Abstract
Objective: In this review, we analyze progress in the treatment of traumatic brain injury with neurotrophins, growth factors and cell and tissue neurotransplantation. The primary objective of these therapies is to reduce neurologic deficits associated with the trauma by inducing neuroplasticity. These therapies are restorative and not necessarily neuroprotective.
Main outcome measures: An extensive literature on administration of neurotrophics factors and cell and tissue cerebral transplantation is reviewed. The effects of these therapeutic approaches on brain biochemical, molecular, cellular, and tissue responses are summarized.
Conclusion: The cumulative data indicate that cell therapy shows substantial promise in the treatment of neural injury.
TRAUMATIC BRAIN INJURY (TBI), defined as brain damage caused by externally inflicted trauma to the head, may result in significant impairment of an individual's physical, cognitive, and psychosocial function. TBI remains a major public health problem worldwide. In the United States, an estimated 1.5 to 2 million people incur TBI each year. The number of people surviving TBI has increased significantly in recent years because of faster and more effective emergency care, quicker and safer transportation to specialized treatment facilities, and advances in acute medical management. TBI strikes people across the age range and is the leading cause of disability among children and young adults. Each year, approximately 70,000 to 90,000 individuals have a TBI so severe that they are left with irreversible and debilitating loss of function. The result is frequently a dramatic change in the individual's life course, profoundly disorganizing effects on the family, and huge medical and related expenses over a lifetime. 1
For persons with TBI, brain injury not only causes damage in the lesion area, but also affects the structurally intact brain network connected to the lesion. 2 Regulating selected gene expression (such as neurotrophic factors) and stimulating endogenous restorative mechanisms (such as synaptogenesis and neurogenesis) can attenuate cellular damage, remodel brain and subsequently improve behavioral function after TBI. 3 Structural changes provoked by external stimuli are called "plasticity." In brain areas surrounding the lesion in trauma, as well as those remote from it, the plasticity of the brain is increased because of alterations of neurotransmitter expression, trophic factor expression and membrane properties of neurons. Lesion-induced plasticity may restore function in the perilesional zone. 4 Brain damage causes neuronal cell death and diffusive axonal injury, disrupts the neuronal circuitry, and results in specific behavior deficits that may or may not be compensated by injury-evoked plasticity processes, 5 even though the plasticity can be greatly modulated by interventions ranging from intensive medical care to pharmacologic therapy. 6
A vast literature on adult brain plasticity demonstrates that the adult brain is a highly dynamic structure. 7 Until quite recently, however, the belief that the entire population of nerve cells in the adult brain was generated exclusively during embryonic development was dogma. However, we now know that neuroplasticity should be thought not only to be a matter of subtle changes in synapses (synaptogenesis) and neuronal connections but also as the generation of new nerve cells (neurogenesis).
The concept of neuronal plasticity in the adult brain was formulated by Donald Hebb, who postulated that synapses that are frequently transmitting action potentials are selectively strengthened in the process, whereas other synapses disappear. 8 This view has since been extended to include plasticity of many definable anatomical substrates, such as synapses, neurites, or entire cells (cellular level). Changes at the cellular level are in turn based on changes at biochemical and molecular levels 7 and also influence tissue and organic function.
Neurotransplantation and cell transplantation have become widely recognized as powerful experimental tools for studying structure-function relationships, development, neuroplasticity, and regeneration in the adult central nervous system (CNS), 9 and have recently shown promise to repair brain injury and to restore function after TBI. Tissue and cell therapy may have advantages over single pharmacotherapy in that: (1) the grafts may anatomically reconstruct the injured brain; (2) the grafts may establish connections with host cells; (3) exogenous cells entering brain may produce many neurotrophins or growth factors 10,11; (4) exogenous cells provoke endogenous cell to express neurotrophins and growth factors 10; (5) the interaction between exogenous cells and endogenous cells is dynamic and sensitive to the microenvironment; and (6) exogenous cells target the injured area. Transplantation may also activate latent or silent pathways that exist in brain or promote newly formed pathways after injury, and thereafter benefit functional improvement.
This review is devoted to analysis of the literature as well as our investigations about the influence of the different tissues and cell grafts on the compensatory-restorative processes (neuroplasticity) in the central nervous system after TBI.