Molecular modifications by regulating cAMP signaling and oxidant-antioxidant defence mechanisms, produce antidepressant-like effect: A possible mechanism of etazolate aftermaths of impact accelerated traumatic brain injury in rat model

Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper-emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative-nitrosative stress markers levels, while, significant decreases in antioxidant enzymes markers level were observed. However, no significant change was observed in serum CORT level. Chronic ETZ (0.5 and 1 mg/kg) treatment significantly attenuated TBI-induced behavioral deficits and restored the TBI induced derangements in molecular and biochemical markers. This study indicates that ETZ modulates cAMP signaling and oxidative/antioxidant markers in the TBI model suggesting its prospect as a potential candidate for the pharmacotherapy of depression. (C) 2016 Elsevier Ltd. All rights reserved.