The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy.
A number of studies have validated the importance of caspase activation in ischemia-induced brain damage. Caspases participate in both the initiation and execution phases of apoptosis, and play a central role in neuronal death after global cerebral ischemia. In focal ischemia, apoptosis occurs in the penumbra during the secondary phase of expansion of the lesion. However, ultrastructural and biochemical analysis have also shown signs of apoptosis in the initial lesion, or infarct core, which is traditionally considered necrotic. Specific caspase pathways are activated in the core and in the penumbra, and participate in both cytoplasmic and nuclear apoptotic events, notwithstanding their initial classification as activator or initiator caspases. This confirms previous suggestions that caspase inhibition holds tremendous neuroprotective potential in stroke and other apoptosis-related degenerative diseases. Consequently, two new approaches, aimed at treating stroke-induced brain damage by anti-apoptotic molecules, are being developed in academic and industrial laboratories. These are based, respectively, on the use of small peptide sequences corresponding to the preferred cleavage site of a caspase, and on genomic constructions derived from the fusion of endogenous anti-caspase molecules with a protein transduction domain from the human immunodeficiency virus-1. Fusion proteins containing endogenous caspases inhibitors efficiently counteract apoptosis in vitro. In in vivo models of focal cerebral ischemia, fusion proteins successfully cross the blood brain barrier and protect cells from ischemic death. This new approach by protein therapy could prove to be an interesting alternative for the reduction of the dramatic consequences of stroke, provided that the long-term efficiency of this protection in terms of functional recovery is demonstrated.
Onténiente
Brigitte
B
INSERM U421/IM3, Université Paris-Val-de-Marne, 8, rue du Général Sarrail, 94010 Créteil Cedex, France. ontenien@im3.inserm.fr
Couriaud
Cécile
C
Braudeau
Jérôme
J
Benchoua
Alexandra
A
Guégan
Christelle
C
D017209:Apoptosis; D002545:Brain Ischemia / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D020521:Stroke / Q000188:drug therapy / Q000209:etiology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors