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transduction of the apoptotic signal. Therefore, it will be important to determine the contribution of each of these different extracellular events to the overall apoptotic cell loss that occurs in stroke and trauma models.

Exploration of the potential of blocking the apoptotic cascade as a neuroprotective strategy has been limited by a lack of small-molecule inhibitors of selected points in the apoptotic cascade that have drug-like pharmaceutical properties and good CNS penetrability. Current exploratory strategies involve the use of competitive caspase inhibitors containing tri- and tetrapeptide amino acid sequences that are preferred by certain caspases. While these inhibitors have been modified to enhance cell permeability and stability, the delivery of sufficient levels to the cells of interest over a broad time window and to areas distant to the site of injury may be very limited. Thus, evidence of their efficacy has been limited primarily to in vitro studies. In addition, the short half-life of these peptide-based compounds (e.g., the caspase-3 inhibitor z-DEVD-fmk) may reduce their effective concentration. For example, the presence of numerous proteases released in the injured brain or spinal cord could certainly limit the amounts of intact peptide that ultimately cross the blood-brain barrier. Nevertheless, these compounds are effective in models of CNS injury.81 There are several unanswered concerns regarding the pharmacological inhibition of apoptosis in the injured CNS. Firstly, will inhibition of caspase-dependent apoptosis shift the mode of death to caspase-zndependent apoptosis of necrosis? Secondly, is caspase activation a normal physiological process that plays a role in cellular functions such as cytoskeletal rearrangement? Thirdly, might caspase inhibitors lead to the survival of dysfunctional cells? Further study with improved anti-apoptotic new compound entities will be required to address these questions.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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