Drug development for stroke: importance of protecting cerebral white matter

Multiple pharmacological mechanisms have been identified over the last decade which can protect grey matter from ischaemic damage in experimental models. A large number of drugs targeted at neurotransmitter receptors and related mechanisms involved in ischaemic damage have advanced to clinical trials in stroke and head injury based on their proven ability to reduce grey matter damage in animal models. The outcome to date of the clinical trials of neuroprotective drugs has been disappointing. Although the failure to translate preclinical pharmacological insight into therapy is multifactorial, we propose that the failure to ameliorate ischaemic damage to white matter has been a major factor. The recent development of quantitative techniques to assess ischaemic damage to cellular elements in white matter, both axons and oligodendrocytes, allows rigorous evaluation of pharmacologic mechanisms which may protect white matter in ischaemia. Such pharmacological approaches provide therapeutic opportunities which are both additional or alternatives to those currently being evaluated in man.