The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction

Abstract

Artemin (ART) signals through the GFRα-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfrα-3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.

Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize NociceptorsIn Vitroand Produce Thermal HyperalgesiaIn Vivo

“…Also, Gardell et al (2003) used artemin concentrations that were 300 times greater than that used in this study; this difference raises the possibility that high artemin concentrations have other effects that mask the hyperalgesic action reported here. However, in contrast to Gardell et al (2003), a similar study found that artemin injection [either intraperitoneally (5 m/kg) or intrathecally (10 g/d)] in rats did not block hyperalgesia produced by spinal nerve ligation (Bolon et al, 2004). This suggests that, even in the same species, the method of artemin application appears to dramatically alter efficacy.…”

Artemin Overexpression in Skin Enhances Expression of TRPV1 and TRPA1 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Heat and Cold

“…To understand how this condition becomes intractable, interest has focused on the role of growth factors such as NGF and artemin in the development and maintenance of pain conditions. The effect of artemin on pain after nerve injury in the rat has been investigated using spinal nerve ligation (SNL) injury models (Gardell et al, 2003;Bolon et al, 2004). Gardell and colleagues (Malan et al, 2000;Gardell et al, 2003) reported that subcutaneous injection of artemin (1 mg/ kg) 3 d after nerve ligation significantly reduced tactile and thermal hypersensitivity within 24 h and normalized changes in spinal dynorphin levels, a pronociceptive agonist of the -opioid receptor that typically rises after SNL.…”

Facteurs neurotrophiques pour les motoneurones

“…En effet, dans un modèle murin de SLA, des souris transgéniques qui expriment des formes mutées de SOD1 (superoxyde dismutase-1) [8,9] (➜), quatre facteurs neurotrophiques se sont avérés être parmi les six traitements les plus efficaces testés (à l'exception, comme attendu, des modificateurs de SOD1) [10]. Nos données sur l'action préférentielle de l'HGF vis-à-vis des motoneurones LMC pourraient expliquer les puissants effets thérapeutiques de ce facteur contre la fonte de la masse musculaire et la parésie des membres, accord avec son expression restreinte dans les muscles des membres [7].…”

“…Enfin, l'ARTN apparaît comme un nouveau facteur de survie pour les motoneurones préganglionnaires du système parasympathique qui innervent les neurones postganglionnaires du côlon distal, de la vessie et des organes génitaux. Ceci est en concordance avec l'expression d'ARTN au niveau de ces organes [8], et également avec celle de son récepteur GFR3 dans les corps cellulaires et les axones des motoneurones préganglionnaires. Ces observations ont-elles des implications thérapeutiques ?…”

“…Elle favorise la migration et l'adhérence cellulaires [5], et stabilise les protrusions et les filopodes, ce qui facilite les contacts entre les cellules [6,7]. Récemment, il a été montré que l'expression de la fascine était induite par Tax [8,9] et que la protéine participait à la transmission du virus [10].…”