Local isoform‐specific NOS inhibition: A promising approach to promote motor function recovery after nerve injury

Abstract

Physical injury to a nerve is the most frequent cause of acquired peripheral neuropathy, which is responsible for loss of motor, sensory and/or autonomic functions. Injured axons in the peripheral nervous system maintain the capacity to regenerate in adult mammals. However, after nerve transection, stumps of damaged nerves must be surgically joined to guide regenerating axons into the distal nerve stump. Even so, severe functional limitations persist after restorative surgery. Therefore, the identification of molecules that regulate degenerative and regenerative processes is indispensable in developing therapeutic tools to accelerate and improve functional recovery. Here, I consider the role of nitric oxide (NO) synthesized by the three major isoforms of NO synthases (NOS) in motor neuropathy. Neuronal NOS (nNOS) seems to be the primary source of NO that is detrimental to the survival of injured motoneurons. Endothelial NOS (eNOS) appears to be the major source of NO that interferes with axonal regrowth, at least soon after injury. Finally, NO derived from inducible NOS (iNOS) or nNOS is critical to the process of lipid breakdown for Wallerian degeneration and thereby benefits axonal regrowth. Specific inhibitors of these isoforms can be used to protect injured neurons from degeneration and promote axonal regeneration. A cautious proposal for the treatment of acquired motor neuropathy using therapeutic tools that locally interfere with eNOS/nNOS activities seems to merit consideration.

Viral Vectors as Tools to Investigate the Role of Dysregulated Proteins in Nervous System Pathologies: the Case of Acquired Motor Neuropathies

“…Regenerative and survival capacities could be differentially compromised in adult motoneurons following transection or avulsion of the peripheral nerve. However, crushing of a motor nerve causes an immediate and complete suppression of neuromuscular connectivity but, unlike transection, it preserves the endoneural tube, thus providing neurotrophic support and a physical guide for the growing proximal axonal endings (Moreno-López, 2010). A few weeks after nerve crushing, muscle re-innervation takes place without significant neuronal loss.…”

“…This experimental model has been useful to test the role and effectiveness of diverse factors in degenerative/regenerative processes after nerve injury by means of functional and anatomical approaches. The hypoglossal systemhypoglossal motoneurons (HMNs), XIIth nerve and their target muscle (the tongue)-has been well characterized by our group in physiological and pathological conditions (González-Forero et al, 2004;Montero et al, 2008;2010;Sunico et al, 2005;2008;2010;. This motor system offers several advantages, since muscle and motoneuron activities can be accurately measured and its peripheral and central partners are easily accessible to carry out damage strategies, local microinjections and electrophysiological recordings.…”

“…This may occur though a normally present redundant pathway and may be due to differences in expression of alternatively spliced isoforms of a particular NOS. For example, NOS catalytic activity levels in the brain of nNOS knockout mice are persistently low, which may mask the effect of nNOS deficiency (Moreno-López, 2010). Therefore, results obtained from knockouts, although useful, must be interpreted with caution.…”

“…Strikingly, administration of the relatively specific eNOS inhibitor L-N(5)-(l-iminoethyl)ornithine (L-NIO) accelerated the onset of muscle reinnervation after hypoglossal nerve crushing by promoting axonal regrowth (Sunico et al, 2008). Contradictions can be explained by differences in the lesion model and in the dose and relative specificity of NOS inhibitors (Moreno-López, 2010). In any case, these results pointed to eNOS as the major source of detrimental NO in axonal regeneration, at least in the first week after nerve injury.…”

“…Currently, gene therapy is mainly being focused on the study of genetic disorders such as cancer, diabetes mellitus, cardiovascular diseases and nervous system pathologies, among others. More specifically, regarding the applications in the nervous system, this chapter will highlight the potential of viral vectors as tools for the investigation of the role of altered proteins in neuropathological processes and review our recently published findings (Sunico et al, 2008;2010;Montero et al, 2010) in the context of the existing literature. Briefly, we have used AVVs and LVVs to study the function of 2 dysregulated proteins in pathological events occurring at the peripheral (nerve) and central (motoneuron) levels after the severe crushing of a motor nerve in adult rats.…”