Spontaneous regeneration in the CNS is poor due to several reasons, mainly the presence of inhibitory factors. Considerable research is in progress to understand the mechanism of this inhibition, which forms the basis of strategies to promote regeneration in the CNS. Degradation of inhibitors such as chondroitin sulfate proteoglycans in the glial scar at the site of spinal cord injury by application of chondroitinase ABC promotes regeneration of corticospinal tract axons in experimental animals. Inhibitors of axonal regeneration in myelin include Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein. These can be blocked with antibodies or peptides to facilitate regeneration. Developments in nanobiotechnology and nanomedicines also show potential for CNS repair. The combination of stem cell transplantation with nanoscaffolds is promising for the repair of traumatic brain injury.
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• Spontaneous regeneration is poor in the CNS following damage.
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• Several strategies for repair of the CNS are under investigation, including new technologies such as nanobiotechnology.
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• Stem cells are promising for repair of the CNS.
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• Neurotrophic factors for regeneration of the CNS can be delivered by genetically engineered cells/gene therapy.
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• Important applications for techniques of CNS repair are in CNS trauma, stroke, and degenerative neurologic disorders.
Historical note and terminology
The term "regeneration" is used to describe all activities leading to the regrowth of cells and tissues of the body. It includes both anatomical and physiological structures; however, structural regeneration does not necessarily lead to restoration of function. The term "functional regeneration" implies recovery of the function that can occur without regeneration by compensatory mechanisms. Regeneration follows damage or loss of cells and tissues that may be the result of trauma or pathological processes resulting in necrosis or apoptosis.
Regeneration, in most body tissues, occurs to a variable degree. Traditionally, neural tissues (excepting peripheral nerves) were nonregenerative, an idea that was recognized as early as 1550 BC and well documented during the 19th century (25). In the earlier part of the 20th century, Ramon y Cajal reached the following conclusion in his monumental work on degeneration and regeneration of the nervous system: Once the development has ended, the founts of growth and regeneration of the axons and dendrites dry up irrevocably. In adult centers, the nerve paths are something fixed, ended, and immutable (29). The view of axonal regeneration in the central nervous system as abortive or poor remained widely accepted for several decades. Evidence started to emerge during the last quarter of the 20th century that, under certain circumstances, regeneration could occur successfully in the mammalian central nervous system. Discoveries in neurobiology have provided insight into possible ways in which neuronal regeneration in the CNS may be encouraged.
In Principal of Compensation, Hughling Jackson explained the functional recovery that occurs following damage to the central nervous system. This explanation was based on his theory of cerebral localization (46). Functional recovery is related to neuroplasticity (or plasticity) of the nervous system. Plasticity consists of the central nervous system’s ability to adapt, in both an anatomical and functional sense, its structural organization to new situations emerging during its maturation, in addition to those resulting from injuries. Goldstein was an important figure in developing the concept of neuroplasticity during the early part of the 20th century (11). Investigators in this field had already recognized the plasticity exhibited by brain microglia during development and under pathological conditions (07). In 1979, Cotman and Scheff put forward the concept of reactive synaptogenesis, whereby the neighboring neurons make new synaptic contacts to replace those lost and play a major role in the restoration of function following brain damage (05).
Some of the basic concepts of regeneration and repair taking place after central nervous system injury have led to strategies for treatment and rehabilitation of patients with brain damage. Initial attempts to use neural grafts to repair the damage in experimental animals took place more than a century ago (35). During the last quarter of the 20th century, neural grafting techniques have been refined and are under investigation in patients with neurodegenerative diseases such as Parkinson disease and spinal cord injury.
Several medical, surgical, and rehabilitation approaches for neurologic disorders involve repair, regeneration, and plasticity. Some of the measures to achieve regeneration fall in the category of tissue engineering, which is defined as use of combination of cells, materials, and engineering methods to replace body tissues and restore their function. This article will review the fundamentals of regeneration in the nervous system as a basis for therapy for conditions associated with central nervous system damage.