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Find video protocols related to scientific articles indexed in Pubmed.
Blood-brain barrier models: in vitro to in vivo translation in preclinical development of CNS-targeting biotherapeutics.
Expert Opin Drug Discov
PUBLISHED: 11-13-2014
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Introduction: The majority of therapeutics, small molecule or biologics, developed for the CNS do not penetrate the blood-brain barrier (BBB) sufficiently to induce pharmacologically meaningful effects on CNS targets. To improve the efficiency of CNS drug discovery, several in vitro models of the BBB have been used to aid early selection of molecules with CNS exposure potential. However, correlative studies suggest relatively poor predictability of in vitro BBB models underscoring the need to combine in vitro and in vivo BBB penetration assessment into an integrated preclinical workflow. Areas covered: This review gives a brief general overview of in vitro and in vivo BBB models used in the pre-clinical evaluation of CNS-targeting drugs, with particular focus on the recent progress in developing humanized models. The authors discuss the advantages, limitations, in vitro-in vivo correlation, and integration of these models into CNS drug discovery and development with the aim of improving translation. Expert opinion: Often, a simplistic rationalization of the CNS drug discovery and development process overlooks or even ignores the need for an early and predictive assessment of the BBB permeability. Indeed, past failures of CNS candidates in clinical trials argue strongly that the early deployment of in vitro and in vivo models for assessing BBB permeability, mechanisms of transport and brain exposure of leads, and the co-development of BBB delivery strategies will improve translation and increase the clinical success of CNS pipelines.
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The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action.
Pain
PUBLISHED: 08-11-2011
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The role of muscarinic receptor subtype-1 (M1) in chronic pain is unclear. In an attempt to gain an understanding of its role, we have tested xanomeline, an M1/M4-preferring agonist, together with nonselective (scopolamine and pirenzepine), and selective (MT-7 and MT-3) muscarinic receptor (M1 and M4, respectively) antagonists in a number of inflammatory and neuropathic pain models. Xanomeline potently and effectively reversed tactile allodynia and heat hyperalgesia associated with established neuropathic and inflammatory pain in both rat and mouse models. Scopolamine and pirenzepine completely blocked the analgesic response to xanomeline, confirming that the analgesic effect is mediated by the muscarinic system. The highly selective M1 receptor toxin, MT-7, almost completely abolished the analgesic response to xanomeline when administered supraspinally. However, the highly selective M4 receptor toxin, MT-3, only marginally reversed the analgesia when given supraspinally, and had no effect when given spinally. In conclusion, the data presented show that the nonselective muscarinic agonist xanomeline is analgesic in models of persistent pain and suggest that the activation of supraspinal M1 receptors, and to a lesser extent supraspinal M4 receptors, contributes to that analgesia.
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Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain.
Mol Pain
PUBLISHED: 04-09-2010
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The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.
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A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain.
Pain
PUBLISHED: 01-25-2010
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Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freunds complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.
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Differential expression and pharmacology of native P2X receptors in rat and primate sensory neurons.
J. Neurosci.
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Evidence suggesting the involvement of P2X2 and P2X3 in chronic pain has been obtained mostly from rodent models. Here we show that rodents may be poor predictors of P2X3 pharmacology in human. We demonstrate that monkey and human dorsal root ganglion (DRG) neurons do not express appreciable levels of P2X2 subunit, contrary to rat sensory neurons. Additionally, we report functional P2X3 activity in monkey DRG neurons and confirm the absence of functional P2X2/3 receptors. Interestingly, native P2X3 receptors in rat and monkey DRGs show similar agonist potency, but different antagonist potencies for TNP-ATP [2-O-(2,4,6-trinitrophenyl)-ATP] and RO51. This unexpected difference in antagonist potency was confirmed by comparing rat and human P2X3 receptors in HEK293 cells. Mutagenesis studies reveal that two extracellular residues, A197 and T202, are synergistically responsible for the potency drop in primate P2X3 receptors. These results uncover species-specific P2X3 pharmacology and identify key mechanisms impacting the translatability of potential analgesics targeting P2X3 receptors.
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Understanding chronic inflammatory and neuropathic pain.
Ann. N. Y. Acad. Sci.
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This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grünenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.