transecting the infraorbital nerve (pT-ION). Curcumin was administered by gavage twice daily for 14 days. Nociceptive thresholds were measured using the von Frey and acetone test, and the cognitive functions were evaluated using the Morris water maze test. Dendritic spines and synaptic ultrastructures in the hippocampal CA1 area were observed by Golgi staining and transmission electron microscopy.

Results: Curcumin intervention increased the mechanical and cold pain thresholds of models. It decreased the escape latency and distance to the platform and increased the number of platform crossings and dwell time in the target quadrant of models, and improved spatial learning and memory deficits. Furthermore, it partially restored the disorder of the density and proportion of dendritic spines and the abnormal density and structure of synapses in the hippocampal CA1 region of models.

Conclusion: Curcumin alleviates abnormal orofacial pain and cognitive impairment in pT-ION mice by a mechanism that may be related to the synaptic plasticity of hippocampal CA1, suggesting that curcumin is a potential strategy for repairing cognitive dysfunction under long-term neuropathic pain conditions.

Keywords: chronic pain; cognitive impairment; curcumin; hippocampal CA1 region; synaptic plasticity.

Figure 1

The time course of pT-ION induced orofacial allodynia. (A) The schematic diagram of orofacial branch of the trigeminal nerve and pT-ION surgery. (B) and (C) showed the primary and secondary mechanical hyperalgesia induced by pT-ION in the ipsilateral facial V2 and V3 area, respectively. (D) showed the secondary cold allodynia in the ipsilateral facial V3 area. N = 8 mice/group. ^***P < 0.001 vs. naive group, two-way ANOVA and Tukey’s test.

Figure 2

The learning and memory impairment induced pT-ION mice. The training trials were performed for 4 consecutive days (days 24, 25, 26, and 27 after pT-ION). The probe test was performed after the training (day 28 after pT-ION). (A) Time to reach the hidden platform. (B) Total swimming distance during the trial. (C) Tracks of the mice in the probe test on the fifth day. (D) Number of times the mice crossed over the platform. (E) Spending time to target zone area. N = 8 mice/group. ^*P < 0.05, ^**P < 0.01 and ^***P < 0.001 vs. naive group, (A, B): two-way ANOVA and Tukey’s test, (C–E): one-way ANOVA and Dunnett test.

Figure 3

The effect of curcumin on orofacial allodynia induced by pT-ION. (A) The primary mechanical hyperalgesia in area V2. (B) The secondary mechanical hyperalgesia in area V3. (C) The secondary cold allodynia in area V3. N = 8 mice/group. ^*P < 0.05 and ^***P < 0.001 vs. sham group; ^###P < 0.001 vs. pT-ION group, one-way ANOVA and Tukey’s test.

Figure 4

The effect of curcumin on learning and memory impairment in pT-ION mice. (A) Time to reach the hidden platform. (B) Total swimming distance during the trial. (C) Tracks of the mice in the probe test. (D) Number of times the mice crossed over the platform. (E) Spending time to target zone area. N = 8 mice/group. ^*P < 0.05, ^**P < 0.01 and ^***P < 0.001 vs. sham group; ^#P < 0.05, ^##P < 0.01 and ^###P < 0.001 vs. pT-ION group, (A, B): two-way ANOVA and Tukey’s test, (C–E): one-way ANOVA and Tukey’s test.

Figure 5

The role of curcumin on the decrease of dendritic spine density induced by pT-ION in the mice hippocampal CA1 region. (A) The representative Golgi-Cox-staining images showing the density and morphology of dendritic spines in the cone cell layer of hippocampal CA1 region in each group (scale bar: 5 μm). (B) The analysis of total dendritic spine density in each group. (C) The analysis of mushroom-type dendritic spine density in each group. N = 8 mice/group. ^*P < 0.05 and ^***P < 0.001 vs. sham group; ^###P < 0.001 vs. pT-ION group, one-way ANOVA and Tukey’s test.

Figure 6

The protective effects of curcumin on the density and ultrastructure of synapses of hippocampal CA1 region in pT-ION mice. (A) Representative TEM images showing the density and ultrastructure of synapses of hippocampal CA1 region in each group (scale bar: 1 μm and 200 nm). Bar graphs showing the number of synapses/25 μm² (B), the thickness of the PSD (C), the length of the synaptic active zone (D), the width of the synaptic cleft (E), and the curvature of the synaptic interface (F) in each group. N = 8 mice/group. ^*P < 0.05 and ^***P < 0.001 vs. sham group; ^#P < 0.05, ^##P < 0.01 and ^###P < 0.001 vs. pT-ION group, one-way ANOVA and Tukey’s test.