Abstract
Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.
Highlights
Brain and neural injury is a non-specific disease category that includes traumatic brain injury (TBI), stroke, and intrinsic neurodegenerative diseases
The complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration
Neuroprotective therapeutics have, in general, provided disappointing results in clinical trials, despite the fact that most of the reagents investigated in the clinic showed promise in preclinical studies
Summary
Brain and neural injury is a non-specific disease category that includes traumatic brain injury (TBI), stroke, and intrinsic neurodegenerative diseases. Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here? A 2003 phase II clinical trial assessed the use of Pexelizumab as a potential treatment in CABG patients to reduce complement-mediated tissue damage and associated systemic inflammation, with the goal of reducing neurological injury and deficits [40].
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