Adenosine neuromodulation and traumatic brain injury.

Adenosine is a ubiquitous signaling molecule, with widespread activity across all organ systems. There is evidence that adenosine regulation is a significant factor in traumatic brain injury (TBI) onset, recovery, and outcome, and a growing body of experimental work examining the therapeutic potential of adenosine neuromodulation in the treatment of TBI. In the central nervous system (CNS), adenosine (dys)regulation has been demonstrated following TBI, and correlated to several TBI pathologies, including impaired cerebral hemodynamics, anaerobic metabolism, and inflammation. In addition to acute pathologies, adenosine function has been implicated in TBI comorbidities, such as cognitive deficits, psychiatric function, and post-traumatic epilepsy. This review presents studies in TBI as well as adenosine-related mechanisms in co-morbidities of and unfavorable outcomes resulting from TBI. While the exact role of the adenosine system following TBI remains unclear, there is increasing evidence that a thorough understanding of adenosine signaling will be critical to the development of diagnostic and therapeutic tools for the treatment of TBI.

Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels.

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-d-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker omega-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na(+)-Ca(2+) exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na(+) channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na(+)-Ca(2+) exchanger.

High tolerance and delayed elastic response of cultured axons to dynamic stretch injury.

Although axonal injury is a common feature of brain trauma, little is known of the immediate morphological responses of individual axons to mechanical injury. Here, we developed an in vitro model system that selectively stretches axons bridging two populations of human neurons derived from the cell line N-Tera2. We found that these axons demonstrated a remarkably high tolerance to dynamic stretch injury, with no primary axotomy at strains <65%. In addition, the axolemma remained impermeable to small molecules after injury unless axotomy had occurred. We also found that injured axons exhibited the behavior of "delayed elasticity" after injury, going from a straight orientation before injury to developing an undulating course as an immediate response to injury, yet gradually recovering their original orientation. Surprisingly, some portions of the axons were found to be up to 60% longer immediately after injury. Subsequent to returning to their original length, injured axons developed swellings of appearance remarkably similar to that found in brain-injured humans. These findings may offer insight into mechanical-loading conditions leading to traumatic axonal injury and into potential mechanisms of axon reassembly after brain trauma.