Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model

Abstract

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.

Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice

“…The current study demonstrated that OB induced hyperactivity in mice and decreased the time spent in the central zone of the open field test (OFT), mimicking symptoms of human depression. Our findings are consistent with previous studies and confirm that the olfactory bulb removal procedure was performed correctly [ 25 , 28 , 29 ]. The OFT is commonly used in animal research on the neurobiological basis of depression and anxiety, as well as for screening potential drug targets of these conditions [ 30 , 31 ].…”

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress

“…Notably, the superfusion of prefrontocortical and hippocampal slices with AOPCP (100 μM) reverted the decreased LTP magnitude triggered by repeated stress: thus, AOPCP recovered LTP magnitude both in prefrontocortical slices (17.18 ± 3.76% without and 38.97 ± 3.35% with AOPCP; t = 4.324, p < 0.002, n = 6) (Figure 4B,C) and in hippocampal slices (46.92 ± 3.13% without and 71.64 ± 4.19% with AOPCP; t = 4.730, p = 0.001, n = 6) from stressed rats (Figure 4E,F). The impact of blocking CD73 activity has mostly been associated with the elimination of the formation of ATPderived extracellular adenosine, but guanine nucleotides may also be involved in the effects of AOPCP in the stressed brain given that stressful conditions can trigger the release of guanine nucleotides 83,84 that can also be converted by CD73 into guanosine 85 to exert an antidepressant-like action 86 and modify neuronal function also through A 2A R. 87 To directly probe if the effect of AOPCP specifically involved extracellular adenosine, we tested the effect of AOPCP in the presence of adenosine deaminase to selectively remove endogenous extracellular adenosine. We observed that, whereas AOPCP recovered LTP magnitude in hippocampal slices of stressed rats (Figure 4E,F), AOPCP was devoid of effects on LTP magnitude in the presence of 2 U/mL adenosine deaminase (69.99 ± 3.97% without and 66.62 ± 4.95% with AOPCP; t = 0.7221, p = 0.497, n = 4), thus arguing for a critical involvement of extracellular adenosine in the effect of AOPCP.…”

Detecting Fear-Memory-Related Genes from Neuronal scRNA-seq Data by Diverse Distributions and Bhattacharyya Distance

“…The enrichment of the mitochondrial acetyl-CoA biosynthetic process from pyruvate supports the long-term hypothesis that neurons themselves may de novo format transmitter glutamate from pyruvate carboxylation in vivo, leading to synthesis of TCA cycle intermediates, and thus keep the stable density of glutamate in neurons [ 72 , 73 ]. Although the activation-induced oxidative metabolism and glycolysis in neurons has been reported in early research [ 74 , 75 , 76 , 77 ], this is the first time that the regulation of such processes are observed from scRNA-seq data analysis.…”