Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. To date, there is unmet need for a therapeutic intervention that improves lost brain function after TBI. TBI induces endogenous neurogenesis, which might be a substrate for self‐repair mechanisms of the brain. However, TBI‐induced neurogenesis is not sufficient for recovery because of the limited survival capacity of those newborn neurons. Changes in the microenvironment following the injury, including reactive astrogliosis are main factors, which affect neuronal survival and axonal regeneration. Adenosine kinase (ADK), the key adenosine‐metabolizing enzyme, has been studied in several brain disorders including epilepsy, schizophrenia, and stroke. Recently, we reported an association between ADK expression levels and TBI‐induced neurogenesis and cell proliferation in adult mice. Here we hypothesized that ADK inhibition promotes neuronal survival and differentiation after TBI. In this study, adult male C57BL/6 mice were subjected to TBI, modeled by a controlled cortical impact (CCI). Animals were randomized into two groups and injected five times with either 5‐ITU (1.3 mg/kg, i.p.) or vehicle (20% DMSO, control) 24 hours after the injury. To track the fate of newborn cells, BrdU (50 mg/kg, i.p.) was injected once a day for seven days beginning 24 hours after the injury. Animals were perfused two weeks after the injury to assess the effect of ADK blockade on TBI‐induced neurogenesis. The number of BrdU/NeuN double‐labeled cells was significantly higher in 5‐ITU treated animals as compared with control (P = 0.0028). Moreover, astrogliosis, which is known to compromise axonal re‐growth after TBI, was significantly reduced in 5‐ITU treated animals compared to controls as reflected by the number of total GFAP and BrdU/GFAP positive cells (P = 0.01 and P = 0.0001, respectively). Strikingly, the volume of the injury cavity was significantly reduced in 5‐ITU treated mice versus control mice (P = 0.009). In summary, these data suggest that inhibition of ADK may promote regenerative processes after TBI by increasing the differentiation of the newborn neurons and by reducing astrogliosis