Spinal cord injury (SCI) resulting in impaired neurological functions creates suffering and economic burden. Directly after the injury, the conservation of tissue at the lesion site and the preservation of the connectivity through the injury epicenter have highest priority. This tissue preservation will not only reduce neurological deficits, but also and allows for more rapid and extensive recovery. Advances in clinical care intended to accomplish this goal include early surgical decompression, support of blood pressure, and the subject of this chapter - experimental neuroprotective therapeutics. The scientific foundation of neuroprotection is that "harmful" secondary injury processes extend and distribute the tissue loss caused by the primary injury event. Existing clinical knowledge together with preclinical experimental evidence has supported phase III clinical trial translation of some neuroprotective agents in the past four decades. Although some have had positive results, the magnitude of improvement was small, and associated complications and controversy surrounding certain therapeutics diminished their role in SCI care. However, these trials generated knowledge valuable to guide current work. Neuroscientists continue to develop new therapeutic approaches by demonstrating neuroprotective efficacy in small and large animal models. A consensus now exists that the preclinical data set to support the expensive process of translation must be very robust and include a well conducted independent replication. Primary endpoints for pivotal clinical trials have been clarified on the basis of aggregate experience and extensive studies on the natural history of SCI. "Secondary injury" consists of numerous mechanisms, and the probability of a robust protective effect of a single agent is small. It is necessary to design rational combinations of therapies to increase efficacy.
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