Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.

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The role of markers of inflammation in traumatic brain injury.

The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1beta (IL-1beta), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1beta was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1beta after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1beta, which was blocked by a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1beta induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione] and phospholipase A2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1beta induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.

/pdf/glial-cytokine-neuronal-interactions-underlying-the-1rkcgwpun9.pdf

Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain

Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family

Despite the fact that traumatic brain injury (TBI) is a silently growing epidemic, we are yet to understand its multifaceted pathogenesis, where various cellular pathways are initiated in response to both the primary mechanical insult and secondary physiologically mediated injury Although the brain has traditionally been considered an immunologically privileged site, evidence to the contrary exists in studies of central nervous system (CNS) pathology, in particular TBI Transmigration of leukocytes following blood brain barrier (BBB) disruption results in activation of resident cells of the CNS, such as microglia and astrocytes, to possess immunological function Both infiltrating peripheral immune cells and activated resident cells subsequently engage in the intrathecal production of cytokines, important indicators of the presence of neuroinflammation Cytokines can either promote this neurotoxicity, by encouraging excitotoxicity and propagating the inflammatory response, or attenuate the damage through neuroprotective and neurotrophic mechanisms, including the induction of cell growth factors Certain cytokines perform both functions, for example, interleukin-6 (IL-6) This review article discusses the notion that the inflammatory response to TBI is no longer a peripherally mediated phenomenon, and that the CNS significantly influences the immunological sequence of events in the aftermath of injury

Modulation of immune response by head injury.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

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Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.

Interleukin-1 (IL-1) is an important mediator of immunoinflammatory responses in the brain. In the present study, we examined whether prostaglandin E(2) (PGE(2)) production after IL-1beta stimulation is dependent upon activation of protein kinases in astroglial cells. Astrocyte cultures stimulated with IL-1beta or the phorbol ester, PMA significantly increased PGE(2) secretion. The stimulatory action of IL-1beta on PGE(2) production was totally abolished by NS-398, a specific inhibitor of cyclo-oxygenase-2 activity, as well as by the protein synthesis inhibitor cycloheximide, and the glucocorticoid dexamethasone. Furthermore, IL-1beta induced the expression of COX-2 mRNA. This occurred early at 2 h, with a maximum at 4 h and declined at 12 h. IL-1 beta treatment also induced the expression of COX-2 protein as determined by immunoblot analysis. In that case the expression of the protein remained high at least up to 12 h. Treatment of cells with protein kinase C inhibitors (H-7, bisindolylmaleimide and calphostin C) inhibited IL-1beta stimulation of PGE(2). In addition, PKC-depleted astrocyte cultures by overnight treatment with PMA no longer responded to PMA or IL-1. The ablation of the effects of PMA and IL-1beta on PGE(2) production, likely results from down-regulation of phorbol ester sensitive-PKC isoenzymes. Immunoblot analysis demonstrated the translocation of the conventional isoform cPKC-alpha from cytosol to membrane following treatment with IL-1beta. In addition, IL-1beta treatment led to activation of extracellular signal-regulated kinase (ERK1/2) and p38 subgroups of MAP kinases in astroglial cells. Interestingly, the inhibition of ERK kinase with PD 98059, as well as the inhibition of p38 MAPK with SB 203580, prevented IL-1beta-induced PGE(2) release. ERK1/2 activation by IL-1beta was sensitive to inhibition by the PKC inhibitor bisindolylmaleimide suggesting that ERK phosphorylation is a downstream signal of PKC activation. These results suggest key roles for PKC as well as for ERK1/2 and p38 MAP kinase cascades in the biosynthesis of PGE(2), likely by regulating the induction of cyclo-oxygenase-2, in IL-1beta-stimulated astroglial cells.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0703557

Induction of COX-2 and PGE2 biosynthesis by IL-1β is mediated by PKC and mitogen-activated protein kinases in murine astrocytes

A method for three-dimensional 3-D optical distortion (refraction) correction on anterior segment Optical Coherence Tomography (OCT) images has been developed. The method consists of 3-D ray tracing through the different surfaces, following denoising, segmentation of the surfaces, Delaunay representation of the surfaces, and application of fan distortion correction. The correction has been applied theoretically to realistic computer eye models, and experimentally to OCT images of: an artificial eye with a Polymethyl Methacrylate (PMMA) cornea and an intraocular lens (IOL), an enucleated porcine eye, and a human eye in vivo obtained from two OCT laboratory set-ups (time domain and spectral). Data are analyzed in terms of surface radii of curvature and asphericity. Comparisons are established between the reference values for the surfaces (nominal values in the computer model; non-contact profilometric measurements for the artificial eye; Scheimpflug imaging for the real eyes in vivo and vitro). The results from the OCT data were analyzed following the conventional approach of dividing the optical path by the refractive index, after application of 2-D optical correction, and 3-D optical correction (in all cases after fan distortion correction). The application of 3-D optical distortion correction increased significantly both the accuracy of the radius of curvature estimates and particularly asphericity of the surfaces, with respect to conventional methods of OCT image analysis. We found that the discrepancies of the radii of curvature estimates from 3-D optical distortion corrected OCT images are less than 1% with respect to nominal values. Optical distortion correction in 3-D is critical for quantitative analysis of OCT anterior segment imaging, and allows accurate topography of the internal surfaces of the eye.

