Glutamate, a neurotransmitter that is released in excess amounts during a spinal cord injury, can cause potassium to enter the cell, resulting in the death of nearby neurons by necrosis or apoptosis. Glutamate, however, must first bind to receptor proteins that also act as potassium and calcium gates before these ions can enter neurons. Researchers have studied drugs that block glutamate receptors in the hope of preventing excess potassium and calcium from entering and killing the neuron (Lea and Faden, 2003). The results of human clinical trials of glutamate receptor blockade outside the field of spinal cord injury, however, have been disappointing, with little evidence of efficacy (Muir and Lees, 2003). Some blocking strategies have induced rather than prevented cell death (Lea and Faden, 2003). The key to neuroprotection may be more selective targeting of glutamate receptor subtypes, some of which are responsible for activation (e.g., metabotropic glutamate receptors) and others of which are responsible for inhibition (e.g., ionotropic glutamate receptors) (Lea and Faden, 2003; Movsesyan et al., 2004).
The effects of erythropoietin in mediating tissue protection after a spinal cord injury have also been explored in laboratory experiments. Erythropoietin is a protein that is primarily responsible for stimulating red blood cell production; however, in animals given erythropoietin immediately after a spinal cord injury, the rate of survival of the neurons responsible for controlling movements increased and the treatment resulted in benefits to neurological function (Celik et al., 2002; Brines et al., 2004). Ongoing studies are attempting to replicate and further explore this approach.
Neurons need more than oxygen to survive and flourish. Their sustenance depends on trophic factors, which are small proteins secreted by neighboring cells that come into contact with neuronal cell bodies, dendrites, and areas along the length of the axons. Several trophic factors have successfully been introduced by injection or by minipumps in animal models of spinal cord injury: brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and fibroblast growth factor (FGF), among others (Xu et al., 1995a; Bamber et al., 2001; Jones et al., 2001; Schwab, 2002). The key is to ensure the delivery of the most appropriate factors, as different classes of neurons depend on different trophic factors and some trophic factors may have deleterious effects, such as inducing sensory neurons to become hypersensitive to pain (Krenz and Weaver, 2000). Also key is placement of the appropriate factor at the best anatomical site to deliver levels high enough and continuously enough to keep neurons alive and promote their regrowth. Methods of delivering trophic factors include transplanta-