Neuroprotective and anti-stress effect of A68930 in acute and chronic unpredictable stress model in rats

The neurorescuing effect of A68930 (a potent selective D1 agonist) and its role on the regulation of hypothalamus–pituitary–adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25 mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D1 agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.

► Tyrosine hydroxylase and glucocorticoid receptor were analyzed in stress models.
► A68930 normalized the stress-induced alterations in distinct brain regions.
► A68930 inhibits oxidative stress by modulation of antioxidant system.
► A68930 may be of therapeutic use for the treatment of dopamine-related disorders.