Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress

Abstract

Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Moreover, the significantly increased levels of hippocampal malondialdehyde (MDA; an indicator of lipid peroxidation), induced by ARS were not observed in stressed mice treated with guanosine. Although no changes were found in the hippocampal levels of reduced glutathione (GSH), the group submitted to ARS procedure presented enhanced glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) activities and reduced catalase (CAT) activity in the hippocampus. Guanosine was able to prevent the alterations in GPx, GR, CAT activities, and in SOD/CAT activity ratio, but potentiated the increase in SOD activity elicited by ARS. Altogether, the present findings indicate that the observed antidepressant-like effects of guanosine might be related, at least in part, to its capability of modulating antioxidant defenses and mitigating hippocampal oxidative damage induced by ARS.

Guanosine and its role in neuropathologies

“…This antioxidant activity may be related, at least partially, to its ability to stimulate the endogenous antioxidant response. This hypothesis is in agreement with previous studies showing that this nucleoside can induce an increase in the expression and/or activity of endogenous antioxidant enzymes such as HO-1 [92,100] and superoxide dismutase (SOD) [97].…”

“…In addition, we also demonstrated that this behavioral effect of guanosine appears to be dependent, at least in part, on the antioxidant properties of this nucleoside, since the guanosine-induced amelioration of the depressive-like behavior was accompanied by a reduction in oxidative stress through the restoration of the normal activity of endogenous antioxidant enzymes in the hippocampus. In particular, guanosine caused a significant increase in the activity of superoxide dismutase (SOD) in mice submitted to ARS, reinforcing the notion that some of the protective effects of this nucleoside are only observed following an initial insult [97]. Recently, we also found that chronic treatment (21 days) with guanosine has an antidepressant-like effect in the TST, which is likely unrelated to its acute effect, since in this study animals were tested 24 h after receiving the last guanosine dose.…”

“…1), it is not surprising that this nucleoside was shown to be neuroprotective both in vitro and in vivo against a plethora of different insults, including excitotoxins [95,96], apoptosis induced by staurosporine [86], stress-induced oxidative damage [97], sepsis-induced cognitive impairment [98], hepatic encephalopathy [99], azide-induced oxidative damage [100], lipopolysaccharide (LPS)-induced inflammation [94], ischemic damage [63,101,102], toxicity induced by amyloid β peptide (Aβ) [91,103] as well as 1-methyl-4-phenylpyridinium (MPP + ) and 6-hydroxydopamine (6-OHDA) [36,[104][105][106], and spinal cord injury (SCI) [107,108]. Based on these studies, the modulation of the purinergic system has emerged as a therapeutic approach for the treatment of various neurological conditions, and guanosine in particular may be a therapeutic target for several of these neuropathologies.…”

Near-infrared photobiomodulation combined with coenzyme Q10 for depression in a mouse model of restraint stress: reduction in oxidative stress, neuroinflammation, and apoptosis

“…As a result of immobilization, the incidence of some neurochemical alterations in the brain can lead to neurobehavioral deficits such as immobility in the FST and TST (Wang, et al, 2016; Xu et al, 2017). The latter behavioral tests are widely employed to screen the efficiency of antidepressant drugs (Bettio et al, 2014; Cryan et al, 2005; Porsolt, et al, 1977). In agreement with other reports (Bettio, et al, 2014; Freitas et al, 2014), five days of sub-chronic restraint stress in our study resulted in an increase in the immobility time as compared to the control animals.…”

Protective effects of carnosol against oxidative stress induced brain damage by chronic stress in rats

“…Regarding these parameters, the decreased GPx and GR activities were found in the hippocampus of rats submitted to the chronic restraint stress procedure, a response that is probably related to an increase in the ROS production following the chronic stressor or decrease in the antioxidant production [35]. The overproduction of superoxide anion (O2•−) is one of the main factors involved in the stress-induced oxidative damage in the brain [36]. The present study has been indicated that the hippocampal activity of SOD was decreased in the rats submitted to chronic restraint stress.…”