Androgen-induced neurite outgrowth is mediated by neuritin in motor neurones
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... Androgens are neuroactive compounds which may regulate molecular and cellular events modulating several brain functions. Androgens regulate sexual and aggressive behaviour (Howell and Shalet 2001), memory, cognitive status (Moffat et al. 2002; Naghdi et al. 2003; Yaffe et al. 2003), mood (Seidman 2003) as well as other brain functions
. Most of these effects are mediated by the androgen receptor (AR), a ligand-activated transcription factor which belongs to the nuclear steroid receptor superfamily (Lamb et al. 2001; Gelmann 2002) and is highly expressed in a distinct neuronal population of the CNS
(McAbee and DonCarlos 1998; Fernandez-Guasti et al. 2000).
... spinal cord motor neurones express a high level of 5α-R 2, similar to those usually found in the prostate
(a typical androgen-dependent structure) and several times higher that those normally detectable in the CNS (Poletti et al. 1997a, 2001; Poletti and Martini 1999; Pozzi et al. 2003).
... It clearly appears that both DHT (p < 0.01) and testosterone (p < 0.05) significantly increased the number of phosphorylated neurofilaments of NSC34/mAR; however, DHT was capable of stimulating neurite outgrowth at levels significantly higher than those obtained with its precursor testosterone
(p < 0.01).
The effects of testosterone appear to be mediated by its 5α-reduced derivative. In fact, finasteride, a selective 5α-R 2 inhibitor that blocks DHT formation, completely counteracted the trophic effect exerted by testosterone on neurite outgrowth.
This study confirms this idea firstly by demonstrating that DHT regulates neuritin expression and neurite outgrowth more effectively than its precursor testosterone
and secondly by demonstrating that the trophic effects of testosterone on neurite elongation can be fully blocked by the use of the selective 5α-R 2 inhibitor finasteride.
... All together the data presented may become relevant to understanding the effects of a particular type of mutation found in the AR of patients affected by a motor neurone disorder known as spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease
(Kennedy et al. 1968).
... Similarly, a recent study has indicated that Alzheimer's disease in male patients may be linked with a different mutation in the CAG triplet repeat domain of the AR, along with reduced testosterone levels in blood serum
(Lehmann et al. 2004; Okun et al. 2004).
Testosterone levels in the blood have also been implicated in the pathology of Parkinson's disease in male patients (Okun et al. 2004). Some of these symptoms may be alleviated by testosterone replacement therapy (Okun et al. 2002).
... Finally, another motor neurone disease, the sporadic amyotrophic lateral sclerosis
, is characterized by a 2 : 1 higher incidence in men compared with women. It has also been shown that free testosterone (but not total testosterone) is significantly decreased in amyotrophic lateral sclerosis patients compared with age-matched controls, suggesting a possible involvement of androgens in the pathophysiology of sporadic amyotrophic lateral sclerosis
The involvement of androgens in the control of neuritin expression, described in the present study, and its putative effect as molecular mediator of the androgenic effects on axonal elongation in motor neurones underlines a possible a link with these clinical observations. Observations derived from the study of these pathologies substantiate the argument that AR exerts a trophic effect on motor neurones
(Brooks et al. 1997, 1998).