Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel N-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5–6-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.

https://pubs.rsc.org/en/content/articlepdf/2017/md/c6md00523c

Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination.

The potential for positron emission tomography (PET) to detect neuroinflammation in vivo has sparked a remarkable interest in various disciplines of neuroscience. Early PET radioligands, such as [11C]PK(R)-11195 for the 18-kDa translocator protein (TSPO) and [11C]L-deprenyl for monoamine oxidase B, have been used in studies designed to clarify the role of neuroinflammation in a variety of psychiatric and neurological disorders. Recent years have witnessed the development of several second-generation PET radioligands for TSPO and radioligands to measure endogenous targets that are active in various stages of the inflammatory cascade, such as cyclooxygenase and arachidonic acid. Here, we discuss some of the biomarkers for neuroinflammation that are available for quantification with PET, as well as recent findings from studies where neuroinflammation has been assessed in neurodegenerative disorders. In addition, we highlight the challenges to accurate interpretation of PET studies of neuroinflammation.

Neuroinflammation in Neurodegenerative Disorders-a Review.

The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.

/pdf/microglia-in-retinal-degeneration-r7pgcemwt0.pdf

Microglia in Retinal Degeneration.

Although motor deficits are gaining attention in autism research much less attention has been paid to the physical activity patterns in this group of children. The participants in this study were a group of children with autism spectrum disorder (N = 72) between the ages of 9-18 years. This cross-sectional study explored the physical activity patterns of seventy-two children with autism spectrum disorder as they aged. Results indicated significant differences between the mean time spent in moderate to vigorous physical activity and the mean time spent in sedentary activity. Older children with autism spectrum disorder are significantly more physically inactive, compared to younger children. Physical activity programs and interventions need to address this deficit, in physical activity. Children with autism have a similar trend in physical activity patterns compared to their peers without autism; associated benefits and future research will be discussed.

/pdf/the-physical-activity-patterns-of-children-with-autism-3gm6jyfvrr.pdf

The physical activity patterns of children with autism

The 18-kDa translocator protein (TSPO) has been implicated in steroid biogenesis and neuroinflammation Here, the authors create viable and fertile global TSPO knockout mice, challenging the assumption that TSPO is essential for mouse development but suggesting that it may have a role under certain disease conditions

/pdf/positron-emission-tomography-and-functional-characterization-28wihqosl7.pdf

Positron emission tomography and functional characterization of a complete PBR/TSPO knockout

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Positron emission tomography and functional characterization of a complete PBR/TSPO knockout