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      Pregabalin treatment for neuropathic pain may damage intervertebral disc tissue

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          Abstract

          The aim of the present study was to determine whether pharmaceutical preparations with pregabalin (PGB) as an active ingredient, which are widely prescribed by clinicians, exert toxic effects on human primary nucleus pulposus (NP) and annulus fibrosis (AF). Primary human cell cultures were obtained from intact (n=6) and degenerated (n=6) tissues resected from the two groups of patients. Different doses of PGB were applied to these cultures and cells were subjected to molecular analyses at 0, 24 and 48 h. Cell vitality, toxicity and proliferation were assessed using a spectrophotometer. The expression of chondroadherin (CHAD), a (member of the NP-specific protein family), hypoxia-inducible factor-1α (HIF-1α) and type II collagen (COL2A1) was measured using reverse transcription-quantitative polymerase chain reaction. The results revealed that cell intensity increased in a time-dependent manner and cell vitality continued in the cultures without pharmaceuticals. Cell proliferation was suppressed in the PGB-treated cultures independent from the dose and duration of application. PGB was demonstrated to suppress the expression of CHAD and HIF-1α. In contrast, COL2A1 gene expression was not revealed in any experimental group. The present study utilized an in vitro model and the PGB active ingredient used herein may not be representative of clinical applications; however, the results demonstrated that PGB has a toxic effect on NP/AF cell cultures containing primary human intervertebral disc tissue. In summary, the use of pharmacological agents containing PGB may suppress the proliferation and differentiation of NP/AF cells and/or tissues, which should be considered when deciding on an appropriate treatment regime.

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          Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.

          Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2-delta (alpha2-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha2-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.
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            Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern?

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              Notochordal cells in the adult intervertebral disc: new perspective on an old question.

              The intervertebral disc is a tissue positioned between each of the vertebrae that accommodates applied biomechanical forces to the spine. The central compartment of the disc contains the nucleus pulposus (NP) which is enclosed by the annulus fibrosus and the endplate cartilage.The NP is derived from the notochord, a rod-like structure of mesodermal origin. Development of the notochord is tightly regulated by interactive transcription factors and target genes. Since a number of these molecules are unique they have be used for cell lineage and fate mapping studies of tissues of the intervertebral disc. These studies have shown that in a number of species including human, NP tissue retains notochordal cells throughout life. In the adult NP, there are present both large and small notochordal cells, as well as a progenitor cell population which can differentiate along the mesengenic pathway. Since tissue renewal in the intervertebral disc is dependent on the ability of these cells to commit to the NP lineage and undergo terminal differentiation, studies have been performed to assess which signaling pathways may regulate these activities. The notch signaling pathway is active in the intervertebral disc and is responsive to hypoxia, probably through HIF-1a. From a disease viewpoint, it is hypothesized that an oxemic shift, possibly mediated by alterations in the vascular supply to the tissues of the disc would be expected to lead to a failure in notochordal progenitor cell activation and a decrease in the number of differentiated cells. In turn, this would lead to decrements in function and enhancement of the effect of agents that are known to promote disc degeneration.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                August 2018
                12 June 2018
                12 June 2018
                : 16
                : 2
                : 1259-1265
                Affiliations
                [1 ]Department of Neurosurgery, Namik Kemal University School of Medicine, Tekirdag 59100, Turkey
                [2 ]Department of Medical Pharmacology, Istanbul Medipol University School of Medicine, Istanbul 34810, Turkey
                [3 ]Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Namik Kemal University, Tekirdag 59030, Turkey
                [4 ]Department of Neurosurgery, Istanbul Rumeli University, Corlu Reyap Hospital, Tekirdag 59860, Turkey
                [5 ]Department of Orthopedic and Traumatology, Abant Izzet Basal University School of Medicine, Bolu 14000, Turkey
                [6 ]Department of Neurosurgery, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul 34433, Turkey
                [7 ]Department of Neurosurgery, Istanbul Medeniyet University School of Medicine, Istanbul 34730, Turkey
                [8 ]Department of Orthopedic and Traumatology, Istanbul Medipol University School of Medicine, Istanbul 34214, Turkey
                [9 ]Department of Neurosurgery, Istanbul Esenyurt University, Esencan Hospital, Istanbul 34517, Turkey
                Author notes
                Correspondence to: Dr Numan Karaarslan, Department of Neurosurgery, Namik Kemal University School of Medicine, 1-14 Campus Street, Tekirdag 59100, Turkey, E-mail: numikara@ 123456yahoo.com
                Article
                ETM-0-0-6289
                10.3892/etm.2018.6289
                6090477
                30112057
                3e6db510-bde0-4909-9036-8b7a16f54cf8
                Copyright: © Karaarslan et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 09 November 2017
                : 23 March 2018
                Categories
                Articles

                Medicine
                annulus fibrosis,chondroadherin,type ii collagen,hypoxia-inducible factor-1α,intervertebral disc,nucleus pulposus,pregabalin,primary cell culture,cytotoxicity

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