57: Repairing the Damaged Brain

Introduction

• Damage to Axons Affects Neurons and Neighboring Cells

  • Axon Degeneration Is an Active Process

  • Axotomy Leads to Reactive Responses in Nearby Cells

• Central Axons Regenerate Poorly After Injury

• Therapeutic Interventions May Promote Regeneration of Injured Central Neurons

  • Environmental Factors Support the Regeneration of Injured Axons

  • Components of Myelin Inhibit Neurite Outgrowth

  • Injury-Induced Scarring Hinders Axonal Regeneration

  • An Intrinsic Growth Program Promotes Regeneration

  • Formation of New Connections by Intact Axons Can Lead to Functional Recovery

• Neurons in the Injured Brain Die but New Ones Can Be Born

• Therapeutic Interventions May Retain or Replace Injured Central Neurons

  • Transplantation of Neurons or Their Progenitors Can Replace Lost Neurons

  • Stimulation of Neurogenesis in Regions of Injury May Contribute to Restoring Function

  • Transplantation of Nonneuronal Cells or Their Progenitors Can Improve Neuronal Function

  • Restoration of Function Is the Aim of Regenerative Therapies

• An Overall View

For much of its history neurology has been a discipline of outstanding diagnostic rigor but little therapeutic efficacy. Simply put, neurologists have been renowned for their ability to localize lesions with great precision but until recently have had little to offer in terms of treatment. During the past decade this situation has begun to change.

Advances in our understanding of the structure, function, and chemistry of the brain's neurons, glial cells, and synapses have led to new ideas for treatment. Many of these are now in clinical trials and some are already available to patients. Developmental neuroscience is emerging as a major contributor to this sea change for three main reasons. First, efforts to preserve or replace neurons lost to damage or disease rely on recent advances in our understanding of the mechanisms that control the generation and death of nerve cells (see Chapters 52 and 53). Second, efforts to improve the regeneration of neural pathways following injury draw heavily on what we have learned about the growth of axons and the formation of synapses (see Chapters 54 and 55). Third, there is increasing evidence that some devastating brain disorders, such as autism and schizophrenia, are the result of disturbances in the formation of neural circuits in embryonic or early postnatal life. Accordingly, studies of normal development may provide an essential foundation for discovering precisely what has gone wrong in disease.

In this chapter we focus on the first two of these issues: How neuroscientists hope to augment the limited ability of neurons to recover normal function. We shall begin by describing how axons degenerate following the separation of the axon and its terminals from the cell body. The regeneration of severed axons is robust in the peripheral nervous system of mammals and in the central nervous system of lower vertebrates, but very poor in the central nervous system of mammals. Many investigators have sought the reasons for these differences in the hope that understanding them will lead to methods for augmenting recovery of the human brain and spinal cord ...