Experimental neurology
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Experimental neurology · Feb 2015
Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury.
Facet joint injury induces persistent pain that may be maintained by structural plasticity in the spinal cord. Astrocyte-derived thrombospondins, especially thrombospondin-4 (TSP4), have been implicated in synaptogenesis and spinal sensitization in neuropathic pain, but the TSP4 response and its relationship to synaptic changes in the spinal cord have not been investigated for painful joint injury. This study investigates the role of TSP4 in the development and maintenance of persistent pain following injurious facet joint distraction in rats and tests the hypothesis that excitatory synaptogenesis contributes to such pain. ⋯ Blocking injury-induced spinal TSP4 expression with antisense oligonucleotides or reducing TSP4 activity at its neuronal receptor in the spinal cord with gabapentin treatment both attenuate the allodynia and dorsal horn synaptogenesis that develop after painful facet joint loading. Increased spinal TSP4 also facilitates the development of allodynia and spinal hyperexcitability, even after non-painful physiological loading of the facet joint. These results suggest that spinal TSP4 plays an important role in the development and maintenance of persistent joint-mediated pain by inducing excitatory synaptogenesis and facilitating the transduction of mechanical loading of the facet joint that leads to spinal hyperexcitability.
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Experimental neurology · Feb 2015
Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury.
Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. ⋯ Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant difference between MNTS1- and GFP-control transplanted groups. Nevertheless, our overall findings support the potential of syngeneic NPC transplantation to enhance endogenous neuroreparative responses and may therefore be an effective treatment for TBI.
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Experimental neurology · Feb 2015
Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice.
The importance of free radical-induced oxidative damage after traumatic brain injury (TBI) has been well documented. Despite multiple clinical trials with radical-scavenging antioxidants that are neuroprotective in TBI models, none is approved for acute TBI patients. As an alternative antioxidant target, Nrf2 is a transcription factor that activates expression of antioxidant and cytoprotective genes by binding to antioxidant response elements (AREs) within DNA. ⋯ This was accompanied by decreased oxidative damage to mitochondrial proteins, suggesting the mechanistic connection of the two effects. Lastly, delaying the initial administration of CA up to 8h post-TBI was still capable of reducing cytoskeletal breakdown, thereby demonstrating a clinically relevant therapeutic window for this approach. This study demonstrates that pharmacological Nrf2-ARE induction is capable of neuroprotective efficacy when administered after TBI.
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Experimental neurology · Feb 2015
Desmoplakin is involved in organization of an adhesion complex in peripheral nerve regeneration after injury.
Peripheral nerves have the unique capability to regenerate after injury. Insights into regeneration of peripheral nerves after injury may have implications for neurodegenerative diseases of the nervous system. In this study, we analyzed the expression and function of desmoplakin in peripheral nerve regeneration. ⋯ A complex of N-cadherin, plakoglobin, desmoplakin and vimentin was shown in motoneuronal cell cultures and peripheral nerves after injury in vivo. Motor nerve fiber regeneration and localization of N-cadherin and vimentin to axonal growth fronts were reduced in conditionally desmoplakin-ablated mice. These data indicate a function of desmoplakin in motor nerve regeneration by linking N-cadherin to intermediate filaments in regenerating motor axons.