Best time window for the use of calcium‐modulating agents to improve functional recovery in injured peripheral nerves—An experiment in rats

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More than 10 million people sustain nerve injuries around the world each year. Severe peripheral nerve injuries can lead to devastating long‐term functional impairments for patients, while also burdening family members and society. Although advancements in modern techniques and tools have been made, the final functional outcome after nerve repair remains far from ideal. The first extensive study of nerve repair results came from Woodhall and Beebe in 1956, who reported on 3,656 injuries sustained during World War II with an average 5‐year follow‐up (Mackinnon and Dellon, 1988). The results of this study were relatively poor, tainting the concept of nerve repair in the minds of surgeons for years. Despite modern‐day advantages of microsurgical techniques, fair to poor outcomes are unfortunately still common, with only about 50% of patients regaining useful function after nerve injury and repair (Lee and Wolfe, 2000). For this reason, a large focus on research to improve the results of nerve repair and regeneration still exists. Strategies to reach this end fall under four major categories: pharmacologic agents, immune system modulators, enhancing factors, and entubulation conduits. Our previous studies have demonstrated encouraging results from using calcium‐modulating agents to speed calcium clearance from damaged peripheral nerves, which was correlated with improved nerve regeneration and functional recovery (Yan et al., 2010).
Calcium plays a central role in maintaining neuron homeostasis. Under normal conditions, healthy neurons are able to maintain a Ca2+ concentration gradient of 10−7 M intracellularly and 10−3 M extracellularly (Tymianski and Tator, 1996). However, if the mechanisms for maintaining this gradient are disrupted, as seen after nerve injury, excess Ca2+ can accumulate inside the cell. Abnormally high Ca2+ influx can easily overwhelm the neuron membrane adenosine triphosphate (ATP)‐driven Ca2+ pump (calcium‐ATPase) and can also cause the Na+/Ca2+ exchange transport mechanism to operate in reverse, pumping Ca2+ in and Na+ out, resulting in an uncontrolled rise in the concentration of unbound intracellular Ca2+ (Blaustein, 1988; Mattson et al., 1989; Kiedrowski et al., 1994). High intracellular Ca2+ is also a result of compromises to the Schwann cell membrane (myelin sheath) secondary to mechanical insult or ischemia (Lucas et al., 1985; Shi et al., 1989; Chen et al., 1998; Strautman et al., 1990). Numerous studies have demonstrated that high calcium levels are associated with accelerated axonal injury, Wallerian degeneration, and activation of numerous Ca2+‐dependent cascades including those of apoptosis (Jancso et al., 1984; Goldberg et al., 1989; Manev et al., 1989; LoPachin and Lehning, 1997; Martinez and Ribeiro, 1998; Ward et al., 2005; Vander et al., 2008; Dietz et al., 2009; Ma et al., 2009). The goal of this study is to investigate the effect of peripheral nerve injury on local calcium concentration, calcium‐ATPase expression, and nerve functional recovery over the course of 24 weeks during nerve regeneration to determine an optimal time frame in which calcium‐modulating therapy should be initiated to speed nerve regeneration.
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