Abstract
Neuropathic pain caused by a primary injury or dysfunction in the peripheral or central nervous system is a tremendous therapeutic challenge. Here, we have collected the first evidence from a single study on the potential contributions to neuropathic pain development by enzymes in the kynurenine pathway [tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO1/2), kynurenine 3-monooxygenase (KMO); kynureninase, 3-hydroxyanthranilate-3,4-dioxygenase (HAOO)] at the spinal cord and dorsal root ganglia (DRG) levels. At the spinal cord, mRNA levels of IDO2, KMO, and HAOO were elevated as measured on day 7 after chronic constriction injury in a rat model, parallel to the C1q-positive cell activation. According to our data obtained from primary microglial cell cultures, all enzymes of the kynurenine pathway except TDO were derived from these cells; however, the activation of microglia induced stronger changes in IDO2 and KMO. Our pharmacological studies gave evidence that the repeated intraperitoneal administration of minocycline, a microglia/macrophage inhibitor, not only attenuated tactile and thermal hypersensitivity but also diminished the levels of IDO2 and KMO mRNA. Our further pharmacological studies confirmed that IDO2 and KMO enzymes take part in the development of neuropathic pain, since we observed that the repeated administration of IDO2 (1-methyl-D-tryptophan) and KMO [UPF 648 – (1S,2S)-2-(3,4-dichlorobenzoyl)cyclopropanecarboxylic acid] inhibitors diminished hypersensitivity development as measured on days 2 and 7. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology in rats and indicate that IDO2 and KMO represent novel pharmacological targets for treating neuropathy.
Highlights
The treatment of neuropathic pain remains a major challenge
The Development of Hypersensitivity Appears in Parallel to the Changes in C1q, IDO1, IDO2, TDO, kynurenine 3-monooxygenase (KMO), KYNU, and HAOO mRNA in the Spinal Cord and dorsal root ganglia (DRG) 2–28 Days After the constriction injury (CCI)
It has been shown that the TDO level does not change or even decrease in pathological conditions (Comai et al, 2005; Braidy et al, 2011). These results are consistent with our observations where we demonstrated that the level of TDO mRNA decreases on days 2 and 7 after CCI in the DRG, while in the spinal cord, there are no significant changes
Summary
The treatment of neuropathic pain remains a major challenge. its essential mechanisms need to be elucidated. The available International Association for the Study of Pain (IASP) data suggest that one in five Europeans suffers from moderate to severe chronic pain of various origins. Due to such conditions, they are forced to apply major changes in their lives. We hypothesize that the inhibition of the activity of selected kynurenine pathway enzymes is a way to protect neurons from injuries and, as a consequence, diminish neuropathic pain development. In 2013, Amaral et al (2013) recommended UPF 648 as a potent KMO inhibitor for therapies against neurodegenerative diseases, but there is a lack of such studies involving neuropathic pain. It has been demonstrated that the IDO inhibitor 1-methyl-D-tryptophan (1-D-MT) is therapeutically valuable in cancer (Brito et al, 2015); it has not been examined for neuropathy
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