Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation

Abstract

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

Tauroursodeoxycholic acid produces antidepressant‐like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation, oxido‐nitrosative stress, and endoplasmic reticulum stress

“…For example, disturbance of brain hydrogen sulfide generation has been shown to promote the formation of depression-like behaviors via induction of ER stress [57]. In addition, sodium phenylbutyrate, a well-known inhibitor of ER stress, is reported to abrogate depression-like behaviors induced by chronic restraint stress via attenuation of neuroinflammation, oxido-nitrosative stress, and ER stress [22]. Our results regarding the improvement effects of TUDCA on mice depression-like behaviors further support the role of neuroinflammation, oxido-nitrosative stress, and ER stress in depression formation.…”

Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade

“…1. SPB was prepared freshly in saline everyday, and the selected doses of SPB and LPS were chosen based on the previous study performed in our laboratory [3,18]. On the seventh day, LPS (0.83 mg/kg) was administrated into mice 30 min after drug administration.…”

“…Sodium phenylbutyrate (SPB) is a low molecular weight fatty acid that is approved by FDA for the treatment of urea cycle disorders in human. Numerous studies revealed the ER stress inhibition capacity of SPB in different animal models [16][17][18][19]. SPB acts as a chemical chaperone that supports the posttranslational modification, folding of unfolded proteins, and thereby, reduces the protein-folding load of ER.…”

Phenylbutyrate ameliorates prefrontal cortex, hippocampus, and nucleus accumbens neural atrophy as well as synaptophysin and GFAP stress in aging mice

“…Several reports using the MWM test, a test used to assess spatial learning and memory, have shown that aging reduces both spatial learning and memory (Eichenbaum et al, 2017; Jordan, 2020). In agreement with previous reports in adult mice (Jangra et al., 2017; Xu et al., 2015; Yao et al., 2014), our results suggest that the PBA improves the response of the old mice, in the MWM test, for both the learning and for the memory process. This cognitive improvement was not related to an increase in locomotor activity in a new environment.…”

“…How PBA increases the number of dendritic spines of the pyramidal neurons of the PFC, the CA1 subregion of the hippocampus and medium spiny neurons of the NAcc in old mice is not known at the present time. However, several reports have suggested that PBA has anti‐inflammatory and antioxidant properties (Jangra et al., 2017; Wang, Zhang, Jiang, & Zhang, 2018; Zeng et al., 2017). In addition, recent reports also suggest that PBA reduces endoplamasmic reticulum (ER) stress (for review see Khan, Komarya, & Jena, 2017).…”