Abstract graphic.
The BDNF-TrkB signaling pathway and its downstream cascades are involved in the synthesis of synapses which then regulates learning and memory. Intraperitoneal injection of LPS damages the BDNF-TrkB signaling pathway and its downstream cascade leading to cognitive dysfunction. 7,8-DHF can penetrate the blood-brain barrier and activate TrkB receptors, alleviating learning and memory deficits.
Figure 1. Behavioral tests and pro-inflammation levels in LPS mice. (A-C) There was no significant difference in the time spent in exploring the same objects between the Control and LPS mice during the training phase. In the testing phase, when exposed to the novel object, LPS mice spent less time on the novel object and presented lower discrimination ratio compared with the Control group (n=10). (D) Compared to the Control mice, the concentration of IL-1β, IL-6 and TNF-α serum levels were significantly increased in LPS mice (n=4). Data are presented as mean ± SEM. *P < 0.05; **P< 0.01; ****P < 0.0001.
Figure 2. The protein levels of the BDNF-TrkB signaling pathway and its downstream cascades in the hippocampus. (A-D) Compared with the Control mice, the levels of BDNF and p-TrkB proteins were decreased in LPS mice, no difference was found in the expression of TrkB (n=4). (E-G) The protein level of Bax was increased and the level of Bcl-2 was reduced in the LPS group compared to the Control group (n=4). (H-S) The protein expression of p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 in LPS mice was lower than in Control mice. There was no statistical difference in the levels of ERK1/2, CaMK2, CREB and GluR1 proteins between the Control and LPS groups (n=4). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 3. The protein levels of the BDNF-TrkB signaling pathway and its downstream cascades in the mPFC. (A-D) The protein levels of BDNF and p-TrkB were reduced in LPS mice compared to the Control mice, and no difference was found in the level of TrkB between these two groups (n=4). (E-G) Compared with the Control group, the expression of Bax was increased and the level of Bcl-2 was decreased in LPS group (n=4). (H-S) The expression of p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 in LPS mice were downregulated. There was no statistical difference in the levels of ERK1/2, CaMK2, CREB and GluR1 proteins between the Control and LPS groups (n=4). Data are presented as mean ± SEM. *P< 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
Figure 4. The protein levels of the BDNF-TrkB signaling pathway and its downstream cascades in the EC. (A-D) The expression of BDNF and p-TrkB were decreased in LPS mice compared to Control mice, and no statistical difference was observed in the expression of TrkB between these two groups (n=4). (E-G) The level of Bax was up-regulated and the level of Bcl-2 was decreased in the LPS group compared to Control mice (n=4). (H-S) The expression of p-CaMK2 and p-CREB was decreased in LPS mice. There was no significant difference in protein levels of ERK1/2, p-ERK1/2, CaMK2, CREB, GluR1 and p-GluR1 between the Control and LPS groups (n=4). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01.
Figure 5. 7,8-DHF alleviated LPS-induced learning and memory deficits in the mice. (A-C) During the training phase, there was no statistical difference in the time spent with objects after using 7,8-DHF or ANA12 in LPS mice. In the testing phase, the time spent on the novel object and the discrimination ratio were increased in LPS mice after administration of 7,8-DHF, however, ANA12 completely reversed the effects of 7,8-DHF (n=10). Data are presented as mean ± SEM. ***P< 0.001; ****P < 0.0001; N.S. P> 0.05.
Figure 6. 7,8-DHF restored the LPS-induced BDNF-TrkB signaling pathway and its downstream cascade disorders in the hippocampus. (A-D) There were no statistical changes in the expression of BDNF and TrkB in LPS mice after using 7,8-DHF or ANA12. The expression of p-TrkB was increased in LPS mice after using 7,8-DHF, however, ANA12 reversed the effects of 7,8-DHF (n=5). (E-G) 7,8-DHF decreased the expression of Bax and increased the level of Bcl-2 in LPS mice, while ANA12 completely reversed these changes (n=5). (H-S) The expression of p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 in LPS mice was increased after using 7,8-DHF, however, ANA12 reversed the effects of 7,8-DHF. No statistical differences were observed in protein levels of ERK1/2, CaMK2, CREB and GluR1 in LPS groups after using 7,8-DHF or ANA12 (n=5). Data are presented as mean ± SEM. *P < 0.05; **P< 0.01; ***P < 0.001; N.S. P> 0.05.
Figure 7. 7,8-DHF restored the LPS-induced BDNF-TrkB signaling pathway and its downstream cascades disorder in the mPFC. (A-D) There were no significant differences in protein levels of BDNF and TrkB in LPS mice after administration of 7,8-DHF or ANA12. The level of p-TrkB was increased in LPS mice after administration of 7,8-DHF, however, ANA12 reversed the effects of 7,8-DHF (n=5). (E-G) The level of Bax was reduced and the level of Bcl-2 was increased in LPS mice after administration of 7,8-DHF, while ANA12 completely reversed these changes (n=5). (H-S) The levels of p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 in LPS mice were increased after administration of 7,8-DHF, however, ANA12 reversed the effects of 7,8-DHF. There were no statistical differences in protein levels of ERK1/2, CaMK2, CREB and GluR1 in LPS groups after administration of 7,8-DHF or ANA12 (n=5). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; N.S. P > 00.5.
Figure 8. 7,8-DHF restored the LPS-induced BDNF-TrkB signaling pathway and its downstream cascade disorder in the EC. (A-D) No statistical difference was observed in the expression of BDNF and TrkB in LPS mice after using 7,8-DHF or ANA12. 7,8-DHF clearly increased the expression of p-TrkB in LPS mice, while ANA12 reversed the therapeutic effects of 7,8-DHF (n=5). (E-G) 7,8-DHF reduced the level of Bax and increased the level of Bcl-2 in the LPS group, however, ANA12 reversed these changes (n=5). (H-S) The expression of p-CaMK2 and p-CREB was increased in LPS mice after administration of 7.8-HDF, while ANA12 completely reversed the effects of 7,8-DHF. There was no significant difference in protein levels of ERK1/2, p-ERK1/2, CaMK2, CREB, GluR1 and p-GluR1 in LPS groups after using 7,8-DHF or ANA12 (n=5). Data are presented as mean ± SEM. *P < 0.05; **P< 0.01; ***P < 0.001; N.S. P> 00.5.