Androgens activate mitogen‐activated protein kinase signaling: Role in neuroprotection

Abstract

Recent evidence indicates that testosterone is neuroprotective, however, the underlying mechanism(s) remains to be elucidated. In this study, we investigated the hypothesis that androgens induce mitogen-activated protein kinase (MAPK) signaling in neurons, which subsequently drives neuroprotection. We observed that testosterone and its non-aromatizable metabolite dihydrotestosterone (DHT) rapidly and transiently activate MAPK in cultured hippocampal neurons, as evidenced by phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2. Importantly, pharmacological suppression of MAPK/ERK signaling blocked androgenmediated neuroprotection against b-amyloid toxicity. Androgen activation of MAPK/ERK and neuroprotection also was observed in PC12 cells stably transfected with androgen receptor (AR), but in neither wild-type nor empty vectortransfected PC12 cells. Downstream of ERK phosphorylation, we observed that DHT sequentially increases p90 kDa ribosomal S6 kinase (Rsk) phosphorylation and phosphorylationdependent inactivation of Bcl-2-associated death protein (Bad). Prevention of androgen-induced phosphorylation of Rsk and Bad blocked androgen neuroprotection. These findings demonstrate AR-dependent androgen activation of MAPK/ERK signaling in neurons, and specifically identify a neuroprotective pathway involving downstream activation of Rsk and inactivation of Bad. Elucidation of androgen-mediated neural signaling cascades will provide important insights into the mechanisms of androgen action in brain, and may present a framework for therapeutic intervention of age-related neurodegenerative disorders.

Androgen cell signaling pathways involved in neuroprotective actions

“…Importantly, we also observed that androgen neuroprotection in this culture system requires activation of a MAPK/ERK signaling pathway, as pharmacological inhibition of MAPK/ERK signaling by MEK inhibitors blocked both androgen-induced ERK phosphorylation and androgen neuroprotection. In our PC12 cell paradigm, we observed parallel findings of androgen activation of a neuroprotective MAPK/ERK signaling in cell lines stably transfected with AR but not in either wild type or empty vector-transfected cell lines (Nguyen et al, 2005). Perhaps in contrast to our findings, testosterone did not increase ERK phosphorylation in cerebellar granule cells (Wong et al, 2003).…”

“…In cultured neurons, androgens can protect against a variety of insults, including serum deprivation (Brooks et al, 1998;Hammond et al, 2001), oxidative stress (Ahlbom et al, 2001), and Aβ (Nguyen et al, 2005;Park et al, 2007;Pike, 2001;Zhang et al, 2004). In our studies, we have found that testosterone provides partial protection against Aβ toxicity (Fig.…”

“…First, we found that testosterone and DHT rapidly and transiently induced activation of MAPK/ERK in cultured hippocampal neurons as evidenced by phosphorylation of ERK-1 and ERK-2 (Nguyen et al, 2005). Importantly, we also observed that androgen neuroprotection in this culture system requires activation of a MAPK/ERK signaling pathway, as pharmacological inhibition of MAPK/ERK signaling by MEK inhibitors blocked both androgen-induced ERK phosphorylation and androgen neuroprotection.…”

“…In our studies, we have found that testosterone provides partial protection against Aβ toxicity (Fig. 2), by activating a rapid, non-genomic pathway (Pike, 2001) that involves MAPK signaling (Nguyen et al, 2005). This testosterone neuroprotection is mimicked by DHT but not 3α-diol and is not attenuated by antagonists to estrogen receptors (Pike, 2001).…”

Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor

“…phosphorylation of NMDARs and extracellular signal-regulated kinase (ERK). For example androgens have been shown in vitro to regulate the phosphorylation of ERK within minutes [9,10].…”