Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 47
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Neuroprotection with Growth Factors and Intracellular Signaling in Focal Cerebral Ischemia

A.M. Planas, C. Justicia, B. Friguls and V. Petegnief

Cerebral Ischemia Group, Department of Pharmacology and Toxicology, IIBB-CSIC, IDIBAPS, Barcelona, Spain

In recent years, there has been considerable basic research on neuroprotective drugs for the treatment of cerebral ischemia. As a result, a number of drugs have been found that act at different levels, attenuating the cascade of reactions that cause neuronal loss and, ultimately, brain damage in laboratory animals. However, this research has had disappointing results when it has been transferred to stroke patients. The reasons for this contradiction are complex and require thorough analysis both by basic researchers (drug administration time, functional recuperation, subject's age, and physiological status, including high blood pressure, diabetes, etc.) and by clinicians (treatment window, patient selection
criteria, etc.).

It is clear that a key aspect of protection against ischemia is to minimize its duration and, when possible, recanalize the tissue using thrombolytic therapy, provided that patients meet certain clinical requirements and the treatment can be given in the first 3-6 h. Hence the number of patients who are eligible for receiving this treatment is limited. In many clinical trials performed in the past, the treatment windows were more than 24 h. Therefore, it remains possible that some drugs that have shown favorable results in animals may also be effective in patients if the administration time is reduced.

Among other compounds, the results obtained with growth and neurotrophic factors have been encouraging. Thus, for example, our group has shown that the acute administration of the growth factor TGF-a reduces the volume of cerebral infarct in rats, both in permanent ischemia (1) and in ischemia/reperfusion (2). This protective effect of TGF-a is effective in adult rats even when administered 3 h after occluding the middle cerebral artery for 1 h. One of the drawbacks of this treatment is the administration route, which, in our case, has been intraventricular. As a result of this and other treatment limitations with these factors, any consideration of their therapeutic possibilities must be viewed with caution.

However, numerous studies are currently underway aimed, on one hand, at enhancing the entry into the brain of compounds that do not naturally cross the blood-brain barrier and, on the other hand, at developing selective gene therapies to promote the expression of certain molecules in certain cells. In any case, the study of factors with neuroprotective action is interesting in order to identify the intracellular signaling pathways that are activated, which opens another avenue for therapeutic intervention.

At an intracellular level, studies are in progress on signaling pathways that promote neuron survival, either because they enhance the so-called survival pathways or because they inhibit death pathways. Focal cerebral ischemia causes activation of the pathways of the MAP kinases ERK1/2 in neurons and the endothelium 1 h after commencement of ischemia. This effect is mitigated by therapy with TGF-a. A priori identifies ERK as a signaling pathway involved in cell death, which is in line with previous data from the literature that show the neuroprotective effect of an ERK1/2 activation inhibitor (3). However, the initial stimulus that promotes ERK activation in ischemia is unknown.

With the aim of elucidating whether the excitotoxic action of the massive stimulation of NMDA receptors was involved in ERK1/2 activation, we administered MK-801, a noncompetitive antagonist of the NMDA receptor with neuroprotective action. To our surprise, we found that instead of attenuating the ERK1/2 signal induced by ischemia, MK-801 activated it, which led us to question the role of ERK1/2 in cell death. However, MK-801 also enhanced the ischemia-induced activation of Akt, a classic survival pathway (4), while TGF-a did not modify Akt activation. These observations show the complex context of interaction between multiple signaling pathways that will ultimately lead to cell survival or death.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 47
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com