Pharmacological Evaluation of Silymarin and Protocatechuic Acid in Experimentally Induced Depression in Rodents

Abstract

Silymarin and protocatechuic acid (PCA) are naturally occurring polyphenolic flavonoids exhibiting neuroprotection through improving endogenous antioxidant system in rodents. Based on the role of oxidative stress in modulating depressive disorders and the relationship between neuroprotective and antioxidant potential of silymarin and PCA, the main objective of the present study was to investigate possible antidepressant like activity of silymarin and PCA in rodents. The depressive behaviors were induced by acute restraint stress (ARS) in mice, olfactory bulbectomized (OBX) technique in rats and chronic unpredictable mild stress (CUMS) in mice. Normal mice when administered with PCA and silymarin at various doses by orally did not exhibited significant behavioral changes, suggesting both drugs do not induce any effects in non-depressed condition. Animals subjected to ARS, OBX and CUMS stress elicited significant increase in immobility time and exploratory behavior (ambulatory and rearing behavior in OBX and crossing in CUMS). PCA, silymarin and fluoxetine treatment significantly attenuated the immobility time and exploratory behavior in FST and OFT test respectively. Mice exposed to different CUMS paradigms induced significant decrease in body weight, and preference to sucrose solution which were found to be reversed with PCA or silymarin or fluoxetine treatment significantly. The ARS, OBX and CUMS exposed mice and rats showed elevation of serum corticosterone; MDA formation, and depletion of enzymatic and non enzymatic antioxidants namely, SOD, CAT and GSH in cerebral cortex and hippocampus respectively, which were significantly improved with PCA and silymarin treatment. Monoamines 5-HT, DA and NE along with brain derived neurotrophic factor (BDNF) were reduced significantly in hippocampus and cerebral cortex in OBX and CUMS stressed mice and they were augmented subsequently with PCA or silymarin or fluoxetine treatment. The OBX subjected rats and CUMS exposed mice elicited significant elevation of TNF-α and IL-6 in hippocampus and cerebral cortex and the same were attenuated with PCA or silymarin or fluoxetine. CPP-a NMDA competitive antagonist attenuated immobility time in FST, similar to that of silymarin (200 mg/kg). In addition, the attenuated immobility time in FST was not restored with silymarin in CPP pretreated mice, indicating NMDA receptors are not involved in the antidepressant like activity of silymarin in the present study. Thus, the present findings demonstrated that silymarin and PCA exhibited antidepressant like activity probably through alleviating monoaminergic, BDNF, cytokines systems, along with oxidative stress by modulation of corticosterone response, and antioxidant defense system in mice.