Development of novel pharmacotherapies for the treatment of traumatic injury to the nervous system has
been ongoing for over 40 years. Despite many promising compounds discovered using animal models, no treatments
have successfully translated into the clinic. The central dogma in this field is that brain trauma initiates a
complex chain of biochemical events leading to secondary brain damage and sustained neurological deficits. The
delayed secondary brain injury is likely to result from multiple insults including oxidative stress, mitochondrial
dysfunction, breakdown of the blood brain barrier, dysregulated release of glutamate, pro-inflammatory cytokines,
and other mediators. However, therapies targeting these systems have generally met with failure in clinical trials.
The purpose of this review is to summarize the models used for preclinical neurotrauma research, provide a brief
overview of previous failed clinical trials in head and spinal cord injury, and finally, to review involvement of the cholinergic system and
discuss implications for future research. Possibilities and pitfalls of targeting the cholinergic system for neuroprotection and/or enhancement
of functional recovery are also discussed.