About 600,000 Americans suffer ischemic stroke each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke is therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today and since many patients present far beyond the three hour window of current treatments, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of molecules able to protect neural tissue from ischemic damage Considerable evidence is available supporting a role of apoptosis in cerebral ischemia especially when the excitotoxic insult is relatively mild. Neuronal necrosis also occurs and the balance between the relative importance of these two cell death pathways is variable.

Previous studies have reported that the reference GSK-3 inhibitor, lithium protects neurons from apoptosis and promotes neurite growth including that induced by NMDA. In vivo, cerebral artery occlusion results in the activation of GSK-3 further implicating this enzyme in stroke. Furthermore, in their 1998 publication Nonaka & Chuang (click here for abstract) reported that chronic lithium pretreatment significantly improved neurological deficits in animals subjected to cerebrovascular occlusion. This was related to a 50% reduction in ischemic infarct size. In a more recent study Dr Chuang’s group at the National Institute of Mental Health further investigate the utility of lithium in the context of stroke. In the May edition of PNAS this group report that in addition to pretreatment with lithium, its administration 3 hours after middle cerebral artery occlusion conferred an improvement in neurological deficit that was comparable to treatment immediately after occlusion. The effects of lithium correlated with a reduction in apoptosis and with an increase in levels of HSP70, a factor that has long been associated with cellular stress and more importantly an endogenous mechanism that has evolved to protect cells against stress. In addition to HSP70, its transcription factor HSF1was also elevated by lithium and this is likely related to the inhibition of GSK-3 by lithium since GSK-3 has been shown to negatively regulate both DNA binding activity of HSF1 and its subsequent transcriptional activation of HSP70.

This data therefore further implicates GSK-3 as a target for the treatment of stroke and most importantly this study suggests that GSK-3 inhibitors such as lithium may be effective at least 3 hours after the onset of stroke. In addition to inhibiting GSK-3 lithium has a number of other modes of action. These include lithium’s ability to inhibit N-methyl-D-aspartate receptors, up-regulate cytoprotective Bcl-2, down-regulate proapoptotic p53 and Bax, inhibit glutamate-induced mitogen-activated protein kinase activation, facilitate glutamate uptake into presynaptic nerve endings, induce the expression of brain-derived neurotrophic factor in discrete brain areas, and enhance neurogenesis in the hippocampus. These actions require long-term treatment and could be more likely involved in the ‘‘delayed’’ phase of the neuroprotective effects of this drug. In conclusion therefore through its effect on GSK-3 and other molecular targets, lithium represents a promising treatment for the treatment of stroke at a time-period currently devoid of effective and safe treatment options. Clinical trials to evaluate this possibility are eagerly awaited. Readers wishing to access a full analysis of the pharmaceutical and therapeutic potential of GSK-3 inhibitors may wish to access LeadDiscovery’s recent dossier on this subject (Click here for access).

Entry date Monday, June 30, 2003

Adapted from Ren et al, Proc Natl Acad Sci U S A. 2003 May 13;100(10):6210-5

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