The axotomy‐induced neuropeptides galanin and pituitary adenylate cyclase‐activating peptide promote axonal sprouting of primary afferent and cranial motor neurones

Abstract

The neuropeptides galanin and pituitary adenylate cyclase-activating peptide (PACAP) are markedly up-regulated in response to peripheral nerve lesion. Both peptides are involved in neuronal differentiation and neurite outgrowth during development. In this study, we investigated the effects of galanin and PACAP on axonal elongation and sprouting by adult rat sensory neurones in vitro and facial motor neurones in vivo. Dissociated rat dorsal root ganglion neurones were plated on laminin substrate and analysed morphometrically. Both the mean axonal length and the number of branch points significantly increased in the presence of galanin or PACAP (2-5 microm). Effects on axonal collateralization were investigated in the rat facial nerve lesion model by direct application of the peptides to collagen-filled conduits entubulating the transected facial nerve stumps. Triple retrograde labelling of brainstem neurones confirmed that the peptides potently induce axonal sprouting of cranial motor neurones. The number of neurones regenerating into identified rami of the facial nerve increased up to fivefold. Biometrical analysis of whisking behaviour revealed that galanin and PACAP impaired the functional outcome when compared with vehicle-treated animals 8 weeks after surgery. In conclusion, although galanin and PACAP have been established as neurotrophic molecules with respect to axonal development and regeneration, their potential as treatments for peripheral nerve lesions appears limited because of the extensive stimulation of collateral axon branching. These branches are misrouted towards incorrect muscles and cause impairment in their coordinated activity.

Regulation of neuronal pituitary adenylate cyclase-activating polypeptide expression during culture of guinea-pig cardiac ganglia

“…PACAP expression may be a mechanism supporting cardiac neuron survival and regeneration following injury in vivo (Moller et al, 1997a,b;Armstrong et al, 2003;Boeshore et al, 2004;Suarez et al, 2006). In the present study we used explant cultured cardiac ganglia as a model system to quantify the PACAP expression which occurs when cardiac neurons are injured.…”

“…However, PACAP expression increases markedly in these neurons following axotomy or explant culture (Zhang et al, 1995(Zhang et al, ,1996Moller et al, 1997a,b;Zhou et al, 1999;Pettersson et al, 2004). It is hypothesized that the increased expression of PACAP may be a response to injury that supports cell survival and regeneration (Moller et al, 1997a,b;Armstrong et al, 2003;Boeshore et al, 2004;Pettersson et al, 2004;Suarez et al, 2006).…”

“…However, PACAP expression increases markedly in these neurons following axotomy or explant culture (Zhang et al, 1995(Zhang et al, ,1996Moller et al, 1997a,b;Zhou et al, 1999;Pettersson et al, 2004). It is hypothesized that the increased expression of PACAP may be a response to injury that supports cell survival and regeneration (Moller et al, 1997a,b;Armstrong et al, 2003;Boeshore et al, 2004;Pettersson et al, 2004;Suarez et al, 2006).In acutely isolated guinea pig cardiac ganglia, all the intrinsic neurons are innervated by extrinsic PACAP-IR fibers, but very few of the cardiac neurons exhibit PACAP immunoreactivity Calupca et al, 2000;Parsons et al, 2006). Following explant culture, the extrinsic PACAP-IR fibers degenerate and the percentage of cholinergic neurons expressing PACAP increases significantly (Calupca et al, 2000;Girard et al, 2006b).…”

Effects of Alpha 1- and Alpha 2-Adrenoreceptor Stimulation on Galanin mRNA Expression in Primary Cultured Superior Cervical Ganglion Neurons

“…The neurotrophic actions of Gal are demonstrated by the upregulation of Gal expression both in DRG neurons and in SCG neurons after nerve injury (Holmberg et al, 2005;Holmes et al, 2005). And also, exogenous Gal signifi cantly increased the mean axonal length and the number of branch points (Suarez et al, 2006) and capsaicin-evoked neuropeptide release (Yang et al, 2008). In the present study, upregulation or downregulation of Gal mRNA expression stimulated by distinct adrenoreceptors in cultured SCG neurons implicated that Gal may also involved in modulation of responses in peripheral nerve fi bers.…”

Perspective is everything: An irreverent discussion of CNS–immune system interactions as viewed from different scientific traditions

“…And to bring this all back to neurotransmitters and neuropeptides, kinetics and relevance, I bring up the cross-regulatory role of neurotransmitter, PACAP in a model of neuroprotective T cell responses (Armstrong et al, 2003;Armstrong et al, 2004;Boeshore et al, 2004;Suarez et al, 2006). Following axotomy, PACAP expression is robustly increased in the facial motoneuron nucleus for several days, but only in wild-type and not T cell deficient mice.…”