The contribution of astrocytes and microglia to traumatic brain injury

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(4), P. 692 - 702

Published: March 5, 2015

Traumatic brain injury (TBI) represents a major cause of death and disability in developed countries. Brain injuries are highly heterogeneous can also trigger other neurological complications, including epilepsy, depression dementia. The initial often leads to the development secondary sequelae; cellular hyperexcitability, vasogenic cytotoxic oedema, hypoxia-ischaemia, oxidative stress inflammation, all which influence expansion primary lesion. It is widely known that inflammatory events following TBI contribute widespread cell chronic tissue degeneration. Neuroinflammation multifaceted response involving number types, both within CNS peripheral circulation. Astrocytes microglia, cells CNS, considered key players initiating an after injury. These capable secreting various cytokines, chemokines growth factors, undergo changes morphology. Ultimately, these local microenvironment thus determine extent damage subsequent repair. This review will focus on roles microglia astrocytes TBI, highlighting some processes, pathways mediators involved this response. Additionally, beneficial detrimental aspects responses be examined using evidence from animal models human post-mortem studies.

Language: Английский

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Are cannabidiol and Δ⁹‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(3), P. 737 - 753

Published: Sept. 26, 2014

Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent presence Δ(9) -tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and -tetrahydrocannabivarin (THCV). Results from some these fostered view CBD THCV modulate effects THC via direct blockade cannabinoid CB1 receptors, thus behaving like first-generation receptor inverse agonists, such as rimonabant. Here, we review in vitro ex vivo mechanistic THCV, synthesize data a meta-analysis. Synthesized regarding mechanisms then used to interpret results recent pre-clinical animal clinical trials. The indicates rimonabant-like their action appear very unlikely produce unwanted CNS effects. They exhibit markedly disparate profiles at receptors: is low-affinity ligand can nevertheless affect activity an indirect manner, while high-affinity potent antagonist yet only occasionally produces resulting antagonism. has also high affinity for CB2 receptors signals partial agonist, differing both These illustrate how do always predict pharmacology underlie necessity testing compounds before drawing any conclusion on functional given target.

Language: Английский

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Dopamine receptors – IUPHAR Review 13

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(1), P. 1 - 23

Published: Oct. 17, 2014

The variety of physiological functions controlled by dopamine in the brain and periphery is mediated D1, D2, D3, D4 D5 GPCRs. Drugs acting on receptors are significant tools for management several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression Parkinson's disease. Recent investigations receptor signalling have shown that receptors, apart from their canonical action cAMP-mediated signalling, can regulate a myriad cellular responses to fine-tune expression dopamine-associated behaviours functions. Such mechanisms may involve alternate G protein coupling or non-G involving ion channels, tyrosine kinases proteins such as β-arrestins classically involved GPCR desensitization. Another level complexity growing appreciation roles played heteromers. Applications new vivo techniques significantly furthered understanding receptors. Here we provide an update current knowledge regarding complex biology, physiology pharmacology

Language: Английский

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Lysophospholipid receptor nomenclature review: IUPHAR Review 8

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(15), P. 3575 - 3594

Published: March 7, 2014

Lysophospholipids encompass a diverse range of small, membrane‐derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7‐transmembrane GPCRs , constituent members which have continued to be identified after their initial discovery in the mid‐1990s. Here we briefly review this class receptors, with particular emphasis on protein and gene nomenclatures reflect cognate ligands. There six lysophospholipid receptors interact lysophosphatidic acid ( LPA ): names 1 – 6 italicized LPAR1‐LPAR6 (human) Lpar1‐Lpar6 (non‐human). five sphingosine 1‐phosphate (S1P) receptors: S1P ‐S1P 5 S1PR1‐S1PR5 S1pr1‐S1pr5 Recent additions receptor family resulted proposed for lysophosphatidyl inositol (LPI) name LPI LPIR1 Lpir1 (non‐human) three serine LyPS 2 3 LYPSR1‐LYPSR3 Lypsr1‐Lypsr3 along variant form does not appear exist humans is provisionally named 2L . This nomenclature incorporates previous recommendations from International U nion B asic C linical P harmacology, H uman G enome O rganization, Gene Nomenclature Committee, M ouse I nformatix.

Language: Английский

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Salidroside ameliorates insulin resistance through activation of a mitochondria‐associated AMPK/PI3K/Akt/GSK3β pathway

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 172(13), P. 3284 - 3301

Published: March 5, 2015

Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects on diabetic mice explore underlying mechanisms.The type 2 diabetes were investigated. Increasing doses (25, 50 100 mg·kg(-1) ·day(-1)) administered p.o. db/db for 8 weeks. Biochemical analysis histopathological examinations conducted salidroside. Primary cultured mouse hepatocytes used further mechanisms vitro.Salidroside dramatically reduced blood serum insulin levels alleviated resistance. Hypolipidaemic amelioration liver steatosis observed after administration. In vitro, dose-dependently induced an increase phosphorylations AMPK PI3K/Akt, as well glycogen synthase 3β (GSK3β) hepatocytes. Furthermore, salidroside-stimulated activation found suppress expression PEPCK glucose-6-phosphatase. Salidroside-induced also resulted phosphorylation acetyl CoA carboxylase, which can reduce lipid accumulation peripheral tissues. isolated mitochondria, inhibited respiratory chain complex I disturbed oxidation/phosphorylation coupling moderately depolarized mitochondrial membrane potential, resulting a transient AMP/ATP ratio.Salidroside exerts antidiabetic effect improving cellular metabolic flux through mitochondria-related AMPK/PI3K/Akt/GSK3β pathway.

