Elsevier

Neuroscience

Volume 151, Issue 1, 2 January 2008, Pages 63-73
Neuroscience

Cellular neuroscience
Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide

https://doi.org/10.1016/j.neuroscience.2007.09.084Get rights and content

Abstract

Peripheral nerve injury models are used to investigate processes that can potentially be exploited in CNS injury. A consistent change that occurs in injured peripheral neurons is an induction in expression of pituitary adenylyl cyclase activating peptide (PACAP), a neuropeptide with putative neuroprotective and neuritogenic actions. PACAP-deficient mice were used here to investigate actions of endogenous PACAP after facial nerve injury. Although motor neuron survival after axotomy was not significantly different in PACAP deficient vs. wild type mice, recovery of axon regeneration after crush injury was significantly delayed. The impaired regeneration was associated with 8- to 12-fold increases in gene expression of proinflammatory cytokines tumor necrosis factor-α, interferon-γ, interleukin (IL) -6, and a 90% decrease in the anti-inflammatory cytokine IL-4 at the injury site. Similar cytokine changes and an increased microglial response were observed in the brainstem facial motor nucleus. Because immunocompromised animals such as SCID mice are known to exhibit peripheral nerve regeneration defects, the observations raise the novel hypothesis that PACAP is critically involved in a carefully controlled immune response that is necessary for proper nerve regeneration after injury.

Section snippets

Animals

PACAP deficient (knockout, KO) mice, were previously generated by targeted mutagenesis (Colwell et al., 2004). The gene targeting strategy removed sequences encoding PACAP and also PACAP-related peptide, a peptide of unknown biological significance. These mice were found by sensitive radioimmunoassay to not express PACAP in the brain or peripheral sites (Colwell et al., 2004). All mice used in these experiments were 2 to 4-month-old females, and were generated after backcrossing the mutation to

Motor neuron survival after axotomy in PACAP-deficient mice

PACAP has been shown to act as a neuronal survival factor on cultured cerebellar granule, sensory, autonomic and other types of neurons, and has been shown to promote neuron survival in various in vivo experimental CNS injury paradigms (reviewed in Waschek 2002, Atlasz et al 2007, Botia et al 2007). Thus, it was of considerable interest to determine if lack of endogenous PACAP results in impaired neuron survival after facial nerve axotomy. However, we found no difference between the PACAP KO

Discussion

An abundance of in vivo and in vitro data indicates that exogenous PACAP can act on developing or injured neurons to promote their survival (Vaudry et al 2000, Waschek 2002). Tissue cultures studies also indicate that PACAP can stimulate neurite outgrowth (Waschek, 2002), guide growth cones from immature neurons (Guirland et al., 2003) and regulate myelinogenesis (Lee et al., 2001), suggesting that PACAP might also act in the process of axon regeneration after injury. The generation of a PACAP

Acknowledgments

This work was supported by NIH grants HD06576 and HD04612, and grants from the Norman Cousins Center for Psychoneuroimmunology, and the Roman Reed Spinal Cord Injury Research Fund of California. We thank Dr. He-Jing Wang for help with statistical analyses of the data.

References (40)

  • A. Arimura et al.

    PACAP functions as a neurotrophic factor

    Ann N Y Acad Sci

    (1994)
  • B.D. Armstrong et al.

    Impairment of axotomy-induced pituitary adenylyl cyclase-activating peptide gene expression in T helper 2 lymphocyte-deficient mice

    Neuroreport

    (2006)
  • B.D. Armstrong et al.

    Restoration of axotomy-induced PACAP gene induction in SCID mice with CD4+ T-lymphocytes

    Neuroreport

    (2004)
  • B.D. Armstrong et al.

    Lymphocyte regulation of neuropeptide gene expression after neuronal injury

    J Neurosci Res

    (2003)
  • C.S. Colwell et al.

    Selective deficits in the circadian light response in mice lacking PACAP

    Am J Physiol Regul Integr Comp Physiol

    (2004)
  • M. Delgado et al.

    Vasoactive intestinal peptide prevents activated microglia-induced neurodegeneration under inflammatory conditions: potential therapeutic role in brain trauma

    FASEB J

    (2003)
  • M. Delgado et al.

    Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide stimulate the induction of Th2 responses by up-regulating B7.2 expression

    J Immunol

    (1999)
  • M. Delgado et al.

    The significance of vasoactive intestinal peptide in immunomodulation

    Pharmacol Rev

    (2004)
  • C. Guirland et al.

    Direct cAMP signaling through G-protein-coupled receptors mediates growth cone attraction induced by pituitary adenylate cyclase-activating polypeptide

    J Neurosci

    (2003)
  • H. Kato et al.

    Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells

    Mult Scler

    (2004)
  • Cited by (99)

    • Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus

      2017, Experimental Neurology
      Citation Excerpt :

      gp130 Signaling is known to drive the expression of the neuropeptides Vip, galanin, Pacap, and Cck (Habecker et al., 2009; Rao et al., 1993a; Sun and Zigmond, 1996a; Zigmond et al., 1998; Zigmond, 2011; Zigmond et al., 1996). Galanin and Pacap expression have been directly linked to axon regeneration, as a knockout or inhibition of these neuropeptides shows significantly impaired regeneration (Armstrong et al., 2008; Hobson et al., 2006; Holmes et al., 2000; Kerr et al., 2000). We measured the injury-induced mRNA expression of these neuropeptides, as well as the RAG Gap43, in SCG and DRG 48 h after axotomy.

    View all citing articles on Scopus
    View full text