Immunoglobulin G: A Potential Treatment to Attenuate Neuroinflammation Following Spinal Cord Injury

# The Author(s) 2010. This article is published with open access at Springerlink.com Introduction Spinal cord injury (SCI) is caused by two related but mechanistically distinct events: the primary injury to the spinal cord is caused by a mechanic trauma; the secondary injury is a cascade of cellular and molecula

The NAMPT inhibitor FK866 reverts the damage in spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.</p> <p>Methods</p> <p>We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.</p> <p>Results</p> <p>Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.</p> <p>We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.</p> <p>Conclusions</p> <p>Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.</p

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI

MicroRNA Dysregulation in the Spinal Cord following Traumatic Injury

Spinal cord injury (SCI) triggers a multitude of pathophysiological events that are tightly regulated by the expression levels of specific genes. Recent studies suggest that changes in gene expression following neural injury can result from the dysregulation of microRNAs, short non-coding RNA molecules that repress the translation of target mRNA. To understand the mechanisms underlying gene alterations following SCI, we analyzed the microRNA expression patterns at different time points following rat spinal cord injury

Molecular mechanisms in Schwann cell survival and death during peripheral nerve development, injury and disease

The mechanisms determining the fate of Schwann cells during disease and injury of the adult mammalian peripheral nervous system (PNS) are becoming defined by current advances in molecular neurobiology. It is now apparent that the molecular pathways which regulate the production of the mature myelinating Schwann cell during development may also apply to degenerative and regenerative mechanisms following PNS diseas

OS14.4.A The Neuroplastic Potential of the Human Brain before and After Glioma Surgery: Towards “Interventional Neurorehabilitation

Abstract INTRODUCTION The human brain is a highly neuroplastic ‘complex’ network: it self-organises without a hard blueprint, adapts to evolving circumstances, and can withstand insults. However, similar to other naturally occurring networks, brain networks can only endure a finite amount of damage before cognitive processes are affected. In this study, we first sought to establish the brain networks governing domain-general cognition (DGC) in healthy individuals across the lifespan. We then sought to map, track, and potentially rehabilitate networks governing DGC through connectomics and non-invasive brain stimulation (NIBS) when damaged by low-grade gliomas (LGG) and surgical oncology. METHODS Using MRI and cognitive data from n=629 individuals (aged 18–88, Female= 51%), we assessed the structural, functional, and topological relevance of the spatially-distributed multiple-demand (MD) system for DGC. Next, in n=17 patients undergoing glioma surgery, we longitudinally acquired connectomic and cognitive data at multiple time points: pre-surgery and post-surgery Day 1, Month 3, Month 12. In an independent cohort of n=34 patients, we sought to establish the safety profile for “interventional neurorehabilitation”: connectome-driven NIBS in the acute post-operative period to accelerate cognitive recovery. RESULTS In healthy individuals, the MD system across multiple scales of biological organisation was positively associated with higher-order cognition (Catell’s fluid intelligence). In our patients, pre-operative LGG infiltration into the structural MD system was negatively associated with the number of long-term cognitive deficits, suggesting a functional reorganisation. Mixed-effects modelling demonstrated the resilience of the functional MD system to infiltration and resection, while the early post-operative period was critical for effective neurorehabilitation. Graph analyses revealed increased perioperative modularity can distinguish patients with long-term cognitive improvements at one-year follow-up. Finally, NIBS within two weeks post-craniotomy had a 90% (n=31/34) recruitment rate into the trial. There were no seizures or serious complications due to NIBS in this patient population. Transient headaches and tingling were reported in a minority of patients. CONCLUSION For the first time, we elucidate long-term cognitive and network trajectories following LGG surgery while establishing a positive safety-profile for NIBS in the acute post-operative period. We argue that “mesoscale” brain mapping serves as a robust biomarker for intervention-related plasticity for future clinical trials. While we performed these experiments in the context of neurosurgery, connectomics and NIBS could be adopted across diverse neuro-oncological care pathways (i.e. chemotherapy/radiation). </jats:sec