Neuronal plasticity of trigeminal ganglia in mice following nerve injury

Lynds, Randi; Lyu, Chuang; Lyu, Gong-Wei; Shi, Xie‐Qi; Rosén, Annika; Mustafa, Kamal; Shi, Tie‐Jun Sten

doi:10.2147/jpr.s120092

Cited by 20 publications

(19 citation statements)

References 75 publications

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“…Our results show a wide distribution of the FRMD6 protein in the mouse spinal cord, in agreement with the distribution of its transcript shown in the ALLEN BRAIN ATLAS [45][46][47][48][49][50][51] . The increase of FRMD6-immunoreactivity in laminae I-II seven days after sciatic nerve axotomy likely occurs in local neurons; it is less likely to be associated with primary afferents, also because there is a downregulation in cytoplasmic FRMD6 and its mRNA in DRG neuron cell bodies after axotomy.…”

Section: Discussionsupporting

confidence: 90%

Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Lyu

Mulder

et al. 2020

Sci Rep

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FRMD6, a member of the group of FERM-domain proteins, is involved both in communication between cells, interactions with extracellular matrix, cellular apoptotic and regenerative mechanisms. FRMD6 was first discovered in the rodent sciatic nerve, and in the present immunohistochemical study we investigated the distribution of FRMD6 in the dorsal root ganglia (DRGs), sciatic nerve and spinal cord following sciatic nerve injury. FRMD6-immunoreactivity was found in the cytoplasm, nucleus or both, and in a majority of DRG neurons. FRMD6-immunoreactivity co-existed with several wellknown neuronal markers, including calcitonin gene-related peptide, isolectin B4 and neurofilament 200 in mouse DRGs. After peripheral nerve injury, the FRMD6 mRNA levels and the overall percentage of FRMD6-positive neuron profiles (NPs) were decreased in ipsilateral lumbar DRGs, the latter mainly affecting small size neurons with cytoplasmic localization. Conversely, the proportion of NPs with nuclear FRMD6-immunoreactivity was significantly increased. In the sciatic nerve, FRMD6immunoreactivity was observed in non-neuronal cells and in axons, and accumulated proximally to a ligation of the nerve. In the spinal cord FRMD6-immunoreactivity was detected in neurons in both dorsal and ventral horns, and was upregulated in ipsilateral dorsal horn after peripheral nerve axotomy. Our results demonstrate that FRMD6 is strictly regulated by peripheral nerve injury at the spinal level. FRMD (protein 4.1, ezrin, radixin and moesin) 6, also known as Willin, is a member of the 4.1 superfamily and was first identified in the sciatic nerve of rats by northern blot analysis 1. Recently, the FRMD6 transcripts were detected in mouse lumbar dorsal root ganglia (DRGs) and spinal cord by RNAseq (see Supplementary Table 4) 2. Human FRMD6 has been shown to be a homolog of Ex in Drosophila, which is a putative tumor suppressor 3,4. FRMD6/Ex, as an upstream regulator, is a component of multiple upstream molecular complexes in the Salvador/ Warts/Hippo (Hippo) signaling pathway network that, mostly via MST1/2 (mammalian STE20-like protein kinase) and LATS1/2 (large tumour suppressor homolog), regulates the activity of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), two downstream homologous transcriptional co-activators 5-8. This pathway, originally identified in drosophila 9,10 and more recently shown to be well conserved in mammalians 11 , regulates cellular proliferation, differentiation, apoptosis and tissue homoeostasis 5,6. In human, analysing tissues from healthy and diseased donors by immunohistochemistry, FRMD6-immunoreactivity was observed in cytoplasm, plasma membrane or nucleus of various normal tissues (e.g., intestine) and carcinoma, and sometimes with a mixed intracellular distribution 12. However, the functional associations between these subcellular localizations and physiopathologic processes are still not elucidated. Moreover, FRMD6 transcripts were detected predominantly in fibroblasts within the perine...

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Section: Discussionsupporting

confidence: 90%

Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Lyu

Mulder

et al. 2020

Sci Rep

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“…Moreover, minocycline has several inhibitory effects on microglial cells, including inhibition of microglial proliferation and hypertrophic morphology and reduction in the production of proinflammatory factors (40–42). In this regard, there is evidence for the existence of resident microglial cells in the normal rat TG (43), as demonstration of microglia activation in different orofacial pain models (44,45). Finally, minocycline is suggested to decrease the excitability of different neuronal populations by decreasing glutamatergic transmission (46–48).…”

Section: Discussionmentioning

confidence: 99%

Contribution of intraganglionic CGRP to migraine-like responses in male and female rats

et al. 2019

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Objective To evaluate whether intraganglionic calcitonin gene-related peptide induced differential migraine-like responses in male and female rats. Methods Calcitonin gene-related peptide was injected in the trigeminal ganglion of male and female rats followed by assessment of periorbital mechanical allodynia with von Frey hairs. The influence of systemic treatment with sumatriptan or intraganglionic treatment with minocycline and propentofylline was determined on the calcitonin gene-related peptide-induced mechanical allodynia in male and female rats. One additional group was exposed to an aversive light 24 h after calcitonin gene-related peptide priming, followed by evaluation of periorbital mechanical threshold, and another group was tested in the elevated-plus maze. Results Intraganglionar calcitonin gene-related peptide-induced periorbital mechanical allodynia in female (0.5 to 6 h) and male rats (0.5 to 4 h). Systemic sumatriptan briefly attenuated the mechanical allodynia, but intraganglionar minocycline or propentofylline injection was effective only in male rats. Calcitonin gene-related peptide induced photic sensitivity in female and male rats (lasting 4 h and 1 h, respectively), as well as anxiety-like behavior. Conclusions Intraganglionar calcitonin gene-related peptide may play a major role in migraine-like responses, including periorbital mechanical allodynia, light sensitivity and anxiety like-behavior. Female rats are likely to be more susceptible to calcitonin gene-related peptide effects and a better understanding of the sexual dimorphism in calcitonin gene-related peptide signaling may help to improve migraine therapy.

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“…In this frame, it was quite surprising that we did not detect any significant difference in neuropeptide protein expression at the Sp5C level, neither among groups, nor between sides. Lynds and co-workers [ 104 ] reported no differences in neuropeptide (CGRP and SP) levels between ipsi- and contralateral TG two weeks after IoN transection injury, while Xu and colleagues [ 105 ] described a reduction of CGRP and SP protein levels in the ipsilateral caudal medulla eight days after partial IoN ligation. Taken together, these findings suggest that in our model the neuropeptide release at central sites might have taken place at early time points after surgery, and therefore went undetected since we only measured it on day +27, or alternatively, that CGRP and SP are mostly involved at the peripheral terminals [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model

Demartini¹,

Greco²,

Zanaboni

et al. 2018

IJMS

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Transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions, including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels by means of the antagonist ADM_12 in trigeminal neuropathic pain, in order to identify possible therapeutic targets. A single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP), substance P (SP), and cytokines gene expression in trigeminal ganglia, cervical spinal cord, and medulla induced in the IoN-CCI rats. By contrast, no significant differences between groups were seen as regards CGRP and SP protein expression in the pars caudalis of the spinal nucleus of the trigeminal nerve. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. Our findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain, and in particular, in trigeminal mechanical allodynia. Furthermore, they provide grounds for the use of ADM_12 in the treatment of trigeminal neuropathic pain.

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Neuronal plasticity of trigeminal ganglia in mice following nerve injury

Cited by 20 publications

References 75 publications

Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Contribution of intraganglionic CGRP to migraine-like responses in male and female rats

Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model

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