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11 pages, 1902 KiB

Open AccessArticle

Preventive Intrathecal Injection of Bupivacaine Alleviated Microglia Activation and Neuropathic Pain in a Rat Model of Chronic Constriction Injury

by Chih-Cheng Wu, Cheng-Yi Chang, Chung-Yuh Tzeng, Jen-Hsuan Huang, Chih-Jen Hung, Wen-Ying Chen, Su-Lan Liao, Yu-Hsiang Kuan and Chun-Jung Chen

Int. J. Mol. Sci. 2022, 23(13), 7197; https://doi.org/10.3390/ijms23137197 - 28 Jun 2022

Cited by 5 | Viewed by 2303

Abstract

Spinal microglia are crucial to neuronal hyper-excitability and pain hypersensitivity. The local anesthetic bupivacaine is commonly used for both peripheral and spinal anesthesia. The pain-relief effects resulting from the peripheral and systemic administration of bupivacaine have been previously reported. In this study, the [...] Read more.

Spinal microglia are crucial to neuronal hyper-excitability and pain hypersensitivity. The local anesthetic bupivacaine is commonly used for both peripheral and spinal anesthesia. The pain-relief effects resulting from the peripheral and systemic administration of bupivacaine have been previously reported. In this study, the preventive effects of intrathecal bupivacaine administration against neuropathic pain were revealed in a rat model of sciatic nerve chronic constriction injury (CCI). Using a CCI rat model, pain hypersensitivity, characterized by mechanical allodynia and thermal hyperalgesia, correlated well with microglia M1 polarization, activation and pro-inflammatory cytokine expression in both spinal cord dorsal horns and sciatic nerves. Bupivacaine attenuated pain behaviors and inflammatory alternations. We further identified that the Interferon Regulatory Factor 5 (IRF5)/P2X Purinoceptor 4 (P2X4R) and High Mobility Group Box 1 (HMGB1)/Toll-Like Receptor 4 (TLR4)/NF-κB inflammatory axes may each play pivotal roles in the acquisition of microglia M1 polarization and pro-inflammatory cytokine expression under CCI insult. The relief of pain paralleled with the suppression of microglia M1 polarization, elevation of microglia M2 polarization, and inhibition of IRF5/P2X4R and HMGB1/TLR4/NF-κB in both the spinal cord dorsal horns and sciatic nerve. Our findings provide molecular and biochemical evidence for the anti-neuropathic effect of preventive bupivacaine. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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16 pages, 446 KiB

Open AccessArticle

Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy

by Milena Ślęczkowska, Rowida Almomani, Margherita Marchi, Bianca T. A. de Greef, Maurice Sopacua, Janneke G. J. Hoeijmakers, Patrick Lindsey, Erika Salvi, Gidon J. Bönhof, Dan Ziegler, Rayaz A. Malik, Stephen G. Waxman, Giuseppe Lauria, Catharina G. Faber, Hubert J. M. Smeets and Monique M. Gerrits

Int. J. Mol. Sci. 2022, 23(13), 7190; https://doi.org/10.3390/ijms23137190 - 28 Jun 2022

Cited by 11 | Viewed by 2993

Abstract

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 [...] Read more.

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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16 pages, 4186 KiB

Open AccessArticle

Analgesic Effect of Tranilast in an Animal Model of Neuropathic Pain and Its Role in the Regulation of Tetrahydrobiopterin Synthesis

by Swarnalakshmi Raman, Arief Waskitho, Resmi Raju, Takuma Iwasa, Daisuke Ikutame, Kazuo Okura, Masamitsu Oshima and Yoshizo Matsuka

Int. J. Mol. Sci. 2022, 23(11), 5878; https://doi.org/10.3390/ijms23115878 - 24 May 2022

Cited by 4 | Viewed by 2178

Abstract

Trigeminal neuralgia is unilateral, lancinating, episodic pain that can be provoked by routine activities. Anticonvulsants, such as carbamazepine, are the drugs of choice; however, these possess side-effects. Microvascular decompression is the most effective surgical technique with a higher success rate, although occasionally causes [...] Read more.

