Chronic administration of baicalein decreases depression-like behavior induced by repeated restraint stress in rats

Abstract

Baicalein (BA), a plant-derived active flavonoid present in the root of Scutellaria baicalensis, has been widely used for the treatment of stress-related neuropsychiatric disorders including depression. Previous studies have demonstrated that repeated restraint stress disrupts the activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depression. The behavioral and neurochemical basis of the BA effect on depression remain unclear. The present study used the forced swimming test (FST) and changes in brain neurotransmitter levels to confirm the impact of BA on repeated restraint stress-induced behavioral and neurochemical changes in rats. Male rats received 10, 20, or 40 mg/kg BA (i.p.) 30 min prior to daily exposure to repeated restraint stress (2 h/day) for 14 days. Activation of the HPA axis in response to repeated restraint stress was confirmed by measuring serum corticosterone levels and the expression of corticotrophin-releasing factor in the hypothalamus. Daily BA administration significantly decreased the duration of immobility in the FST, increased sucrose consumption, and restored the stress-related decreases in dopamine concentrations in the hippocampus to near normal levels. BA significantly inhibited the stress-induced decrease in neuronal tyrosine hydroxylase immunoreactivity in the ventral tegmental area and the expression of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. Taken together, these findings indicate that administration of BA prior to the repeated restraint stress significantly improves helpless behaviors and depressive symptoms, possibly by preventing the decrease in dopamine and BDNF expression. Thus, BA may be a useful agent for the treatment or alleviation of the complex symptoms associated with depression.

Keywords: Baicalein; Chronic stress; Depression; Dopamine; Hypothalamus-pituitary-adrenal axis.

Fig. 1

Experimental schedule of developing repeated restraint stress-induced depression-like behaviors and administration of BA in the rats. IHC, immunohistochemistry.

Fig. 2

Effect of BA administration on body weight (A), serum corticosterone levels (B), and sucrose intake (C) of rats subjected to repeated restraint stress for 14 consecutive days. ^*p<0.05, ^**p<0.01, ^***p<0.001 vs. the SAL group; ^#p<0.05, ^##p <0.01 vs. the STR group.

Fig. 3

Effect of BA administration on immobility time (A), climbing behavior (B), and swimming behavior (C) in the forced swimming test during repeated restraint stress for 14 consecutive days. ^*p<0.05 vs. the SAL group; ^#p<0.05 vs. the STR group.

Fig. 4

Effect of BA administration on activity counts of locomotor activity in the open-field test during repeated restraint stress.

Fig. 5

Effect of BA administration on the mean number of corticotrophin-releasing factor (CRF) expression in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) expression in the ventral tegmental area (VTA). Representative photographs and the relative percentage values are indicated in (A~C), respectively. (a): CRF expression of hypothalamus in the SAL group, (b): CRF expression of hypothalamus in the STR group, (c): CRF expression of hypothalamus in the STR+BA40 group, (d): TH expression of VTA in the SAL group, (e): TH expression of VTA in the STR group, and (f): TH expression of VTA in the STR+BA40 group. The scale bar indicates 50 µm. ^**p<0.01 vs. the SAL group; ^#p<0.05 vs. the STR group.

Fig. 6

Effect of BA administration on dopamine (A) and serotonin (B) concentration in the hippocampus and medical prefrontal cortex of rats subjected to repeated restraint stress for 14 consecutive days. ^*p<0.05, ^**p<0.01 vs. the SAL group; ^#p<0.05 vs. the STR group.

Fig. 7

Effect of BA administration on the expression of (BDNF) mRNA in rats subjected to repeated restraint stress for 14 consecutive days. PCR bands on agarose gel and their relative intensities are indicated in (A) and (B), respectively. The expression levels of BDNF mRNA were normalized to that of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA as an internal control. ^**p<0.01 vs. the SAL group; ^#p<0.05 vs. the STR group.