Guanosine In Vivo Administration Improves Mitochondrial Membrane Potential and Respiratory Capacity in the Mouse Prefrontal Cortex

Brain homeostasis depends on mitochondrial function and adequate substrate availability. Guanosine (GUO), a naturally occurring purine nucleoside, has emerged as a neuromodulator with neuroprotective properties; however, its impact on mitochondrial bioenergetics across distinct brain regions remains poorly understood. Male Swiss mice (3 months old) were treated with GUO (8 mg/kg) by voluntary oral consumption for 26 days. Mitochondrial function was assessed in the prefrontal cortex and hippocampus using fluorescence-based assays for mitochondrial membrane potential and DCF-detectable reactive species, high-resolution respirometry, and enzymatic activity assays. Behavioral performance was evaluated using the open-field test and the novel object recognition (NOR) task. GUO increased mitochondrial membrane potential in the prefrontal cortex. In addition, GUO-treated mice showed higher prefrontal cortical OXPHOS capacity and maximal electron transfer system (ETS) capacity, supporting increased mitochondrial respiratory capacity in this brain region. This prefrontal cortical mitochondrial profile occurred without parallel changes in citrate synthase activity, NADH dehydrogenase activity, complex II activity, or complex IV activity. The evaluated hippocampal bioenergetic parameters remained without detectable GUO-associated changes under the present experimental conditions. Behavioral analyses did not indicate GUO-associated changes in locomotor activity or recognition memory performance in the NOR task. These findings indicate that chronic GUO administration increases prefrontal cortical mitochondrial membrane potential and respiratory spare capacity, while supporting the need for further studies to determine whether these mitochondrial changes translate into functional protection under pathological or metabolic stress conditions.