Optical distortion correction in Optical Coherence Tomography for quantitative ocular anterior segment by three-dimensional imaging

We address the measurement and correction of fan distortion in optical coherence tomography (OCT). This effect arises from the scanning system configuration and prevents one, in general, from obtaining quantitative topographic data from OCT. Computer simulations allowed us to quantify the effect and evaluate its dependence on the scanning mirror separation and design of the collimating lens, as well as to estimate the optimal axial position of that lens to minimize the fan distortion. We also developed a numerical algorithm based on 3-D ray propagation for the correction of the residual fan distortion. The effect was studied experimentally using a custom developed time-domain OCT in a Michelson configuration provided with a confocal channel, and the accuracy of the fan distortion correction algorithm tested on samples of known dimensions (flat surfaces and spherical lenses). With a proper calibration of the system with use of an onfocal channel, this algorithm makes it possible for time-domain OCT devices to be used as topographers.

/pdf/optical-coherence-tomography-for-quantitative-surface-1g0if197b0.pdf

Optical coherence tomography for quantitative surface topography

We present an optimization method to retrieve the gradient index (GRIN) distribution of the in-vitro crystalline lens from optical path difference data extracted from OCT images. Three-dimensional OCT images of the crystalline lens are obtained in two orientations (with the anterior surface up and posterior surface up), allowing to obtain the lens geometry. The GRIN reconstruction method is based on a genetic algorithm that searches for the parameters of a 4-variable GRIN model that best fits the distorted posterior surface of the lens. Computer simulations showed that, for noise of 5 μm in the surface elevations, the GRIN is recovered with an accuracy of 0.003 and 0.010 in the refractive indices of the nucleus and surface of the lens, respectively. The method was applied to retrieve three-dimensionally the GRIN of a porcine crystalline lens in vitro. We found a refractive index ranging from 1.362 in the surface to 1.443 in the nucleus of the lens, an axial exponential decay of the GRIN profile of 2.62 and a meridional exponential decay ranging from 3.56 to 5.18. The effect of GRIN on the aberrations of the lens also studied. The estimated spherical aberration of the measured porcine lens was 2.87 μm assuming a homogenous equivalent refractive index, and the presence of GRIN shifted the spherical aberration toward negative values (−0.97 μm), for a 6-mm pupil.

/pdf/three-dimensional-reconstruction-of-the-crystalline-lens-35yjy71vop.pdf

Three-dimensional reconstruction of the crystalline lens gradient index distribution from OCT imaging.

We present a method to obtain accurate corneal topography from a spectral optical coherence tomography (sOCT) system. The method includes calibration of the device, compensation of the fan (or field) distortion introduced by the scanning architecture, and image processing analysis for volumetric data extraction, segmentation and fitting. We present examples of three-dimensional (3-D) surface topography measurements on spherical and aspheric lenses, as well as on 10 human corneas in vivo. Results of sOCT surface topography (with and without fan-distortion correction) were compared with non-contact profilometry (taken as reference) on a spherical lens, and with non-contact profilometry and state-of-the art commercial corneal topography instruments on aspheric lenses and on subjects. Corneal elevation maps from all instruments were fitted by quadric surfaces (as well as by tenth-order Zernike polynomials) using custom routines. We found that the discrepancy in the estimated radius of curvature from nominal values in artificial corneas decreased from 4.6% (without fan distortion correction) to 1.6% (after fan distortion correction), and the difference in the asphericity decreased from 130% to 5%. In human corneas, the estimated corneal radius of curvature was not statistically significantly different across instruments. However, a Bland-Altman analysis showed consistent differences in the estimated asphericity and corneal shape between sOCT topographies without fan distortion correction and the rest of the measurements.

/pdf/corneal-topography-from-spectral-optical-coherence-3k93u6nj7h.pdf

Sergio Ortiz

Papers

Induction of COX-2 and PGE2 biosynthesis by IL-1β is mediated by PKC and mitogen-activated protein kinases in murine astrocytes

Optical distortion correction in Optical Coherence Tomography for quantitative ocular anterior segment by three-dimensional imaging

Optical coherence tomography for quantitative surface topography

Three-dimensional reconstruction of the crystalline lens gradient index distribution from OCT imaging.

Corneal topography from spectral optical coherence tomography (sOCT)