Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation

Imado, Eiji; Sun, Samnang; Abawa, Abrar Rizal; Tahara, Takeru; Kochi, Takeshi; Huynh, Tran Ngoc Bao; Asano, Shigetaka; Hasebe, Shigeru; Nakamura, Yoki; Hisaoka-Nakashima, Kazue; Kotake, Yaichiro; Irifune, Masahiro; Tsuga, Kazuhiro; Takuma, Kazuhiro; Morioka, Norimitsu; Kiguchi, Norikazu; Ago, Yukio

doi:10.1016/j.neuint.2022.105415

Cited by 5 publications

(6 citation statements)

References 80 publications

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“…Therefore, we expected that CSF1R antagonists would inhibit and deplete not only spinal microglia but also peripheral macrophages. Among several inhibitors, PLX3397 is orally active and extensively employed to investigate the pathophysiological roles of microglia and macrophages in various neuroinflammation‐associated diseases (Imado et al, 2022; Qu et al, 2017; Zhang et al, 2021). In the field of pain, PLX3397 (or PLX5622) has been used to determine the role of microglia and macrophages in different pain modalities.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of pexidartinib on nerve injury‐induced neuropathic pain in mice

Saika,

Fukazawa,

Hatano

et al. 2024

Glia

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It is well‐established that spinal microglia and peripheral macrophages play critical roles in the etiology of neuropathic pain; however, growing evidence suggests sex differences in pain hypersensitivity owing to microglia and macrophages. Therefore, it is crucial to understand sex‐ and androgen‐dependent characteristics of pain‐related myeloid cells in mice with nerve injury‐induced neuropathic pain. To deplete microglia and macrophages, pexidartinib (PLX3397), an inhibitor of the colony‐stimulating factor 1 receptor, was orally administered, and mice were subjected to partial sciatic nerve ligation (PSL). Following PSL induction, healthy male and female mice and male gonadectomized (GDX) mice exhibited similar levels of spinal microglial activation, peripheral macrophage accumulation, and mechanical allodynia. Treatment with PLX3397 significantly suppressed mechanical allodynia in normal males; this was not observed in female and GDX male mice. Sex‐ and androgen‐dependent differences in the PLX3397‐mediated preventive effects were observed on spinal microglia and dorsal root ganglia (DRG) macrophages, as well as in expression patterns of pain‐related inflammatory mediators in these cells. Conversely, no sex‐ or androgen‐dependent differences were detected in sciatic nerve macrophages, and inhibition of peripheral CC‐chemokine receptor 5 prevented neuropathic pain in both sexes. Collectively, these findings demonstrate the presence of considerable sex‐ and androgen‐dependent differences in the etiology of neuropathic pain in spinal microglia and DRG macrophages but not in sciatic nerve macrophages. Given that the mechanisms of neuropathic pain may differ among experimental models and clinical conditions, accumulating several lines of evidence is crucial to comprehensively clarifying the sex‐dependent regulatory mechanisms of pain.

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Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of pexidartinib on nerve injury‐induced neuropathic pain in mice

Saika,

Fukazawa,

Hatano

et al. 2024

Glia

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“…The estrous cycle stage was specified by a light microscope with a 40 × objective lens. The estrous phase was confirmed by the presence of enucleated cornified cells [ 21 , 22 ]. The morning in which spermatozoa were observed in vaginal smear or vaginal plugs was set as day 0 of pregnancy [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism

Sabet,

Abadi,

Moslemizadeh

et al. 2023

Heliyon

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“…It is now well recognized that the epigenetic effects of PPA, like APAP, are mediated via DNA methylation [182,183]. Specifically, it was shown that PPA attenuates IL-6 cytokine production through downregulation of the expression of the epigenetic modifier DNA methyltransferase 1 and inhibition of DNA methylation in both mice and humans [182,190]. Moreover, PPA modification of mitochondrial morphology and dynamics may, at least partially, be mediated via DNA methylation [183,184,191] (Figure 1).…”

Section: Ppa-epigenetics-asdmentioning

confidence: 99%

“…Moreover, Hence, VPA, APAP, and PPA by virtue of their interactions with glial cells, may also epigenetically affect the function of these cells. For example, VPA may stimulate the proliferation of glial precursors during cortical gliogenesis [114], and prenatal VPA may activate spinal microglia leading to allodynia, whereby pain is felt by a stimulus that does not normally provoke pain [182], or prenatal APAP's detrimental effect on attention-related behavior, may be, at least partly, mediated via glial cells [183,184]. PPA interaction with glial cells and epigenetic modification of these cells has also been documented [153].…”

Section: Apap-epigenetics-asdmentioning

confidence: 99%

“…As alluded to earlier, PPA disruption of biogenesis, bioenergetics, and metabolism in neurons and glial cells has made it a suitable compound in modeling ASD. It is now well recognized that the epigenetic effects of PPA, like APAP, are mediated via DNA methylation [182,183]. Specifically, it was shown that PPA attenuates IL-6 cytokine production through downregulation of the expression of the epigenetic modifier DNA methyltransferase 1 and inhibition of DNA methylation in both mice and humans [182,190].…”

Section: Ppa-epigenetics-asdmentioning

confidence: 99%

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Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder

Csoka,

El Kouhen,

Bennani

et al. 2024

Biomolecules

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

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Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation

Cited by 5 publications

References 80 publications

Sexually dimorphic effects of pexidartinib on nerve injury‐induced neuropathic pain in mice

Sexually dimorphic effects of pexidartinib on nerve injury‐induced neuropathic pain in mice

The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder

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