Molecular mechanisms and management of traumatic brain injury – missing the link?

Beyond a doubt, a detailed description of the molecular neuropathology of TBI represents a challenging task, which is difficult to describe in just a few paragraphs. However, the authors could have expanded their article to include some of what we consider "key" pathways in the cellular and molecular pathophysiology of TBI (Figure 1). For example, the role of neurotoxic proteases, nitric oxide and phospholipases released by damaged tissue, the impact on blood-brain-barrier breakdown by recruited and local inflammatory cells, and the activation of the innate immune system, e.g. the complement system, as a crucial mediator of posttraumatic neuroinflammation, are not mentioned or discussed in the paper. The section devoted to apoptosis provides the reader with some basic textbook information and definitions, but may have benefited from an additional update on the current literature in the field of neuronal apoptosis in TBI. Similarly, the paragraph on gene regulation appears to represent a random selection of candidate genes without a rationale being provided on how alterations in gene regulation may relate to the pathophysiology of TBI. Several references cited refer to studies related to cardiovascular disease, rather than head injury. Most importantly, this section of the manuscript fails to stress the clinical relevance of pathological alterations in gene expression.Finally, as a minor comment, the authors should pay more attention to accuracy in the citation of the pertinent literature. For example, reference #10 is claimed to support a statement on interleukins and cerebral edema, when in fact the citation refers to a publication on programmed cell death in nematodes. Several other examples of inadequate reference to the literature could be mentioned. Finally, the title chosen by the authors appears problematic. The authors claim to provide the "missing link" between molecular mechanisms and therapeutic concepts in TBI. Unfortunately, the review article fails to