Abstract
The goal of this chapter is to discuss the importance of preclinical evaluation of potential therapies for neurological disorders in animal models that mimic the target human disorder as a prelude to the translation of these into clinical trials. The scope of neurological and/or neurosurgical disorders that could be considered herein includes both acute neurological insults as well as chronic conditions such as epilepsy, neuropathic pain and the neurodegenerative disorders, primarily Alzheimer’s disease, Parkinson’s disease and the motor neuron diseases, mainly amyotrophic lateral sclerosis. Animal models for all of these conditions have been devised and used to evaluate potential therapies. However, a single chapter cannot possibly do justice to this wide range of disorders and associated models. Thus, in order to keep the subject of neurological animal studies manageable, the focus of this chapter will be on models and basic principles of preclinical evaluation of therapies in the context of acute neurological injuries including stroke, cardiac arrest and cardiopulmonary resuscitation (CA/CPR), traumatic brain injury (TBI) and spinal cord injury (SCI). These acute insults represent 4 of the most catastrophic consequences that human beings can suffer. Furthermore, the discussion of how to test therapies in models of these conditions will be couched primarily in relation to pharmacological therapies. However, many, if not all principles that define a thorough preclinical evaluation of drugs in animal models are in fact equally applicable to gene and cellular transplant therapies. There are approximately 750,000 strokes per year in the US, most, but certainly not all, affecting the elderly population. About 85% of strokes are ischemic in nature, involving a thromboembolic blockage of a brain artery; up to 15% of strokes are hemorrhagic. There are 2 types of hemorrhagic strokes: intracerebral hemorrhage (ICH) when blood is released into brain parenchyma producing brain damage by triggering brain edema (swelling) and mass effects, resulting in secondary ischemia within the brain tissue, and subarachnoid hemorrhage (SAH) when blood is released into the subarachnoid space from an aneurysm ballooning out from one of the major arteries, also causing a secondary ischemic insult from induction of delayed cerebral vasospasm peaking at 4–7 days after SAH. There are about 30,000 aneurysmal SAH per year in the US with a 2:1 female:male preponderance. Cardiac arrest strikes about 600,000 people per year in the USA and leads to high mortality and poor neurological outcome. Many survivors of CA/CPR have moderate to severe neurological deficits many months following the event. Survival rates following CA/CPR have not changed for decades despite improvements in resuscitation techniques. The lack of effective treatment options to ameliorate reperfusion injury in the postresuscitation period likely accounts for the disappointing survival rates. Recently, however, induction of mild hypothermia in unresponsive cardiac arrest survivors showed improved neurological outcome and 6-month survival. This was the first demonstration in humans that development of brain injury after CA/CPR could be positively influenced by a postischemic intervention. There are an estimated 1.5 million cases per annum of TBI in the US, ranging from mild to severe. Although most TBI cases are mild in severity, about 58,000 are severe (Glasgow Coma Score: 3–8) and 64,000 moderate (Glasgow Coma Score: 9–12) and such individuals often require intensive medical treatment and extended recovery periods. Further, there are about 11,000 new cases of SCI each year in the US with an overall prevalence of approximately 250,000. Although TBI and SCI affect active individuals of any age, most occur in young adults in the second and third decades of life. Moreover, the majority of stroke, TBI and SCI patients now survive their neurological insults due to improvements in emergency, neurological intensive care and surgical treatments. Nevertheless, the need for intensive rehabilitation and the reality of prolonged disability exacts a significant toll on the individual, his or her family and society. Effective ways of maintaining or recovering function could markedly improve the outlook for persons with these insults by enabling higher levels of independence and productivity.
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