Inhibition of Apoptotic Neurodegeneration

Most of the therapeutic strategies discussed thus far are mainly associated with inhibition of 'necrotic' or 'oncotic' CNS neuronal, glial, and microvascular damage after ischemic or traumatic insults. On the other hand, a potentially promising area of neuroprotective drug discovery for treating ischemic and traumatic CNS injury is the development of agents targeting apoptotic cell death. Although apoptosis probably plays some role in the acute phase (first 24-48 h) after ischemic or traumatic insults, a number of studies have documented that apoptosis is perhaps the dominant mechanism of ongoing cell loss over the days, weeks, and possibly months following CNS injury. For example, apoptotic cell death can be detected hours to several weeks following SCI, and occurs in numerous cell types, including neurons, oligodendroglia, and inflammatory cells such as neutrophils, microglia, and macrophages.79

A major factor and potential neuroprotective drug target involved in the intracellular apoptotic cascade is the activation of the cysteine protease caspase-3, which appears to be a common endpoint regardless of the initiating stimulus for apoptosis.80 Indeed, caspase-3 activation has been demonstrated in all types of CNS injury models, including those for TBI, SCI, and stroke.81 The biochemical pathway(s) leading to caspase-3 activation have been extensively studied using in vitro models of apoptotic cell death, and it has been well documented that the mitochondria are thought to play a critical, if not essential, role in caspase-3 activation. Apoptotic signals reaching mitochondria result in the release of cytochrome c and Smac/DIABLO82; the former then interacts with Apaf-1 (apoptosis protease activating factor-1) to promote the caspase-9 activation, an upstream activator of caspase-3. Smac/ DIABLO promotes capsase-9 and caspase-3 activation by removing the inhibitory influence of members of the IAPs

(inhibitor of apoptotic proteins) family. 3 In addition, the mitochondria can also release pro-apoptotic molecules, such as endonuclease g and apoptosis-inducing factor (AIF), which are thought to function independently of caspase activation.84 Therefore, a number of signaling events associated with mitochondria regulate activation of a caspase-dependent and -independent apoptotic cell-death programs. Targeting these signaling events at the mitochondrial level, in addition to upstream apoptotic signaling, will be essential in determining the contribution of this cell-death process to neurological dysfunction in stroke, TBI, and SCI.

To date, it is evident that a clear understanding of the extracellular events leading to transduction of an apoptotic signal in the injured CNS is lacking. This is an important research area, as inhibiting the extracellular signals as far upstream as possible should limit postischemic or posttraumatic apoptosis to a greater degree than targeting the intracellular pathway(s). Several studies have implicated potential candidate molecules as extracellular apoptotic signals in the injured CNS, including pro-inflammatory cytokines, certain growth factors, Fas ligand, and glutamate. There is additional evidence that ROS (e.g., superoxide radical and peroxynitrite) can also lead to apoptosis. What is clear from this limited list is that, although caspase-3 can be considered as the common endpoint in the apoptotic biochemical cascade, there are a number of potentially interruptable extracellular signals that could contribute to

CONH,

O XN

O XN

CONH,
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...

Get My Free Ebook


Post a comment