Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord ...injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.
The Essential Medicinal Chemistry of Curcumin Nelson, Kathryn M; Dahlin, Jayme L; Bisson, Jonathan ...
Journal of medicinal chemistry,
03/2017, Letnik:
60, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their ...extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
•We used liposomal clodronate to deplete microglia in neonatal rats and study the lifelong effects on motivated behavior.•Central liposomal clodronate injection at P1 and P4 depleted forebrain ...microglia for approximately two weeks.•Early-life microglia depletion led to increased locomotion and decreased anxiety and despair behaviors throughout life.•Females that had microglia depleted neonatally had a blunted corticosterone response to acute stress in adulthood.
Microglia, the innate immune cells of the central nervous system, regulate brain development by promoting cell genesis, pruning synapses, and removing dying, newly-born or progenitor cells. However, the role of microglia in the early life programming of behavior under normal conditions is not well characterized. We used central infusion of liposomal clodronate to selectively deplete microglia from the neonatal rat brain and subsequently assessed the impact of microglial depletion on programming of juvenile and adult motivated behaviors. Liposomal clodronate treatment on postnatal days one and four led to greater than 70% loss of forebrain microglia by postnatal day 6 that lasted for approximately ten days. Neonatal microglia depletion led to reduced juvenile and adult anxiety behavior on the elevated plus maze and open field test, and increased locomotor activity. On a test of juvenile social play, microglial depletion led to decreased chase behaviors relative to control animals. There was no change in active social behavior in adults on a reciprocal social interaction test, but there was decreased passive interaction time and an increased number of social avoidance behaviors in clodronate treated rats relative to controls. There was an overall decrease in behavioral despair on the forced swim test in adult rats treated neonatally with clodronate. Females, but not males, treated neonatally with clodronate showed a blunted corticosterone response after acute stress in adulthood. These results show that microglia are important for the early life programming of juvenile and adult motivated behavior.
Highlights • We studied sex differences and hormonal effects on neonatal hippocampal microglia. • Females had more phagocytic microglia compared to males. • More progenitor and non-pyknotic cells ...were phagocytized by microglia in females. • Estradiol increased microglia proliferation and decreased phagocytosis in females. • Females had higher expression of several phagocytic pathway genes.
In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (neurovascular ...coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in "endfeet" that encase the blood vessels. Ca²⁺ signaling within the endfoot mediates neurovascular coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels—nonselective cation channels with considerable Ca²⁺ conductance—have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca²⁺ dynamics in the astrocytic endfoot microdomain and assess their role in neurovascular coupling. We identified local TRPV4-mediated Ca²⁺ oscillations in endfeet and further found that TRPV4 Ca²⁺ signals are amplified and propagated by Ca²⁺-induced Ca²⁺ release from inositol trisphosphate receptors (IP₃Rs). Moreover, TRPV4-mediated Ca²⁺ influx contributes to the endfoot Ca²⁺ response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP₃Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to neurovascular coupling.
Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in ...the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.
Brain sex differences are programmed largely by sex hormone secretions and direct sex chromosome effects in early life, and are subsequently modulated by early life experiences. The brain's resident ...immune cells, called microglia, actively contribute to brain development. Recent research has shown that microglia are sexually dimorphic, especially during early life, and may participate in sex-specific organization of the brain and behavior. Likewise, sex differences in immune cells and their signaling in the adult brain have been found, although in most cases their function remains unclear. Additionally, immune cells and their signaling have been implicated in many disorders in which brain development or plasticity is altered, including autism, schizophrenia, pain disorders, major depression, and postpartum depression. This review summarizes what is currently known about sex differences in neuroimmune function in development and during other major phases of brain plasticity, as well as the current state of knowledge regarding sex-specific neuroimmune function in psychiatric disorders.
•Microglia depletion in neonatal rats induced decreases in neonatal cell genesis.•Microglia depletion decreased cell genesis in male, but not female, hippocampus.•Microglia depletion decreased cell ...genesis in amygdala and cortex of both sexes.•Microglia loss led to increased mitotic cells and hippocampal volume in adolescence.•Microglia thus both support neonatal cell genesis and limit later-life cell genesis.
Microglia, the innate immune cells of the brain, regulate brain development through many processes such as synaptic pruning, supporting cell genesis and phagocytosing living and dying cells. There are sex differences in these same developmental processes throughout the brain, thus microglia may contribute to brain sex differences. We examined whether microglia support a known sex difference in neonatal hippocampal neurogenesis and whether juvenile hippocampal neurogenesis was impacted by the loss of neonatal microglia. We used central infusion of liposomal clodronate to selectively deplete microglia and found decreased cell genesis in the male, but not female, dentate gyrus and hippocampus. We found that loss of microglia decreased cell genesis in the cortex and amygdala of both males and females. We assessed the expression of several cytokines and growth factors that have previously been shown to support cell genesis. We found that expression of Il1b and Tnf were decreased in the hippocampus due to microglia depletion however, there were no sex differences in the expression of any immune genes. In adolescence, there was an increase in the number of mitotic cells in the subgranular zone of the dentate gyrus of previously microglia depleted rats however, the number of newly-born neurons was unchanged in the adolescent animals. We also sought to determine whether there was a sex difference in the number of progenitor cells in the dentate gyrus in the neonatal period. We found no sex differences in the number of progenitor cells. Overall, these studies show that microglia are important for regulating region-specific sex differences in cell genesis in the developing brain.
This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated ...health claims lacks a rigorous scientific foundation. CBD’s reputation as a cure-all puts it in the same class as other “natural” panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the “natural” label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
PDF
