Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy

Caillaud, Martial; Patel, Nipa; White, Alyssa; Wood, Maurice; Contreras, Katherine M.; Toma, Wisam; Alkhlaif, Yasmin; Roberts, Jeanette C.; Tran, Tammy H.; Jackson, Asti; Poklis, Justin L.; Gewirtz, David A.; Damaj, M. Imad

doi:10.1016/j.bbi.2021.01.004

Cited by 34 publications

(37 citation statements)

References 41 publications

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“…In mice, fenofibrate was shown to modestly increase tissue sparing following spinal contusion injury ( Almad et al, 2011 ). The neuroprotective role of fenofibrate was also recently observed in a mouse model of paclitaxel chemotherapy-induced peripheral neuropathy ( Caillaud et al, 2021 ). The enrichment of biological pathways related to PPARα signaling are largely conserved between rodent and human SGC ( Avraham et al, 2021 ).…”

Section: Discussionmentioning

confidence: 79%

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Avraham¹,

Feng²,

Ewan³

et al. 2021

eLife

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Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

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Section: Discussionmentioning

confidence: 79%

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Avraham¹,

Feng²,

Ewan³

et al. 2021

eLife

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show abstract

“…In mice, fenofibrate was shown to modestly increase tissue sparing following spinal contusion injury (Almad et al, 2011). The neuroprotective role of fenofibrate was also recently observed in a paclitaxel chemotherapy-induced peripheral neuropathy (Caillaud et al, 2021). The enrichment of biological pathways related to PPARα signaling are largely conserved between rodent and human SGC (Avraham et al, 2021).…”

Section: Discussionmentioning

confidence: 96%

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Avraham¹,

Feng²,

Ewan³

et al. 2020

Preprint

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Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. This results in part from a failure of central injury to elicit a pro-regenerative response in sensory neurons. However, regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the different regenerative capacities after peripheral or central injury result in part from a lack of response of macrophages, satellite glial cells (SGC) or other non-neuronal cells in the DRG microenvironment remains largely unknown. To answer this question, we performed a single cell transcriptional profiling of DRG in response to peripheral (sciatic nerve crush) and central injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to peripheral and central injuries. Activation of the PPAR signaling pathway in SGC, which promotes axon regeneration after nerve injury, did not occur after central injuries. Treatment with the FDA-approved PPARα agonist fenofibrate, increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries.

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“…At the same time point, results indicated that BTZ caused the significant increase of PPARα gene expression, whereas no changes were detected for PPARγ mRNA levels. The early increase of PPARα in other CIN conditions has been observed [ 35 ], thus suggesting that this PPAR isoform could represent a relevant regulatory first line response attempting to dampen inflammatory conditions, involving phenomena such as endothelial loosening and leukocyte migration [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Rullo

Franchi

Amodeo

et al. 2021

IJMS

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Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

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Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy

Cited by 34 publications

References 41 publications

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

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