Dimethyl fumarate improves cognitive impairment by enhancing hippocampal brain-derived neurotrophic factor levels in hypothyroid rats

Abstract

Background: Dimethyl fumarate (DMF) is an effective drug for multiple sclerosis and can improve the cognitive dysfunction caused by streptozotocin, but the effect on cognitive dysfunction caused by hypothyroidism is unclear.

Methods: After the hypothyroidism rat model induced by propylthiouracil, we gave rats 25 mg/kg DMF by gavage. The body weight during model building and administration was recorded. The levels of T4 and T3 in serum were detected by an automatic biochemical analyzer. Morris water maze test was used to detect the effect of DMF on cognitive learning ability. The effect of DMF on Nissl bodies in the brain tissue was evaluated by Nissl staining. The mRNA and protein levels of BDNF in brain tissue were detected by quantitative reverse transcription-polymerase chain reaction and Western blot. The degrees of p-AKT/AKT and p-CREB/CREB in brain tissue were detected by Western blot.

Results: After DMF treatment, the body weight of hypothyroid rats recovered, and the levels of T3 and T4 in the serum were ameliorated. DMF also reduced the escape latency and distance traveled, and increased the swim speed. The number of Nissl bodies and expression of BDNF, p-AKT/AKT, and p-CREB/CREB in the brain tissue were increased after DMF treatment.

Conclusion: DMF improved the cognitive dysfunction of hypothyroid rats by increasing the level of BDNF in the brain tissue of hypothyroid rats.

Keywords: Brain-derived neurotrophic factor; Cognitive function; Dimethyl fumarate; Hypothyroidism.

Fig. 1

Comparison of the body weight increment among three groups ($\overline{x}$ ±s, n = 10). ^**P < 0.01 compared with the control group, ^##P < 0.01 compared with the PTU group

Fig. 2

Comparison of serum of thyroid-related hormones levels among three groups ($\overline{x}$ ±s, n = 10). A The content of T3; B the content of T4. ^**P < 0.01 compared with the control group, ^##P < 0.01 compared with the PTU group

Fig. 3

Comparison of the escape latency ($\overline{x}$ ±s, n = 10). A and distance traveled; B to reach the platform and the swim speed (C) between three groups in the Morris water maze test. ^**P < 0.01 compared with the control group; ^##P < 0.01 compared with the PTU group

Fig. 4

Effect of DMF on hippocampal neurons of rats (n = 5). A Representative images showing Nissl bodies in the hippocampal CA1 (× 100, Scale bar = 100 mm; × 400, Scale bar = 50 mm.); B Quantitation of pyramidal cells in the CA1 hippocampal region ($\overline{x}$ ±s). The number of Nissl bodies at the same site in each group of rats under a field of view was counted; C The thickness of granular layer of CA1 region of the hippocampus; The average thickness of granular layer was measured at five random positions in CA1 of each slice in each group under the same field of view. ^**P < 0.01 compared with the control group; ^##P < 0.01 compared with the PTU group

Fig. 5

Effect of DMF on BDNF mRNA expression in hippocampal CA1 region of hypothyroidism rats ($\overline{x}$ ±s, n = 3). ^**P < 0.01 compared with the control group. ^#P < 0.01 compared with the PTU group

Fig. 6

Effect of DMF on BDNF, p-AKT/AKT, p-CREB/CREB protein expression levels in hippocampal CA1 region of hypothyroidism rats ($\overline{x}$ ±s, n = 3). A The protein expression of BDNF; B the relative expression of BDNF protein; C the protein expression of p-AKT/AKT and p-CREB/CREB; D the relative expression of p-AKT/AKT; E the relative expression of p-CREB/CREB. ^**P < 0.01 compared with the control group. ^##P < 0.01 compared with the PTU group. Corresponding uncropped full-length gels and blot can be saw in the supplementary information