ABSTRACT
INTRODUCTIONThe central nervous system (CNS) is an intricately evolved organ that requires the precise interplay between neurons, glia and support cells to govern peripheral functions and complex, higher-order central cognition. The brain itself is comprised of roughly 100 billion neurons, each averaging roughly a thousand synaptic connections that participate in a finely choreographed orchestration of intrinsic and extrinsic cellular factors to provide the fundamental framework for developmental wiring and continued synaptic maintenance. Disease or traumatic injury may sever these connections, resulting in loss of function and vastly amplified rates of morbidity and mortality.Promoting CNS regeneration and functional recovery of neural circuitry after injury or disease poses unique challenges
when compared to the natural instigation and growth of neural connectivity during embryonic development. These challenges include diminished rates of intrinsic axon outgrowth capacity, major differences in the scale required for re-connection, and a largely hostile injury microenvironment. To date, no single therapeutic intervention has produced full restoration after injury in the mammalian CNS, although many molecular, cellular, and rehabilitative treatments have been evaluated in both animal and human trials. Pioneering advances in molecular and cellular neurosurgery hold promise in offering safe, highly effective, targeted interventions for positively controlling neural responses to disease and injury. Furthermore, directed neuromodulation may offer insights into mechanisms for enhancing natural human cognitive performance and abilities. This chapter will review both ineffective and promising biological therapies under investigation that are aimed at restoring lost connections due to traumatic injury or neurologic disease and will close with a discussion on where these areas of investigation may take us in the years to come. INTRODUCTION TO NEURAL REGENERATIVE INTERVENTIONSThe adult mammalian central nervous system (CNS) is a tightly structured organ that demands the successful interaction among a vast collection of cell types. Chemically and electrically active neurons, homeostasis-modulating glia, progenitor cells, peripherally derived cells, and vascular elements all work in close juxtaposition to allow for complex neural activity. Traumatic injury or neurodegeneration that damages one or more of these components may lead to major lapses in function, and normal tissue architecture and function are largely unable to be restored once an individual has progressed to maturity and past critical periods of development. When an insult occurs, the various CNS cell types in addition to infiltrating immune and stromal cells from the periphery undergo dramatic changes in cell morphology, motility, and purpose in an effort to halt the injury propagation and maintain or restore a degree of homeostasis and normal performance.Full restoration of the adult CNS faces numerous challenges. Local responses to CNS injury are heterogeneous and often include
hemorrhage, inflammation, excitotoxicity, apoptosis, demyelination, edema and cyst formation, production of free radicals, loss of lipid and membrane integrity, and cellular and collagenous scar formation (Fig. 22.1). Many of these responses may provide early protective benefits, but ultimately impair complete regeneration. For example, early cytokine and chemokine responses by peripheral immune cells and microglia, in addition to physical barriers from fibroblasts and astrocytes, may prove to be advantageous in restricting the primary injury radius [1, 2]. However, these responses, meant to govern spread of the injury, may also later serve to impede migration of progenitor cell populations into the lesion site, as well as limit vascular flow for the clearance of cellular debris and delivery of exogenous therapeutic agents [3].
