Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats

Wei, Rui-Li; Wang, J.; Xu, Yang; Yin, Bin; He, Fangping; Du, Yue; Peng, Guoping; Luo, Benyan

doi:10.1016/j.neuroscience.2015.05.070

Cited by 54 publications

(49 citation statements)

References 58 publications

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“…Nonetheless, PBN has been reported to protect from the excitotoxicity induced by sAβos (Carrillo-Mora et al, 2010) and from the inflammatory conditions in CNS (Wei et al, 2015;Hainz et al, 2017;Zhang et al, 2019). Interestingly, PBN can cross the blood-brain barrier, acting directly on the CNS (Kartzinel et al, 1976;Cowdry et al, 1983) and have been shown to exert neuroprotective effects in several neuropathological contexts including cerebral ischemia-reperfusion (Wei et al, 2015), autoimmune encephalomyelitis (Hainz et al, 2016), sepsisassociated encephalopathy (Zhang et al, 2019), multiple sclerosis (Hainz et al, 2017), and epilepsy (Dossi et al, 2018). Moreover, recent studies reported that gout patients treated with different uricosurics including PBN, exhibit lower risk of developing nonvascular dementia (Hong et al, 2015) and AD (Lu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…(Gomez-Arboledas et al, 2018). Considering that Panx1 channels have been involved in inflammatory conditions (Zhou K. Q. et al, 2019), playing a role in the inflammasome activation in astrocytes and neurons (Silverman et al, 2009), and since PBN appears to exert an anti-inflammatory effect by inhibiting Panx1 activity (Wei et al, 2015;Hainz et al, 2017;Zhang et al, 2019), we evaluated the effect of PBN on sAβos accumulation, amyloid plaques, and GFAP immunoreactivity in Wt and Tg brains (Figure 2). Hippocampal slices were treated during 2 h with 100 µM of PBN and then processed for the evaluation of neurodegeneration parameters.…”

Section: Pannexin 1 Blockade With Probenecid Does Not Affect Neurodegmentioning

confidence: 99%

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Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Flores‐Muñoz

Gómez

Mery

et al. 2020

Front. Cell. Neurosci.

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Section: Discussionmentioning

confidence: 99%

Section: Pannexin 1 Blockade With Probenecid Does Not Affect Neurodegmentioning

confidence: 99%

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Flores‐Muñoz

Gómez

Mery

et al. 2020

Front. Cell. Neurosci.

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“…[1][2][3] By maintaining intracellular stores of GSH, probenecid reduces apoptosis in experimental models. 4 Probenecid also blocks pannexin 1 channels, 5 inhibits pyroptotic neuronal death in vitro, 6 and protects against ischemic damage in mice after middle cerebral artery occlusion 7 and in rats after global cerebral ischemia/reperfusion injury, 8 although the effect of probenecid on GSH levels was not evaluated in these studies. NAC, on the other hand, can serve as a cysteine donor for GSH synthesis, thereby functioning as a substrate for the vital intracellular antioxidant.…”

mentioning

confidence: 99%

Probenecid and N-Acetylcysteine Prevent Loss of Intracellular Glutathione and Inhibit Neuronal Death after Mechanical Stretch Injury In Vitro

Empey

et al. 2016

Journal of Neurotrauma

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Probenecid and N-acetylcysteine (NAC) can preserve intracellular levels of the vital antioxidant glutathione (GSH) via two distinct biochemical pathways. Probenecid inhibits transporter-mediated GSH efflux and NAC serves as a cysteine donor for GSH synthesis. We hypothesized that probenecid and NAC alone would maintain intracellular GSH concentrations and inhibit neuronal death after traumatic stretch injury, and that the drugs in combination would produce additive effects. Sex-segregated rat primary cortical neurons were treated with probenecid (100 μM) and NAC (50 μM), alone and in combination (Pro-NAC), then subjected to mechanical stretch (10s strain rate, 50% membrane deformation). At 24 h, both probenecid and NAC inhibited trauma-induced intracellular GSH depletion, lactate dehydrogenase (LDH) release, and propidium iodide (PI) uptake in both XY- and XX-neurons. Combined Pro-NAC treatment was superior to probenecid or NAC alone in maintenance of intracellular GSH and neuronal death assessed by PI uptake. Interestingly, caspase 3 activity 24 h after mechanical trauma was more prominent in XX-neurons, and treatment effects (probenecid, NAC, and Pro-NAC) were observed in XX- but not XY-neurons; however, XY-neurons were ultimately more vulnerable to mechanical stretch-induced injury than their XX counterparts, as was evidenced by more neuronal death detected by LDH release and PI uptake. In addition, after stretch injury in HT22 hippocampal cells, both NAC and probenecid were highly effective at reducing oxidative stress detected by dichlorofluorescein fluorescence. These in vitro data support further testing of this drug combination in models of traumatic neuronal injury in vivo.

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“…Recent studies have shown that probenecid has neuroprotective and repairing effects on brain disorders (Wei et al 2015;Xiong et al 2014). However, its effect on genome-wide transcription PeerJ reviewing PDF | (2019:07:39856:2:0:NEW 25 Nov 2019)…”

Section: Discussionmentioning

confidence: 99%

“…For example, probenecid has been used as a synergist in the treatment of gout and antibiotics (Baranova et al 2004;Papadopoulos & Verkman 2008). It can reduce the degree of cognitive impairment in afflicted rats (Mawhinney et al 2011), as well as reverse cerebral ischemic injury and cellular inflammation (Wei et al 2015;Xiong et al 2014). 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).…”

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

show abstract

Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats

Cited by 54 publications

References 58 publications

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Probenecid and N-Acetylcysteine Prevent Loss of Intracellular Glutathione and Inhibit Neuronal Death after Mechanical Stretch Injury In Vitro

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

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