Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line

Abstract

Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress-induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress-induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.

Serum Growth Differentiation Factor 15 in Parkinson Disease

“…In addition, oxidative stress is a key mechanism contributing to the higher incidence of PD in men than women. Evidence has indicated that testosterone can increase neurotoxicity induced by oxidative stress in dopamine neurons through a putative membrane androgen receptor [50]. …”

Use of illicit amphetamines is associated with long-lasting changes in hand circuitry and control

“…The elevated corticomotoneuronal excitability in male amphetamine users but not female amphetamine users could be related to levels of gonadal steroid hormones. Testosterone is toxic to dopaminergic neurons experiencing oxidative stress in cell culture (Holmes et al, 2016), and oxidative stress is present in dopaminergic neurons that have been exposed to amphetamine and/or methamphetamine (Yamamoto et al, 2005). Conversely, estrogen can protect nigrostriatal dopaminergic neurons against neurotoxicity induced by methamphetamine or MPTP (Dluzen et al, 1996, Miller et al, 1996.…”

“…We hypothesised that the magnitude of change in the excitability of the motor cortex and/or corticomotoneuronal projection to the hand, and application of grip force during manipulation of novel objects, would be greater (more abnormal) in male amphetamine users than female amphetamine users. This hypothesis is based on the observation that testosterone is toxic to dopaminergic neurons experiencing oxidative stress (Holmes et al, 2016), and oxidative stress is present in dopaminergic neurons that are exposed to amphetamine and/or methamphetamine (Yamamoto et al, 2005). The results of the current study will further understanding of the long-lasting consequences of amphetamine and ecstasy use on the control of movement, and may broaden discussion on treatment and rehabilitation practices in this population.…”

Is testosterone perspective available for neurodegenerative diseases?

“…Oxidative stress is one of the most significant factors that causes dopaminergic system disturbances. 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].…”

“…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]. Depletion of testosterone by orchieoctomy may increase the oxidative stress in brain.…”