The Effect of Environmental Enrichment on Glutathione-Mediated Xenobiotic Metabolism and Antioxidation in Normal Adult Mice

Abstract

Olfactory bulb (OB) plays an important role in protecting against harmful substances via the secretion of antioxidant and detoxifying enzymes. Environmental enrichment (EE) is a common rehabilitation method and known to have beneficial effects in the central nervous system. However, the effects of EE in the OB still remain unclear. At 6 weeks of age, CD-1® (ICR) mice were assigned to standard cages or EE cages. After 2 months, we performed proteomic analysis. Forty-four up-regulated proteins were identified in EE mice compared to the control mice. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes Pathway demonstrated that the upregulated proteins were mainly involved in metabolic pathways against xenobiotics. Among those upregulated proteins, 9 proteins, which participate in phase I or II of the xenobiotic metabolizing process and are known to be responsible for ROS detoxification, were validated by qRT-PCR. To explore the effect of ROS detoxification mediated by EE, glutathione activity was measured by an ELISA assay. The ratio of reduced glutathione to oxidized glutathione was significantly increased in EE mice. Based on a linear regression analysis, GSTM2 and UGT2A1 were found to be the most influential genes in ROS detoxification. For further analysis of neuroprotection, the level of iNOS and the ratio of Bax to Bcl-2 were significantly decreased in EE mice. While TUNEL+ cells were significantly decreased, Ki67+ cells were significantly increased in EE mice, implicating that EE creates an optimal state for xenobiotic metabolism and antioxidant activity. Taken together, our results suggested that EE protects olfactory layers via the upregulation of glutathione-related antioxidant and xenobiotic metabolizing enzymes, eventually lowering ROS-mediated inflammation and apoptosis and increasing neurogenesis. This study may provide an opportunity for a better understanding of the beneficial effects of EE in the OB.

Environmental Enrichment Attenuates Oxidative Stress and Alters Detoxifying Enzymes in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

“…Other previous studies suggested that EE inhibits apoptosis, enhances neuroprotection in the brain of rodent PD models [ 39 , 46 ], and improves neurobehavioral functions in brain disorders including PD [ 13 , 47 ]. It has been suggested that EE can also be the key to provide for the stimulation of various brain regions [ 13 , 48 , 49 , 50 ]. Therefore, the inhibition of apoptosis through protecting cell proliferation of neurogenesis area is a promising therapeutic strategy in the various brain regions of PD.…”

“…In addition, numerous pieces of evidence have demonstrated that precursor cell proliferation was impaired by the onset of PD [41], and that apoptosis was induced by exposure to toxic compounds in PD [42][43][44][45]. Other previous studies suggested that EE inhibits apoptosis, enhances neuroprotection in the brain of rodent PD models [39,46], and improves neurobehavioral functions in brain disorders including PD [13,47]. It has been suggested that EE can also be the key to provide for the stimulation of various brain regions [13,[48][49][50].…”

“…The olfactory bulb acts as an entry site for external materials, delivering signals from the olfactory mucosa, which is directly exposed to the external environment, into the olfactory cortex [ 12 ]. In addition, it provides protection against harmful substances by secreting antioxidant and detoxifying enzymes [ 13 ]. The detoxifying properties of the olfactory bulb play an important role against various neurodegenerative diseases associated with xenobiotics and environmental toxins [ 14 ].…”

“…In a preliminary study investigating the olfactory bulb of normal adult mice, exposure to EE for 2 months resulted in the significant up-regulation of several detoxifying enzymes of phase I and phase II compared with the wild-type control group [ 13 ]. In another study using transgenic PD mice that overexpress human A53T α-synuclein, however, several detoxifying enzymes were found to be significantly increased in the olfactory bulb of PD mice compared to wild-type mice at the early stages of the disease, which were less enhanced in the later stages.…”

Study of silver nanoparticle effects on some molecular responses and metabolic pathways of Phytophthora parasitica

“…Glutathione activity is an important process involved in removing reactive oxygen species (ROS) generated endogenously during xenobiotic metabolism [40]. Glutathione redox is the marker for oxidative stress that plays a crucial role in resisting oxidative stress and maintaining cellular oxidationreduction homeostasis [41].…”