Progesterone modulates pro-inflammatory cytokine expression profile after spinal cord injury: Implications for neuropathic pain

Coronel, Marı́a Florencia; Raggio, María Celeste; Adler, Natalia S.; Nicola, Alejandro F. De; Labombarda, Florencia; González, Susana

doi:10.1016/j.jneuroim.2016.01.011

Cited by 44 publications

(65 citation statements)

References 70 publications

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“…Blocking PR was associated with high NK activity as well as induction of pro-inflammatory cytokines TNFα, IFN-γ and NF-κB that increased resorption rate (Szekeres-Bartho, et al 2005; Tiwari, et al 2016). In the nervous system, after a spinal cord injury, PR modulates the astrocyte response and commitment of oligodendrocyte progenitor cells to enhance remyelination (Labombarda, et al 2015) and progesterone treatment decreases neuropathic pain associated with spinal cord injury (Coronel, et al 2016). The absence of PR signaling in the MSCs exerted an immunosuppressive response that was more pronounced in the males, suggesting that PR expression levels may elucidate disparities in gender specific immune disorders and the potential role for targeting PR as gender-specific medicine.…”

Section: Discussionmentioning

confidence: 99%

Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Kot¹,

Zhong²,

Zhang³

et al. 2017

Journal of Molecular Endocrinology

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Augmenting peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor specific PR inactivation, which recapitulated the high bone mass phenotype. In this work, we employed RNA sequencing analysis to evaluate sex-independent and sex-dependent differences in gene transcription of osteoprogenitors of wild type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction, and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs.

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Section: Discussionmentioning

confidence: 99%

Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Kot¹,

Zhong²,

Zhang³

et al. 2017

Journal of Molecular Endocrinology

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“…Rats were placed on individual acrylic testing chambers (8 × 8 × 18 cm) upon an elevated metal grid and allowed to habituate to the environment for 15 minutes before testing. The animals were tested before initiating OXA administration in order to obtain normal baseline values and at different time points, twice per week, thereafter and until the designated end‐point, as previously described . Only rats showing normal responses to mechanical and thermal stimulation before chemotherapy were included in the experiments (n = 12 in each experimental group).…”

Section: Methodsmentioning

confidence: 99%

“…As previously reported, paw mechanical sensitivity was assessed by evaluating the response to normally innocuous mechanical stimuli using a series of eight calibrated von Frey filaments (1, 2, 4, 6, 8, 10, 15, 26 g; Stoelting, Wood Dale, Illinois). Each hair was delivered to the central plantar area of each hindpaw, and at least six measurements were made, following the “up‐and‐down” method described by Dixon and Chaplan et al A robust and immediate paw withdrawal together with a nocifensive behavior such as repetitive shaking or licking of the paw, intention to either attack the stimulus or escape was considered a positive response.…”

Section: Methodsmentioning

confidence: 99%

“…Seven days after initiating OXA/saline administration, OXA, OXA + HPGCp, and CTL animals (n = 8 in each experimental group) were killed by decapitation after being deeply anesthetized with ketamine/xilazine (90/10 mg/kg, ip). Bilateral lumbar DRG (L3‐L5) and spinal L4‐L5 segments were immediately removed, and the dorsal spinal halves were dissected by cutting through the central canal . Tissues were frozen and stored at −70°C until further studies were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Data shown in Figures and correspond to the mean ± SEM of mRNA levels relative to control values (CTL animals). Statistical analysis was performed by applying one‐way analysis of variance ( anova ) and Neuman‐Keuls multiple comparison post‐test …”

Section: Methodsmentioning

confidence: 99%

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Anti‐allodynic and anti‐inflammatory effects of 17α‐hydroxyprogesterone caproate in oxaliplatin‐induced peripheral neuropathy

Miguel

Raggio

Villar

et al. 2019

J Peripheral Nervous Sys

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Chemotherapy‐induced peripheral neuropathy is a disabling condition induced by several frequently used chemotherapeutic drugs including the front‐line agent oxaliplatin (OXA). Symptoms are predominantly sensory with the development of neuropathic pain. Alternative dosing protocols and treatment discontinuation are the only available therapeutic strategies. The aim of our work was to evaluate the potential of a synthetic derivative of progesterone, 17α‐hydroxyprogesterone caproate (HPGC), in the prevention and treatment of OXA‐evoked painful neuropathy. We also evaluated glial activation at the dorsal root ganglia (DRG) and spinal cord levels as a possible target mechanism underlying HPGC actions. Male rats were injected with OXA and HPGC following a prophylactic (HPGCp) or therapeutic (HPGCt) scheme (starting either before or after chemotherapy). The development of hypersensitivity and allodynic pain and the expression of neuronal and glial activation markers were evaluated. When compared to control animals, those receiving OXA showed a significant decrease in paw mechanical and thermal thresholds, with the development of allodynia. Animals treated with HPGCp showed patterns of response similar to those detected in control animals, while those treated with HPGCt showed a suppression of both hypersensitivities after HPGC administration. We also observed a significant increase in the mRNA levels of activating transcription factor 3, the transcription factor (c‐fos), glial fibrillary acidic protein, ionized calcium binding adaptor protein 1, interleukin 1 beta (IL‐1β) and tumor necrosis factor alpha (TNFα) in DRG and spinal cord of OXA‐injected animals, and significantly lower levels in rats receiving OXA and HPGC. These results show that HPGC administration reduces neuronal and glial activation markers and is able to both prevent and suppress OXA‐induced allodynia, suggesting a promising therapeutic strategy.

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Effects of melatonin on severe crush spinal cord injury–induced reactive astrocyte and scar formation

Krityakiarana

Sompup

Jongkamonwiwat

et al. 2016

J of Neuroscience Research

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The present work aimed at analyzing the effects of melatonin on scar formation after spinal cord injury (SCI). Upregulation of reactive astrocyte under SCI pathological conditions has been presented in several studies. It has been proved that the crucial factor in triggering this upregulation is proinflammatory cytokines. Moreover, scar formation is an important barrier to axonal regeneration through the lesion area. Melatonin plays an important role in reducing inflammation, but its effects on scar formation in the injured spinal cord remain unknown. Hence, we used the model of severe crush injury in mice to investigate the effects of melatonin on scar formation. Mice were randomly separated into four groups; SCI, SCI+Melatonin 1 (single dose), SCI+Melatonin 14 (14 daily doses), and control. Melatonin was administered by intraperitoneal injection (10 mg/kg) after injury. Immunohistochemical analysis, Western blot, and behavioral evaluation were used to explore the effects of melatonin after SCI for 14 days. The melatonin-treated mice presented higher expression of neuronal markers (P < 0.001). Remarkably, the inflammatory response appeared to be greatly reduced in the SCI+Melatonin 14 group (P < 0.001), which also displayed less scar formation (P < 0.05). These findings suggest that melatonin inhibits scar formation by acting on inflammatory cytokines after SCI. Overall, our results suggest that melatonin is a promising treatment strategy after SCI that deserves further investigation. © 2016 Wiley Periodicals, Inc.

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Progesterone modulates pro-inflammatory cytokine expression profile after spinal cord injury: Implications for neuropathic pain

Cited by 44 publications

References 70 publications

Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Anti‐allodynic and anti‐inflammatory effects of 17α‐hydroxyprogesterone caproate in oxaliplatin‐induced peripheral neuropathy

Effects of melatonin on severe crush spinal cord injury–induced reactive astrocyte and scar formation

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