accumulation then leads to neuronal degeneration by enzyme activation, including proteases, kinases, phosphatases, and phospholipases, and induction of additional ROS release.5

The principal mechanism of posttraumatic Ca2 + -mediated secondary neuronal injury involves the activation of the neutral proteases known as calpains.69'70 When activated, calpains degrade cytoskeletal proteins, receptor proteins, signal transduction enzymes, and transcription factors. In the case of cytoskeleton proteins, a-spectrin (a 280 kDa protein that provides structural support to membranes) can be cleaved by calpain at tyrosine 1176 to yield a 150 kDa fragment (SBDP150), or at glycine 1230 to yield a 145 kDa fragment (SBDP145). This is consistent with the notion that cytoskeletal damage is the final common mechanism of posttraumatic neurodegeneration. Therefore, its inhibition is a meaningful biochemical measure of the efficacy of upstream neuroprotective strategies. A key role of calpain activation in mediating posttraumatic axonal damage in acute SCI models has been demonstrated using prototypical calpain inhibitors, including leupeptin, antipain, calpain inhibitor I and II, calpeptin, E64, AK295, MDL28170, SJA6017, and PD150606, which have neuroprotective effects (Figure 10).70 However, the potential translation of calpain inhibition into neuroprotective clinical trials has been limited by a lack of small-molecule inhibitors with sufficient CNS penetration and appropriate pharmaceutical and pharmacokinetic properties for use as drugs. Nevertheless, newer ketoamide calpain inhibitors with improved membrane penetration and water solubility have been discovered, and these need to be evaluated in stroke and CNS injury models (Figure 10).72,73

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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