Testosterone depletion increases the susceptibility of brain tissue to oxidative damage in a restraint stress mouse model

Abstract

Among sex hormones, estrogen is particularly well known to act as neuroprotective agent. Unlike estrogen, testosterone has not been well investigated in regard to its effects on the brain, especially under psychological stress. To investigate the role of testosterone in oxidative brain injuries under psychological stress, we adapted an orchiectomy and restraint stress model. BALB/c mice were subjected to either an orchiectomy or sham operation. After allowing 15 days for recovery, mice were re-divided into four groups according to exposure of restraint stress: sham, sham plus stress, orchiectomy, and orchiectomy plus stress. Serum testosterone was undetectable in orchiectomized groups and restraint-induced stress significantly reduced testosterone levels in sham plus stress group. The serum levels of corticosterone and adrenaline were notably elevated by restraint stress, and these elevated hormones were markedly augmented by orchiectomy. Two oxidative stressors and biomarkers for lipid and protein peroxidation were significantly increased in the cerebral cortex and hippocampus by restraint stress, while the reverse pattern was observed in antioxidant enzymes. These results were supported by histopathological findings, with 4-hydroxynonenal staining for oxidative injury and Fluoro-Jade B staining showing the degenerating neurons. The aforementioned patterns of oxidative injury were accelerated by orchiectomy. These findings strongly suggest the conclusion that testosterone exerts a protective effect against oxidative brain damage, especially under stressed conditions.

Is testosterone perspective available for neurodegenerative diseases?

“…Oxidative stress is described as an unbalanced redox that includes excessive production of reactive oxygen species (ROS) and decreased antioxidant potency, involving enzyme-related activities such as catalase, superoxide dismutase, and the GSH oxidation-reduction system, and several non-enzyme-derived antioxidant substances [13]. Excessive production of ROS may lead to the injury and death of neurons.…”

“…The factor, aging, leads to dopamine auto-oxidation [9] and testosterone may enhance oxidative stress-related neurotoxicity in dopaminergic neurons and then lead to apoptosis [15]. Furthermore, it has been demonstrated that short-term and long-term stress may cause the reduction of blood testosterone levels and modified oxidative redox [13]. On the other hand, testosterone is able to protect against the damage of oxidative stress.…”

“…Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are increasingly spreading worldwide. Neuroinflammation, deposition of misfolded proteins, oxidative stress, mitochondrial dysfunction, and excitotoxicity are main biological processes in the development of neurodegeneration and brain tissue is much more sensitive to oxidative stress than other tissues due to high levels of peroxidizable fatty acids, iron, and limited antioxidant activity [13]. Furthermore, noncoding RNAs, genetic mutations such as PARK1, PARK4, PARK8, PS1, PS2, FTD, APOE, and environmental factors such as pesticides, fungicides, substances from addictive drugs, heavy metals, viruses, might be involved in the development of neurodegeneration ( Figure 2) [18,19].…”

“…Testosterone has bidirectional and converse effects -antioxidant and oxidative stressor-depend on the conditions in the brain [13]. It has been reported that testosterone can enhance oxidative stress-induced neurotoxicity in dopaminergic neurons in rats and then leads to loss of dopamine neurons and neurodegeneration [15].…”

“…Particularly, estrogen exert neuroprotective activity in clinical and animal studies. Estrogen modulates beta-amyloid accumulation and acts as a neuroprotective agent [13]. Furthermore, estrogen has neuroprotective effects on AD and PD.…”