Evaluation of the Effect of Hypericum triquetrifolium Turra on Memory Impairment Induced by Chronic Psychosocial Stress in Rats: Role of BDNF

Abstract

Background: Chronic psychosocial stress impairs memory function and leads to a depression-like phenotype induced by a persistent status of oxidative stress. Hypericum perforatum L. (St. John's wort) is widely used to relieve symptoms of anxiety and depression; however, its long-term use is associated with adverse effects. Hypericum triquetrifolium Turra is closely related to H. perforatum. Both plants belong to Hypericaceae family and share many biologically active compounds. Previous work by our group showed that methanolic extracts of H. triquetrifolium have potent antioxidant activity as well as high hypericin content, a component that proved to have stress-relieving and antidepressant effects by other studies. Therefore, we hypothesized that H. triquetrifolium would reduce stress-induced cognitive impairment in a rat model of chronic stress.

Objective: To determine whether chronic treatment with H. triquetrifolium protects against stress-associated memory deficits and to investigate a possible mechanism.

Methods: The radial arm water maze (RAWM) was used to test learning and memory in rats exposed to daily stress using the resident-intruder paradigm. Stressed and unstressed rats received chronic H. triquetrifolium or vehicle. We also measured levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, cortex and cerebellum.

Results: Neither chronic stress nor chronic H. triquetrifolium administration affected performance during acquisition. However, memory tests in the RAWM showed that chronic stress impaired different post-encoding memory stages. H. triquetrifolium prevented this impairment. Furthermore, hippocampal BDNF levels were markedly lower in stressed animals than in unstressed animals, and chronic administration of H triquetrifolium chronic administration protected against this reduction. No significant difference was observed in the effects of chronic stress and/or H. triquetrifolium treatment on BDNF levels in the cerebellum and cortex.

Conclusion: H. triquetrifolium extract can oppose stress-associated hippocampus-dependent memory deficits in a mechanism that may involve BDNF in the hippocampus.

Keywords: BDNF; Hypericum triquetrifolium; hippocampus; learning; memory; methanolic extract; stress.

Figure 1

Experimental procedure for the different experimental groups. Animals were assigned to four groups at random: Control, Hypericum, sts and sts/Hypericum. The sts and sts/Hypericum groups were exposed to chronic daily psychosocial stress using the resident–intruder model for 9 weeks. H. triquetrifolium (50 mg/kg/day i.p.) was administered daily for 9 weeks in the Hypericum and sts/Hypericum groups. Control and sts groups received the vehicle without plant extract once daily for 9 weeks. Behavioral assessment of spatial working and reference memory commenced at week 10.

Figure 2

Structures of rutin (A) and hypericin (B).

Figure 3

Performance in the radial arm water maze task (days 1–5). (A) The last acquisition trial (T12) represents the learning or acquisition phase, which was followed by (B) the 30 min, (C) 5 h and (D) 24 h memory tests. The sts group showed a significant performance deficit (more errors) in the 30 min and 5 h memory tests, which was reversed by chronic H. triquetrifolium administration. Values are means ± SEM (n = 12–15 rats per group); *p ≤ 0.05.

Figure 4

Memory function measured by days to criterion (DTC) (no errors in two consecutive days) for (A) trials 12, which is the last trail in the acquisition (learning) phase, (B) 30 min short-term memory test, (C) 5 hrs, and (D) 24 hrs long-term memory test. The sts group showed a significantly higher DTC than the control group, indicating that chronic stress impaired 30 min short-term memory. This effect was reduced by chronic H. triquetrifolium administration. Values are mean ± SEM (n = 12–15 rats per group); *p ≤ 0.05.

Figure 5

BDNF levels in the hippocampus, cerebellum, and cortex of rats in the Control, Hypericum, sts and sts/Hypericum groups. (A) Chronic stress reduced the levels of BDNF in the hippocampus; this was reversed by H. triquetrifolium. (B, C) No differences in BDNF levels were observed between groups in the cerebellum (B) or cortex (C). Values are means ± SEM (n = 12–15 rats per group); *p ≤ 0.05.

Scheme 1

Extraction and fractionation scheme of the methanolic extract of the aerial parts of H. triquetrifolium.