Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Due to its high incidence rate and often long-term sequelae, TBI contributes significantly to increasing costs of health care expenditures annually. Unfortunately, advances in the field have been stifled by patient and injury heterogeneity that pose a major challenge in TBI prevention, diagnosis, and treatment. In this review, we briefly discuss the causes of TBI, followed by its prevalence, classification, and pathophysiology. The current imaging detection methods and animal models used to study brain injury are examined. We discuss the potential use of molecular markers in detecting and monitoring the progression of TBI, with particular emphasis on microRNAs as a novel class of molecular modulators of injury and its repair in the neural tissue.

Receptor mediated transcytosis harnessing the cellular uptake and transport of natural ligands across the blood-brain barrier (BBB) has been identified as a means for antibody delivery to the CNS. In this study, we characterized bispecific antibodies in which a BBB-crossing antibody fragment FC5 was used as a BBB carrier. Cargo antibodies were either a high-affinity, selective antibody antagonist of the metabotropic glutamate receptor-1 (BBB-mGluR1), a widely abundant CNS target, or an IgG that does not bind the CNS target (BBB-NiP). Both BBB-NiP and BBB-mGluR1 demonstrated a similar 20-fold enhanced rate of transcytosis across an in vitro BBB model compared with mGluR1 IgG fused to a control antibody fragment. All 3 bispecific antibodies exhibited identical pharmacokinetics in vivo Comparative assessment of BBB-NiP and BBB-mGluR1 revealed that, whereas their serum pharmacokinetics and BBB penetration were identical, their central disposition (brain levels) and elimination (cerebrospinal fluid levels) were widely different, due to central target-mediated removal of the mGluR1-engaging antibody. Central mGluR1 target engagement after systemic administration was demonstrated by a dose-dependent inhibition of mGluR-1-mediated thermal hyperalgesia and by colocalization of the antibody with thalamic neurons involved in mGluR1-mediated pain processing. We demonstrate the feasibility of targeting central G-protein-coupled receptors using a BBB-crossing bispecific antibody approach and emerging principles that govern brain distribution and disposition of these antibodies. These data will be important for designing safe and selective CNS antibody therapeutics.-Webster, C. I., Caram-Salas, N., Haqqani, A. S., Thom, G., Brown, L., Rennie, K., Yogi, A., Costain, W., Brunette, E., Stanimirovic, D. B. Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1.

It was previously shown that pinealectomy causes delayed loss of pyramidal neurons in rat hippocampal layers CA1/3 and that this is reversed by melatonin supplementation. Here, we used immunohistologic detection of doublecortin, a protein expressed in newborn neurons, to determine if melatonin supplementation promotes neurogenesis after pinealectomy. It was found that melatonin supplementation significantly increased the number of doublecortin immunoreactive neurons in the dentate gyrus over the postsurgical intervals of 2, 4, 6, 8, 10 and 17 months. The increase was most evident at 6 months postsurgery and thereafter, and was apparent despite a severe decline in doublecortin-labeled cells over the 17 month postsurgical interval in all groups of rats. Doublecortin immunoreactive cells were not observed in the pyramidal layer itself. These results indicate that melatonin promotes neurogenesis in the dentate gyrus of pinealectomized rats. However, it is equivocal that these newborn neurons migrate to the pyramidal layer and account for the reappearance of neurons at this location in these rats. This study provides further evidence for a role of melatonin in promoting neurogenesis, adding another role to its already remarkably pleiotropic profile. The scope and significance of this newly discovered role remains to be determined.

The amniotic membrane (AM) and amniotic fluid (AF) have a long history of use in surgical and prenatal diagnostic applications, respectively. In addition, the discovery of cell populations in AM and AF which are widely accessible, nontumorigenic and capable of differentiating into a variety of cell types has stimulated a flurry of research aimed at characterizing the cells and evaluating their potential utility in regenerative medicine. While a major focus of research has been the use of amniotic membrane and fluid in tissue engineering and cell replacement, AM- and AF-derived cells may also have capabilities in protecting and stimulating the repair of injured tissues via paracrine actions, and acting as vectors for biodelivery of exogenous factors to treat injury and diseases. Much progress has been made since the discovery of AM and AF cells with stem cell characteristics nearly a decade ago, but there remain a number of problematic issues stemming from the inherent heterogeneity of these cells as well as inconsistencies in isolation and culturing methods which must be addressed to advance the field towards the development of cell-based therapies. Here, we provide an overview of the recent progress and future perspectives in the use of AM- and AF-derived cells for therapeutic applications.

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