Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

Abstract

<jats:title>Abstract</jats:title> <jats:p>We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P &amp;lt; 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P &amp;lt; 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P &amp;lt; 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.</jats:p>

Somatosensory and psychological phenotypes associated with neuropathic pain in entrapment neuropathy

“…Primary publications containing parts of the Oxford CTS cohort have been previously published. 6 , 46 …”

Doxycycline and Minocycline act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells

“…More recently, transcriptional profiling of the skin of patients undergoing surgery for carpal tunnel syndrome revealed that ADCYAP1 (the gene encoding for PACAP) was the most robustly up-regulated and its expression was associated with nerve recovery. Additionally, when human induced pluripotent stem cell-derived sensory neurons were treated with PACAP, it enhanced axonal outgrowth in a dose dependent manner [36]. Together, these studies suggest a prominent role of PACAP induced PAC1 activity in mediating neuronal survival, axon regeneration and remyelination following peripheral nerve injury.…”

Doxycycline and Minocycline Act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells

“…More recently, transcriptional profiling of the skin of patients undergoing surgery for carpal tunnel syndrome revealed that ADCYAP1 (the gene encoding for PACAP) was the most robustly upregulated and its expression was associated with nerve recovery. Additionally, when human induced pluripotent stem cell-derived sensory neurons were treated with PACAP, the peptide enhanced axonal outgrowth in a dose dependent manner [36]. Together, these studies suggest a prominent role of the PACAP/PAC1 axis in mediating neuronal survival, axon regeneration and remyelination following peripheral nerve injury.…”