CNS regeneration: clinical possibility or basic science fantasy?

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Abstract

Following injury to the CNS, severed axons undergo a phase of abortive sprouting in the vicinity of the wound, but do not spontaneously re-grow or regenerate. From a long history of attempts to stimulate regeneraion, a major strategy that has been developed clinically is the implantation of tissue into denervated target regions. Unfortunately trials have so far not borne out the promise that this would prove a useful therapy for disorders such as Parkinson’s disease. Many strategies have also been developed to stimulate the regeneration of axons across sites of injury, particularly in the spinal cord. Animal data have demonstrated that some of these approaches hold promise and that the spinal cord has a remarkable degree of intrinsic plasticity. Attempts are now being made to utilize experimental techniques in spinal patients.

Section snippets

Introduction and history of regeneration in the CNS

Severed axons do not spontaneously re-grow in meaningful numbers in the mammalian central nervous system (CNS). This fact accounts for the devastating and permanent nature of many CNS diseases such as spinal cord injuries. Although the failure of the CNS to recover from many injuries has been recognized since ancient times,1 it has only been in the last 100 years or so that investigations into CNS regeneration have been systematically performed. Early 20th century workers are sometimes

Tissue implantation

Rather than attempting to induce neurons to regenerate their processes, an alternative approach is to simply implant new neurons or neurotransmitter secreting cells directly into the target region. Implanted cells do not receive their normal inputs and therefore presumably secrete neurotransmitters in a relatively unregulated fashion. This approach has been most successfully applied in the treatment of experimental and clinical Parkinson’s disease where the success of pharmacotherapy would tend

Spinal regeneration

Although the inability of axons to regenerate is a feature of the CNS in general, it is perhaps in the area of spinal injury that the problem presents itself most starkly. Clinicians reading this review and reflecting on their own experience may feel that to discuss a solution to such a problem is ingenuous. However, as outlined in the following sections, there are now reasons to believe that it may be possible to promote axonal regeneration and restore function after spinal and other CNS

Regenerative sprouting and CNS inflammation

Following CNS injury, inflammation occurs in the vicinity of the site of trauma. Inflammation in the CNS is dominated by activated microglia and macrophages although lymphocytes are also present together with a brief influx of neutrophils in the first 24 h after injury.69 Hematogenously derived macrophages enter through the injured blood brain barrier and remove myelin and axonal debris and stimulate reactive astrocytosis.70 In areas where the blood brain barrier is not disrupted, such as

The glial scar as a physical barrier

The presence of a dense glial scar at the site of injury has long believed to be a major physical impediment to axonal regeneration.[3], [4], [9], [12], [13], [14], [91], [92] Astrocytes hypertrophy and proliferate following CNS trauma and the processes of mainly fibrous astrocytes rapidly (within 2–3 weeks) form a new glial limitans parallel to the border of the wound.[93], [94], [95] This reconstituted astrocytic boundary, composed of tightly interwoven processes, is much thicker than the

Strategies to stimulate regeneration

A large variety of ingenious strategies have been utilized in an endeavor to stimulate regeneration. Some, such as removing growth inhibitors or altering the genetic composition of regenerating neurons, have been mentioned above. However, the principle method employed has been to bridge the lesion site with various growth facilitating cells and materials. This has been the most successful strategy and a brief overview of experimental attempts utilizing this approach is given below.

Restoration of function and connectivity

The experimental strategies outlined in the above section enable the regeneration of small numbers of fibres across the site of injury and into distal regions of the spinal cord. Axons from a variety of motor tracts have been demonstrated to regenerate, including the corticospinal, rubrospinal, reticulospinal, caerulospinal, and raphespinal tracts together with sensory fibres in the dorsal columns. Where examined, the growth of these axons as they re-enter the spinal cord has tended to be

Clinical trials

The right time to begin clinical trials on these therapeutic approaches is moot. Some argue passionately that spinal injuries are so pernicious that all that is required to begin human evaluation is plausible biology and rodent experiments demonstrative of modest anatomical and behavioural benefits. Others claim that these therapies pose genuine risks, arguing that they may cause worsening deficits, induce sensory fibre ingrowth and chronic pain or promote tumor formation. They would argue that

Conclusions

The basic science data give much reason for hope. Severed axons sprout and persist for long periods in the immediate vicinity of the wound site and are therefore potentially available to regenerate for perhaps years after injury. Data suggest that only relatively small numbers of axons are needed (probably a few percent of the original number present) to mediate near normal motor function. Regenerating motor axons may not need to renervate specific target areas in order for recovery to take

Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia, the Austin Hospital Medical Research Foundation and Parkinson’s Victoria.

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