The vast majority of neurons in the adult mammalian central nervous system are terminally differentiated and if they are injured they will not be able to regenerate their connections. The failure of these neurons to regenerate has been ascribed to the lack of permissive molecules and/or presence of inhibitory molecules in the environment and their intrinsic inability to activate the genetic program for neurite outgrowth.
Many studies of the CNS microenvironment have revealed numerous molecules that inhibit neurite outgrowth as well as a lack of trophic factors. However, many types of neurons are unable to regrow even after permissive factors have been added and inhibitory factors have been neutralized. This strongly suggests the importance of possible intrinsic factors in the regenerative process. A complete understanding of the molecular events required for a successful regeneration is still needed.
In addition to environmental and intrinsic obstacles to regeneration, there is often a build-up of oxidative agents following injury or disease onset that may lead to additional damage in the afflicted region. This accumulation of toxic oxidative agents has been studied in both acute injuries and in chronic neurodegenerative conditions. In Alzheimer's disease, one hallmark of the disorder is the build-up of neurotoxic β-amyloid plaques in the brain. Oxidative stress on neurons, caused by these plaques, has been linked to the pathology of the disease. There is also ample evidence from animal models for enhanced oxidative stress from reactive oxygen species (ROS) in the brain following a cerebral ischemia model of stroke. Direct clinical studies verifying the relation between stroke and oxidative stress are scarce mainly because ROS are shortlived compounds. Indirect evidence for this relationship has come from experimental models and clinical trials demonstrating the efficacy of antioxidant treatment for stroke. These studies show that antioxidants are able to reduce infarct size, edema, and lesion size following cerebral ischemia and as such antioxidant compounds are candidates for stroke therapy.
Oxidative stress frequently leads to cell death and this is consistent with increasing evidence supporting a major role for apoptosis in degenerative and damage-induced neuronal death. The pathology of Parkinson's disease (PD) involves the death of neurons in the substantia nigra, and studies with cell cultures, animal models and PD patients indicate that apoptosis may be the cause of neuronal loss. Acute injuries may also result in substantial neuronal death via apoptosis. The initial mechanical injury of to the spinal cord is followed by a period of secondary injury that increases the size of the lesion. There is now strong morphological and biochemical evidence from a number of laboratories demonstrating the presence of apoptosis during this secondary phase. Apoptosis occurs in populations of neurons, oligodendrocytes, microglia, and, perhaps, astrocytes. There is evidence for the activation of important intracellular pathways known to be involved in apoptosis including some members of the caspase family. Various models of optic nerve injury and cerebral ischemia also support a role for apoptotic cell death following acute injury.
Many factors have been manipulated to protect neurons from damage and to promote regeneration in the CNS. One common strategy is the transplantation of stem cells to the site of injury, theoretically providing an optimal substrate for regenerating neurons. The administration of stem cells in rat models of spinal cord injury has produced mixed results. In some cases the transplant-derived cells survive, differentiate, and result in improved locomotor function. However, despite the multipotent capacity of neural stem cells, many studies report few differentiated cells and little or no functional recovery. The latter results underscore the need to identify and manipulate the extrinsic and intrinsic molecular mechanisms responsible for successful neuroregeneration.
While the cascade of events that occurs during regeneration is still poorly understood, many attempts to alter known players in this process are already underway. As noted earlier, many investigators have attempted to stimulate neuroregeneration by either neutralizing inhibitory molecules, adding permissive molecules, or both. Other efforts seek to limit damage by treating neurons with neuroprotective agents to decrease oxidative stress and apoptosis. A better understanding of the components required for a successful regenerative response is needed to improve therapies. Protection from toxic insults and death, and the repair and regeneration of the injured or degenerating neural tissue are the major hurdles to the effective treatment of central nervous system injuries and degenerative diseases. The search for molecules and functions that may aid in these processes is a crucial step toward treatment.