Abstract
The aim of this study was to investigate the therapeutic effect of growth differentiation factor 5 (GDF-5) on traumatic brain injury (TBI) in mice. We utilized a controlled cortical impact to establish a mouse TBI model, and then stereotaxically administered 25 or 100 ng GDF-5 into the bilateral hippocampal dentate gyrus (DG) of each of the animals. Seven days after the injury, some of the animals were sacrificed for immunohistochemical and immunofluorescence examination of 5-bromo-2′-deoxyuridine (BrdU), Sox-2, doublecortin (DCX) and phosphorylated cAMP response element binding protein (p-CREB). Dendrite quantification was also performed using DCX positive cells. Activation of newborn neurons was assessed 35 days after the injury. The remaining animals were subjected to open field, Y maze and contextual fear conditioning tests 2 months after TBI. As a result, we found that post-injury stereotaxical administration of GDF-5 can improve neural stem cell proliferation and differentiation in the DG of the hippocampus, evidenced by the increase in BrdU, Sox-2, and DCX-labeled cells, as well as the improvement in dendrite arborization and newborn neuron activation in response to GDF-5 treatment. Mechanistically, these effects of GDF-5 may be mediated by the CREB pathway, manifested by the recovery of TBI-induced dephosphorylation of CREB upon GDF-5 administration. Behavioral tests further verified the effects of GDF-5 on improving cognitive and behavioral dysfunction after TBI. Collectively, these results reveal that direct injection of GDF-5 into the hippocampus can stimulate neurogenesis and improve functional recovery in a mouse TBI model, indicating the potential therapeutic effects of GDF-5 on TBI.
Highlights
Traumatic brain injury (TBI) is the leading cause of death and disability around the world, which has been regarded as a major public health care burden borne by millions of people annually [1]
These findings suggest that single dosing with growth differentiation factor 5 (GDF-5), 25, or 100 ng per animal, may promote Neural stem cell (NSC) proliferation during the subacute phase of TBI
To identify the potential molecular mechanisms responsible for the neuroprotective effects of GDF-5, we examined the activation of the cAMP response element binding protein (CREB) signaling pathway, which has been documented to play a critical role in NSC differentiation, neuronal survival, and dendritic growth [19]
Summary
Traumatic brain injury (TBI) is the leading cause of death and disability around the world, which has been regarded as a major public health care burden borne by millions of people annually [1]. A current major challenge associated with secondary brain injury of TBI is a lack of effective treatments due to the complex and heterogeneous nature of the injury [5]. With the documented findings of neurogenesis in adult humans, a novel potential therapeutic strategy has emerged with the goal of enhancing post-injury neurogenesis and improving functional recovery after TBI [7]. To achieve this goal, multiple therapeutic modalities, including small molecules, biologics, and stem cell-based therapies, have been exploited in in vivo experiments [8]. There appears to be good prospects for targeting crucial signaling pathways that coordinate and regulate neurogenesis [9]
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