The <scp>l</scp>‐kynurenine–probenecid combination reduces neuropathic pain in rats

Pineda-Farías, Jorge Baruch; Pérez-Severiano, Francisca; González-Esquivel, Dinora F.; Barragán-Iglesias, Paulino; Bravo‐Hernández, Mariana; Cervantes-Durán, Claudia; Aguilera, Penélope; Rı́os, Camilo; Granados‐Soto, Vinicio

doi:10.1002/j.1532-2149.2013.00305.x

Cited by 31 publications

(24 citation statements)

References 51 publications

(68 reference statements)

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“…This does not allow dismissing a possible role of kynurenine metabolites downstream of IDO1 in mechanical allodnyia. For example, there is evidence that elevating endogenous kynurenic acid has been shown to alleviate neuropathic pain in rats after spinal nerve ligation (Vécsei et al, 2013), and this effect is likely due to antagonism of the NMDA receptor by kynurenic acid (Pineda-Farias et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice

Zhou

Dantzer

Budac

et al. 2015

Brain, Behavior, and Immunity

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Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine-2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mice. SNI resulted in unilateral mechanical allodynia, reduced social interaction, and increased immobility in the forced swim test without changes in locomotor activity. These findings indicate SNI-induced pain and comorbid depression-like behavior. These behavioral responses were accompanied by increases in plasma kynurenine/tryptophan ratios and increased expression of Ido1 and Il1b mRNA in the liver. Interestingly, SNI did not induce detectable changes in spinal cord or brain Ido1 mRNA levels after SNI. SNI was associated with spinal cord inflammatory activity as evidenced by increased Il1b mRNA expression. The SNI-induced increase of liver Ido1and Il1b mRNA was abrogated by intrathecal administration of the IL-1 inhibitor IL-1RA. Intrathecal IL-1RA also inhibited both mechanical allodynia and depression-like behavior. We also show that Ido1 is required for the development of depression-like behavior because Ido1-/- mice do not develop increased immobility in the forced swim test or decreased social exploration in response to SNI. Mechanical allodynia was similar in WT and Ido1-/- mice. In conclusion, our findings show for the first time that neuropathic pain is associated with an increase of Ido1 in liver, but not brain, downstream of spinal cord IL-1β signaling and that Ido1 mediates co-morbid depression. Moreover, comorbidity of neuropathic pain and depression are only partially mediated by a common mechanism because mechanical hyperalgesia develops independently of Ido1.

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Section: Discussionmentioning

confidence: 99%

Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice

Zhou

Dantzer

Budac

et al. 2015

Brain, Behavior, and Immunity

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“…The combination of probenecid and N-Acetylcysteine could potentially both maintain intracellular GSH concentrations and inhibit neuronal death after a traumatic stretch injury (Du et al 2016). Some studies report that probenecid can also reduce neuropathic pain in the spinal cord (Bravo et al 2014;Pineda-Farias et al 2013). Therefore, these reports indicate that probenecid has neuroprotective and reparative effects on central nervous system (CNS) injuries.…”

Section: Manuscript To Be Reviewedmentioning

confidence: 99%

Peer Review #1 of "A transcriptomic study of probenecid on injured spinal cords in mice (v0.1)"

2020

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Background. Recent studies have found that probenecid has neuroprotective and reparative effects on central nervous system (CNS) injuries. However, its effect on genome-wide transcription in acute spinal cord injury (SCI) remains unknown. In the present study, RNA sequencing (RNA-Seq) is used to analyze the effect of probenecid on the local expression of gene transcription eight hours after spinal injury. Methods. An Infinite Horizon impactor was used to perform contusive SCI in mice. The SCI model was made by using a rod (1.3 mm diameter) with a force of 50 Kdynes. Sham-operated mice only received a laminectomy without contusive injury. The injured mice were randomly assigned into either the control (SCI_C) or probenecid injection (SCI_P) group. In the latter group, the probenecid drug was intraperitoneally injected (0.5mg/kg) immediately following injury. Eight hours after the injury or laminectomy, the spinal cords were removed from the mice in both groups. The total RNAs were extracted and purified for library preparation and transcriptome sequencing. Differential gene expressions (DEGs) of the three groups-sham, SCI_C and SCI_P-were analyzed using a DESeq software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs were performed using a GOseq R package and KOBAS software. Real-time quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) was used to validate RNA-Seq results. Results. RNA-Seq showed that, compared to the SCI_C group, the number of DEGs was 641 in the SCI_P group (286 upregulated and 355 downregulated). According to GO analysis, DEGs were most enriched in extracellular matrix, collagen trimer, protein bounding and sequence specific DNA binding. KEGG analysis showed that the most enriched pathways included: cell adhesion molecules (CAMs), Leukocyte transendothelial migration, ECM-receptor interactions, PI3K-Akt signaling pathways, hematopoietic cell lineages, focal adhesions, the Rap1 signaling pathway, etc. The sequence data have been deposited into a Sequence Read Archive

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“…The PROB has enhanced the maximal antiallodynic effect of KYNA, additionally increasing the KYNA level was showed in the cerebrospinal fluid (CSF). Impairments of the motor activity was not observed during the experiments, the expression of the KAT II enzyme was unchanged as well 86 .…”

Section: Kynurenic Acid and Painmentioning

confidence: 79%

Kynurenic acid and it’s amide analogue might be possible drug candidates for controlling the activity of opioid system

Samavati¹

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The l‐kynurenine–probenecid combination reduces neuropathic pain in rats

Cited by 31 publications

References 51 publications

Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice

Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice

Peer Review #1 of "A transcriptomic study of probenecid on injured spinal cords in mice (v0.1)"

Kynurenic acid and it’s amide analogue might be possible drug candidates for controlling the activity of opioid system

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