Androgen Regulates Neuritin mRNA Levels in an In Vivo Model of Steroid-Enhanced Peripheral Nerve Regeneration

Abstract

Following crush injury to the facial nerve in Syrian hamsters, treatment with androgens enhances axonal regeneration rates and decreases time to recovery. It has been demonstrated in vitro that the ability of androgen to enhance neurite outgrowth in motoneurons is dependent on neuritin-a protein that is involved in the re-establisment of neuronal connectivity following traumatic damage to the central nervous system and that is under the control of several neurotrophic and neuroregenerative factors--and we have hypothesized that neuritin is a mediator of the ability of androgen to increase peripheral nerve regeneration rates in vivo. Testosterone treatment of facial nerve-axotomized hamsters resulted in an approximately 300% increase in neuritin mRNA levels 2 days post-injury. Simultaneous treatment with flutamide, an androgen receptor blocker that is known to prevent androgen enhancement of nerve regeneration, abolished the ability of testosterone to upregulate neuritin mRNA levels. In a corroborative in vitro experiment, the androgen dihydrotestosterone induced an approximately 100% increase in neuritin mRNA levels in motoneuron-neuroblastoma cells transfected with androgen receptors, but not in cells without androgen receptors. These data confirm that neuritin is under the control of androgens, and suggest that neuritin is an important effector of androgen in enhancing peripheral nerve regeneration following injury. Given that neuritin has now been shown to be involved in responses to both central and peripheral injuries, and appears to be a common effector molecule for several neurotrophic and neurotherapeutic agents, understanding the neuritin pathway is an important goal for the clinical management of traumatic nervous system injuries.

Recombinant hNeuritin Promotes Structural and Functional Recovery of Sciatic Nerve Injury in Rats

“…It is highly expressed in the developing nervous system, with the level decreasing upon maturation (Naeve et al, 1997). However, Neuritin is upregulated in adult neural structures, such as the olfactory bulb, hippocampus, visual cortex, and Purkinje fibers (Nedivi et al, 1996, 2001; Yamagata et al, 1998) as well as during transient global ischemia, traumatic brain injury, spinal cord injury, and androgen treatment (Di Giovanni et al, 2005b; Han et al, 2007; Fargo et al, 2008; He et al, 2013). The latter was shown to promote functional recovery of injured facial nerves, which was associated with Neuritin upregulation; conversely, blocking androgen reduced Neuritin expression, suggesting a correlation between Neuritin, and functional recovery of injured facial nerves (Fargo et al, 2008).…”

The Effects of Exercise on Synaptic Stripping Require Androgen Receptor Signaling

“…Treatments with testosterone induced acceleration of functional recovery from lower limb paralysis following sciatic nerve crush in the rat [10], [11]. Such treatments are thought to promote elongation of regenerating axons, as they decrease time to recovery after both facial nerve crush injury [12], [13] and recurrent laryngeal nerve injury [14]. In the central nervous system (CNS), testosterone propionate treatment significantly attenuated the amount of synaptic withdrawal and the decrease in average length of the remaining synapses in an adult male hamster model of facial nerve transection [15].…”

A morphological-histochemical study of neurodegenerative and regenerative processes in flexor and extensor collaterals of the sciatic nerve after crushing in the presence of PRP-1

“…The neuroprotective effect of testosterone was shown on the lumbar spinal motoneurons [17]. In the in vivo model of peripheral nerve regeneration induced by this androgen, it regulated the level of neu ritin mRNA; motor neurons demonstrated an acceler ated axonal regeneration and neurite outgrowth [18]. Moreover, neuritin was shown to participate in regen eration processes during both central and peripheral damage.…”

“…Moreover, neuritin was shown to participate in regen eration processes during both central and peripheral damage. This was thought to play the role of an effec tor that acts on some neurotrophic agents; thus, it may be used in clinics for curing traumatic injuries of the nervous system [18].…”