Language: Английский

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Orexin/hypocretin role in reward: implications for opioid and other addictions

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(2), P. 334 - 348

Published: Feb. 17, 2014

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as potential target for anti‐craving medications. Orexins, also known hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus perifornical area, which project widely throughout brain. The absence orexins rodents humans leads to narcolepsy. However, an established role reward seeking. This review will discuss some original studies describing roles seeking well specific works were presented at 2013 International Narcotics Research Conference. signalling can promote drug‐induced plasticity glutamatergic synapses onto dopamine ventral tegmental area ( VTA ), brain region implicated motivated behaviour. Additional evidence suggests orexin drug by initiating endocannabinoid‐mediated synaptic depression GABA ergic inputs , thereby disinhibiting dopaminergic neurons. co‐express inhibitory opioid peptide dynorphin. It has may not mediate per se but rather occludes ‘anti‐reward’ effects Finally, prefrontal cortex central amygdala reinstatement highlight recent work cellular processes underlying addiction‐related behaviours propose novel hypotheses mechanisms impart Linked Articles article part themed section on Opioids: New Pathways Functional Selectivity. To view other articles this visit http://dx.doi.org/10.1111/bph.2015.172.issue-2

Language: Английский

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Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(15), P. 3604 - 3619

Published: April 14, 2014

Agomelatine behaves both as a potent agonist at melatonin MT 1 and 2 receptors neutral antagonist 5‐ HT 2C receptors. Accumulating evidence in broad range of experimental procedures supports the notion that psychotropic effects agomelatine are due to synergy between its melatonergic 5‐hydroxytryptaminergic effects. The recent demonstration existence heteromeric complexes with cellular level may explain how these two properties translate into synergistic action that, for example, leads increases hippocampal proliferation, maturation survival through modulation multiple pathways (increase trophic factors, synaptic remodelling, glutamate signalling) key targets (early genes, kinases). present review focuses on pharmacological this novel antidepressant. Its mechanism action, strikingly different from conventional classes antidepressants, opens perspectives towards better understanding physiopathological bases underlying depression.

Language: Английский

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Role of the endocannabinoid system in diabetes and diabetic complications

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(7), P. 1116 - 1127

Published: June 16, 2015

Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose lipid metabolism, exerting pro-apoptotic effects in pancreatic beta cells facilitating inflammation islets. Furthermore, hyperglycaemia associated with has also been implicated triggering perturbations ECS amplifying pathological processes mentioned above, eventually culminating a vicious circle. Compelling from preclinical studies indicates influences diabetes-induced oxidative stress, inflammation, fibrosis subsequent tissue injury target organs for diabetic complications. In this review, we provide update on contribution pathogenesis microvascular (retinopathy, nephropathy neuropathy) cardiovascular The therapeutic potential targeting is discussed.This article part themed section Endocannabinoids. To view other articles visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Language: Английский

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Utilizing hydrogen sulfide as a novel anti‐cancer agent by targeting cancer glycolysis and pH imbalance

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(18), P. 4322 - 4336

Published: May 15, 2014

Many disparate studies have reported the ambiguous role of hydrogen sulfide (H2 S) in cell survival. The present study investigated effect H2 S on viability cancer and non-cancer cells.Cancer cells were exposed to [using sodium hydrosulfide (NaHS) GYY4137] was examined by crystal violet assay. We then cellular glycolysis vitro enzymatic assays pH regulator activity. Lastly, intracellular (pHi ) determined ratiometric pHi measurement using BCECF staining.Continuous, but not a single, exposure decreased survival more effectively cells, as compared cells. Slow S-releasing donor, GYY4137, significantly increased glycolysis, leading overproduction lactate. also anion exchanger sodium/proton combination metabolic acid production defective regulation resulted an uncontrolled acidification, death. In contrast, no significant acidification or death observed cells.Low continuous targets processes homeostasis potentially serving novel selective anti-cancer strategy.

Language: Английский

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TRP channels in the skin

British Journal of Pharmacology, Journal Year: 2013, Volume and Issue: 171(10), P. 2568 - 2581

Published: Dec. 26, 2013

Emerging evidence suggests that transient receptor potential (TRP) ion channels not only act as 'polymodal cellular sensors' on sensory neurons but are also functionally expressed by a multitude of non-neuronal cell types. This is especially true in the skin, one largest organs body, where they appear to be critically involved regulating various cutaneous functions both under physiological and pathophysiological conditions. In this review, we focus introducing roles several TRP regulation skin barrier, proliferation differentiation, immune functions. Moreover, describe putative involvement development certain diseases identify future channel-targeted therapeutic opportunities.

Language: Английский

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