neuropeptide-y and Rupture

Diminished healing in neuropathic tissues suggests an important regulatory role for peripheral neurogenic factors in connective tissue healing. Although neurogenic factors, including neuropeptides, can induce cell proliferation and influence inflammatory cell chemotaxis in vitro, there is little appreciation of the potential of neuropeptides to affect connective tissue healing in vivo. We created both efferent and afferent peripheral neuropathies in 55 female Wistar rats. First, we showed that neuropathy led to impaired healing of ruptured ligaments. We then showed that local delivery of specific neuropeptides could reverse the functional deficits of these neuropathic ligaments in only 2 weeks. In substance P and vasoactive intestinal peptide-treated medial collateral ligaments (MCLs), the mechanical properties of these healing neuropathic tissues returned to values at or above normally innervated, intact ligaments. In addition, neuropeptide Y stimulated MCL healing in this model. These findings suggest a new paradigm to improve neuropathic soft connective tissue healing.

Topics: Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Female; Femoral Nerve; Ligaments; Neuropeptide Y; Neuropeptides; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Rupture; Substance P; Sympathectomy; Vasoactive Intestinal Peptide; Wound Healing

Nerve regeneration during healing of Achilles tendon rupture in the rat was studied by immunohistochemistry including semi-quantitative assessment. Neuronal markers for regenerating and mature fibers, ie., growth associated protein 43 (GAP-43) and protein gene product 9.5 (PGP 9.5), respectively, were analyzed at different time points (1-16 weeks) post-rupture. In the paratenon, both the ruptured and intact contralateral tendon (control) consistently exhibited immunoreactivity to the two neuronal markers. However, in the proper tendinous tissue only the ruptured tendon showed immunoreactivity to GAP-43 and PGP 9.5. This expression was seen already at week 1 post-rupture to reach a peak at week 6 followed by a successive drop till week 16. Also the occurrence of sensory and autonomic fibers according to immunoreactivity for calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY), respectively, was analyzed. CGRP-positivity was abundantly seen from weeks 2-6 in both perivascular and sprouting free nerve endings in the proper tendon tissue undergoing healing. NPY appeared later, at weeks 6-8 post-rupture around blood vessels mainly located in the surrounding loose connective tissue. Apart from a role in vasoaction (CGRP, vasodilatory; NPY, vasoconstrictory). both neuropeptides have been implicated in fibroblast and endothelial cell proliferation required for angiogenesis. The present study shows that early healing of ruptured tendons is characterized by an orchestrated, temporal appearance of nerve fibers expressing peptides with different actions. The observed pattern of neuronal regeneration and neuropeptide expression may prove to be important for normal connective tissue healing.

Topics: Achilles Tendon; Animals; Calcitonin Gene-Related Peptide; GAP-43 Protein; Immunohistochemistry; Male; Nerve Regeneration; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Rupture; Thiolester Hydrolases; Ubiquitin Thiolesterase; Wound Healing