Experimental neurology
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Experimental neurology · Nov 2014
Agrin requires specific proteins to selectively activate γ-aminobutyric acid neurons for pain suppression.
Agrin, a heparan sulfate proteoglycan functioning as a neuro-muscular junction inducer, has been shown to inhibit neuropathic pain in sciatic nerve injury rat models, via phosphorylation of N-Methyl-d-aspartate receptor NR1 subunits in gamma-aminobutyric acid neurons. However, its effects on spinal cord injury-induced neuropathic pain, a debilitating syndrome frequently encountered after various spine traumas, are unknown. In the present investigation, we studied the 50kDa agrin isoform effects in a quisqualic acid dorsal horn injection rat model mimicking spinal cord injury-induced neuropathic pain. ⋯ Also, the reason why 50kDa agrin only activates the N-Methyl-d-aspartate receptor NR1 subunits in the GABA neurons, but not in sensory neurons, is unknown. Using immunoprecipitation and Western-blot analysis, two dimensional gel separation, and mass spectrometry, we identified several specific proteins in the reaction protein complex, such as neurofilament 200 and mitofusin 2, that are required for the activation of the NR1 subunits of gamma-aminobutyric acid inhibitory neurons by 50kDa agrin. These findings indicate that 50kDa agrin is a promising agent for neuropathic pain treatment.
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Experimental neurology · Nov 2014
Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats.
Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague-Dawley rats (n=123) were subjected to SAH by endovascular perforation. ⋯ CREB siRNA reversed the effects of treatment. TUNEL positive neurons in the cortex were reduced with JWH133 treatment. Thus, CB2R stimulation attenuated EBI after SAH possibly through activation of pCREB-Bcl-2 pathway.
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Experimental neurology · Nov 2014
Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats.
Schwann cells (SCs) have been considered to be one of the most promising cell types for transplantation to treat spinal cord injury (SCI) due to their unique growth-promoting properties. Despite the extensive use as donor cells for transplantation in SCI models, the fate of SCs is controversial due in part to the lack of a reliable marker for tracing the grafted SCs. To precisely assess the fate and temporal profile of transplanted SCs, we isolated purified SCs from sciatic nerves of adult transgenic rats overexpressing GFP (SCs-GFP). ⋯ Except for a significant decrease of angle of rotation in the footprint analysis, we did not observe significant behavioral improvements in BBB locomotor rating scale, thermal withdrawal latency, or footfall errors, compared to the control animals that received no SCs-GFP. We conclude that SCs-GFP can survive remarkably well, proliferate, migrate along the central canal, and myelinate regenerated axons when being grafted into a clinically-relevant contusive SCI in adult rats. Combinatorial strategies, however, are essential to achieve a more meaningful functional regeneration of which SCs may play a significant role.
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Experimental neurology · Nov 2014
Scaling in neurotrauma: how do we apply animal experiments to people?
Scaling is an essential component for translating the clinical outcomes of a neurotrauma model to the human equivalent. This article reviews the principles of biomechanical scaling for traumatic brain injuries, and a number of different approaches to scaling the dose (inputs) and response (outputs) of an animal model to humans are highlighted. A particular focus on blast injury scaling is given as an ongoing area of research, and discussion on the implications of scaling on the current blast TBI literature is provided. The risk of using neurotrauma models without considering an appropriate scaling method is that injuries may be induced with non-realistic loading conditions, and the injury mechanisms produced in the laboratory may not be consistent with those in the clinical setting.
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Experimental neurology · Aug 2014
ReviewImmune modulatory therapies for spinal cord injury--past, present and future.
Historically, the immune response after spinal cord injury was considered largely detrimental owing to the release of neurotoxic factors. While there is validity to this view, there is much greater heterogeneity of immune cells than was previously realized. ⋯ In this review we will discuss the early findings that supported the use of various anti-inflammatory medications as well as the evolving concept that not all immune subtypes are detrimental and some might even be beneficial. In the last section we will highlight the need to characterize better the role of immune cell subsets in the hopes of developing potential therapeutic targets for the future.