Degeneration and regeneration of the nervous system

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

The cellular and molecular basis of peripheral nerve regeneration.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1990.tb15595.x

Insulin-like growth factors I and II

This paper presents a conceptual model for the pathogenesis of work-related musculoskeletal disorders. The model contains sets of cascading exposure, dose, capacity, and response variables, such that response at one level can act as dose at the next. Response to one or more doses can diminish or increase the capacity for responding to successive doses. The model is used as a framework for discussing the development of work-related muscle, tendon, and nerve disorders. It is intended as a beginning, to be modified to explain new findings as they become available. In research, it can help to identify areas needing additional data for the development and expression of work-related musculoskeletal disorders. Researchers can use it to design laboratory and field studies. In practice, it demonstrates the relationship between common exposure factors and different responses. This information can be used to evaluate and design jobs for the prevention of work-related musculoskeletal disorders.

A Conceptual Model for work-related Neck and upper-limb Musculoskeletal Disorders

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are molecules which regulate the development and maintenance of specific functions in different populations of peripheral and central neurons, amongst them sensory neurons of neural crest and placode origin. Under physiological conditions NGF is synthesized by peripheral target tissues, whereas BDNF synthesis is highest in the CNS. This situation changes dramatically after lesion of peripheral nerves. As previously shown, there is a marked rapid increase in NGF mRNA in the nonneuronal cells of the damaged nerve. The prolonged elevation of NGF mRNA levels is related to the immigration of activated macrophages, interleukin-1 being the most essential mediator of this effect. Here we show that transsection of the rat sciatic nerve also leads to a very marked increase in BDNF mRNA, the final levels being even ten times higher than those of NGF mRNA. However, the time-course and spatial pattern of BDNF mRNA expression are distinctly different. There is a continuous slow increase of BDNF mRNA starting after day 3 post-lesion and reaching maximal levels 3-4 wk later. These distinct differences suggest different mechanisms of regulation of NGF and BDNF synthesis in non-neuronal cells of the nerve. This was substantiated by the demonstration of differential regulation of these mRNAs in organ culture of rat sciatic nerve and Schwann cell culture. Furthermore, using bioassays and specific antibodies we showed that cultured Schwann cells are a rich source of BDNF- and ciliary neurotrophic factor (CNTF)-like neurotrophic activity in addition to NGF. Antisera raised against a BDNF-peptide demonstrated BDNF-immunoreactivity in pure cultured Schwann cells, but not in fibroblasts derived from sciatic nerve.

https://rupress.org/jcb/article-pdf/119/1/45/1063459/45.pdf

Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA.

Insulin-like growth factor I (IGF-I) stimulates regeneration of the rat sciatic nerve.

The mechanisms influencing regeneration of peripheral nerves are incompletely known, but growth factors are supposed to play a key role. In the present study, we demonstrate, with the aid of immunohistochemical methods, that somatomedin C (Sm-C/insulin-like growth factor I/IGF-I) rapidly increased from low to high concentrations, reaching peak values in 2 weeks, in regenerating sciatic nerves of adult rats. In addition, IGF-I was demonstrated extracellularly, never observed in the control nerves. Reactive Schwann cells appeared to be the major source for IGF-synthesis. Higher concentrations were seen in tubulated nerves as compared to sutured ones. It is proposed that IGF-I exerts important growth supporting effects on regenerating peripheral nerves.

Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves.

Neuronotrophic activities accumulate in vivo within silicone nerve regeneration chambers.

The possibility that collateral sprouting could occur from intact axons in an undamaged sciatic nerve was studied in the rat by suturing either a 7-day predegenerated or a fresh nerve segment in an end-to-side fashion to the sciatic nerve proper. Following a 14- or 35-day recovery period, the pinch reflex test was performed on the transplanted segment to demonstrate the presence of sensory axons. The majority of cases, using a predegenerated nerve segment but not a fresh segment, responded positively. Neurofilament staining and histological examination confirmed the presence of axons in the attached nerve segment. In another series of experiments, the proximal peroneal fascicle was ligated and cut. Following a 7-day predegeneration period the distal stump was sutured end-to-side to the ipsilateral tibial fascicle. After 90 days, stimulation of the tibial nerve proximal to the attached site induced substantial contraction in both the native gastrocnemius muscle and the foreign tibialis anterior muscle. These findings suggest that collateral sprouting may occur from intact axons, perhaps induced by factors emanating from the attached nerve segment, and subsequently make functional peripheral connections.

Can sensory and motor collateral sprouting be induced from intact peripheral nerve by end-to-side anastomosis?

Regeneration of peripheral nerve through a preformed tissue space. Preliminary observations on the reorganization of regenerating nerve fibres and perineurium

G. Lundborg

Papers

Insulin-like growth factor I (IGF-I) stimulates regeneration of the rat sciatic nerve.

Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves.

Neuronotrophic activities accumulate in vivo within silicone nerve regeneration chambers.

Can sensory and motor collateral sprouting be induced from intact peripheral nerve by end-to-side anastomosis?

Regeneration of peripheral nerve through a preformed tissue space. Preliminary observations on the reorganization of regenerating nerve fibres and perineurium