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