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Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat.

ABSTRACT: Neuroinflammation involving macrophages elevates Prostaglandin E2, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE2. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dose (celecoxib 0.24?mg/kg) provides targeted delivery in chronic constriction injury rats, resulting in significant reduction in the visualized inflammation, infiltration of macrophages, COX-2 and PGE2. Animals exhibit relief from hypersensitivity persisting at least four-days. The total body burden of drug is reduced by >2000 fold over oral drug delivery.

SUBMITTER: Janjic JM

PROVIDER: S-EPMC6056892 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat.

Janjic Jelena M JM Vasudeva Kiran K Saleem Muzamil M Stevens Andrea A Liu Lu L Patel Sravan S Pollock John A JA

Journal of neuroimmunology 20180225

Neuroinflammation involving macrophages elevates Prostaglandin E<sub>2</sub>, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE<sub>2</sub>. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dos ...[more]

PMID: 29519721

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Project description:BackgroundPeripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to understand how inflammasomes participate in central inflammatory reactions accompanying peripheral nerve injury.MethodsAfter axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing.ResultsIn the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4-L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels.ConclusionsOur results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.

Dataset Information

Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat.

Publications

Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat.

Similar Datasets

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