Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels

Abstract

Objective: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats.

Methods: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex.

Results: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats.

Conclusions: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.

Figure 1. Animals received chronic treatment with Hypericum perforatum (hypericum) (20 males, 20 females) or water (20 males, 20 females) once daily during 28 days. 24h after administration of substances, they were submitted to the OF test, NOR test or IA test. A) The same animals were used in the OF and NOR tests [males receiving water or hypericum (n = 10 animals per group) and females receiving water or hypericum (n = 10 animals per group)]. After the NOR test, the animals were killed by decapitation and the brains were removed, with dissection of the hippocampus and frontal cortex for determination of BDNF, NGF, and GDNF levels. Five male and female samples from the water and treatment groups were randomly selected for these analyses. B) A different set of male or female animals receiving water or hypericum (n = 10 animals per group) was used for the IA task. BDNF = brain-derived neurotrophic factor; GDNF = glial cell-line derived neurotrophic factor; IA = inhibitory avoidance; IM = immediate memory; LTM = long-term memory test; NGF = nerve growth factor; NOR = novel object recognition; OF = open-field; STM = short-term memory test.

Figure 2. The open field test was used for assessing locomotor (crossings) and exploratory (rearings) activities after chronic treatment with water or Hypericum perforatum in (A) males (n=10 animals per group) or (B) females (n=10 animals per group). Data represent the mean ± standard error of mean.

Figure 3. The NOR task was used to evaluate recognition memory. Recognition index for the objects in the training and test sessions after treatment with water or Hypericum perforatum appears in (A) for males (n= 10 animals per group) and (B) for females (B) (n= 10 animals per group). Results are presented as means ± standard error of mean of the recognition index. The test session was performed 24 h after the training session. IM = immediate memory; STM = short-term memory; LTM = long-term memory; NOR = novel object recognition. * p < 0.001 different from training test. ^† p < 0.01 different from control group, according to one-way repeated measures ANOVA followed by Tukey's post-hoc test.

Figure 4. The inhibitory avoidance task was used to evaluate aversive memory. Latency time was recorded in training and test sessions after treatment with water or Hypericum perforatum for (A) males (n=10 animals per group) and (B) females (B) (n=10 animals per group). Results are presented as medians ± interquartile ranges (25 and 75). The test session was performed 24 h after the training session. IM = immediate memory; LTM = long-term memory; STM = short-term memory. * p < 0.001 different from training test. ^† p < 0.01 different from control group, according to Kruskal-Wallis test followed by Mann-Whitney U test.

Figure 5. Effects of water or Hypericum perforatum on levels of BDNF (A and B), NGF (C and D) and GNDF (E and F) in hippocampus and frontal cortex of male (n = 5 animals per group) (A, C, E) and female (n = 5 animals per group) (B, D, F) rats. Data represent the mean ± standard error of mean. BDNF = brain-derived neurotrophic factor; GNDF = glial cell-line derived neurotrophic factor; NGF = nerve growth factor; * p < 0.05 according to Student’s t test.