From the bench to bedside: Secondary spinal cord injury, ischemic penumbra after stroke, neural regulation of appetite, microglia in Rett syndrome, signaling pathways in peripheral nerve regeneration

Surgical Neurology International, 2012 · DOI: 10.4103/2152-7806.96865 · Published: May 31, 2012

Simple Explanation

Secondary injury in spinal cord injury has been postulated to be due to an inflammatory response propagated by excessive ATP release in surrounding traumatic areas. In this study, the authors explain that the mechanism behind the spread of ATP relies upon the presence of connexin43 (Cx43) channels. In this study, the authors utilized a peptide termed Tat-NR2B9c. This peptide interrupts the protein–protein interactions of PSD-95, a scaffolding protein that connects with NMDA receptors (NMDARs) to build neurotoxic signaling pathways. By utilizing male Mecp2-mutated mice as a model, the authors of this study show that microglia likely play a role in the pathophysiology of Rett syndrome.

Study Duration

Not specified

Participants

Mice, macaque monkeys

Evidence Level

Not specified

Key Findings

1
The researchers found that ATP levels, astrogliosis, and microglia activation were reduced in the KO mice lacking Cx43. Furthermore, the researchers assessed functional recovery of the mice by measuring compound action potentials (CAPs). They found that Cx43 KO mice exhibited improved preservation of spinal cord conduction than CX43 WT mice after spinal cord injury.
2
Interestingly, they found that within the first 24 h, the treatment group exhibited 55% smaller infarct volumes compared with placebo as measured by DWI imaging. Furthermore, the authors noted a 70% reduction in infarct volume as measured by T2-weighted MRI at the 30-day evaluation period.
3
They found that this transplant resulted in longer life spans, increased growth, increased brain weight, improved gait and tremors, and improved breathing, when compared to controls.

Research Summary

This work suggests that Cx43 plays an important role in secondary inflammatory responses after spinal cord injury. With future research, Cx43 may be able to be targeted with an inhibitor and a neuroprotective treatment could be utilized in humans to minimize post-traumatic inflammation. As a whole, these results indicate that administration of Tat-NR2B9c in non-human primates in the right setting can be neuroprotective. Given the similarity between humans and higher-order primates, Tat-NR2B9c seems like an excellent candidate for translation from the bench to the bedside. Thus, the authors conclude that it is indeed the impaired phagocytic ability of microglia that leads to the Rett syndrome pathology. This is a well-done, logical set of experiments that shed light on a complex neurodevelopmental disease, which has been poorly understood.

Practical Implications

Spinal Cord Injury Treatment

Cx43 may be able to be targeted with an inhibitor to minimize post-traumatic inflammation.

Stroke Treatment

Tat-NR2B9c shows promise as a neuroprotective agent in stroke, potentially synergistic with rt-PA.

Rett Syndrome Treatment

Microglia transplantation or selective Mecp2 expression in myeloid cells may improve Rett syndrome phenotypes.

Study Limitations

1
Translation of Tat-NR2B9c to human clinical trials needs further examination.
2
The role of neural regulation of appetite was only mentioned in the title, but not discussed in the body.
3
Further research is needed for ERK pathway inhibitors to accelerate peripheral nerve regeneration.

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