Trigeminal neuralgia is unilateral, lancinating, episodic pain that can be provoked by routine activities. Anticonvulsants, such as carbamazepine, are the drugs of choice; however, these possess side-effects. Microvascular decompression is the most effective surgical technique with a higher success rate, although occasionally causes adverse effects. The potential treatment for this type of pain remains unmet. Increased tetrahydrobiopterin (BH4) levels have been reported in association with axonal injury. This study aimed to evaluate the effect of tranilast on relieving neuropathic pain in animal models and analyze the changes in BH4 synthesis. Neuropathic pain was induced via infraorbital nerve constriction. Tranilast, carbamazepine, or saline was injected intraperitoneally to assess the rat’s post-intervention pain response. In the von Frey’s test, the tranilast and carbamazepine groups showed significant changes in the head withdrawal threshold in the ipsilateral whisker pad area. The motor coordination test showed no changes in the tranilast group, whereas the carbamazepine group showed decreased performance, indicating impaired motor coordination. Trigeminal ganglion tissues were used for the PCR array analysis of genes that regulate the BH4 pathway. Downregulation of the sepiapterin reductase (Spr) and aldoketo reductase (Akr) genes after tranilast injection was observed compared to the pain model. These findings suggest that tranilast effectively treats neuropathic pain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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14 pages, 4926 KiB

Open AccessArticle

The Contribution of TSLP Activation to Hyperalgesia in Dorsal Root Ganglia Neurons of a Rat

by Chun-Ching Lu, Ying-Yi Lu, Hung-Pei Tsai and Chieh-Hsin Wu

Int. J. Mol. Sci. 2022, 23(4), 2012; https://doi.org/10.3390/ijms23042012 - 11 Feb 2022

Cited by 6 | Viewed by 2267

Abstract

Peripheral nerve injury involves divergent alterations within dorsal root ganglia (DRG) neurons sensitized by persistent inflammation. Thymic stromal lymphopoietin (TSLP) production is crucial in the development of chronic inflammatory responses. Herein, we investigate the changes of TSLP expression in rats’ DRG neurons between [...] Read more.

Peripheral nerve injury involves divergent alterations within dorsal root ganglia (DRG) neurons sensitized by persistent inflammation. Thymic stromal lymphopoietin (TSLP) production is crucial in the development of chronic inflammatory responses. Herein, we investigate the changes of TSLP expression in rats’ DRG neurons between injured and uninjured sides in the same rat. Linalyl acetate (LA) was served as a TSLP inhibitor and given intraperitoneally. Rats were assigned to be group of chronic constriction injury (CCI) of the sciatic nerve and the group of CCI of the sciatic nerve administrated with LA. Over 14 days, the rats were measured for paw withdrawal thresholds. DRGs were collected to assess morphological changes via immunofluorescence study. After receiving CCI, the rats rapidly developed mechanical hyperalgesia. TSLP expression at DRG, on the ipsilateral injured side, was consistent with changes in pain behaviors. TSLP appeared in nerve fibers with both small diameters and large diameters. Additionally, TSLP was expressed mostly in transient receptor potential vanilloid-1 (TRPV1)-positive nociceptive neurons. Administration with LA can attenuate the pain behaviors and expression of TSLP in DRG neurons, and in apoptotic neurons at the injured side, but not in the contra-lateral uninjured side. Overall, these results imply that altered expressions of TSLP in nociceptive DRG neurons contributed to mechanical hyperalgesia in a CCI rat model. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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19 pages, 25792 KiB

Open AccessArticle

TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization

by Lingdi Nie, Liwen Jiang, John P. Quinn, Blair D. Grubb and Minyan Wang

Int. J. Mol. Sci. 2021, 22(22), 12273; https://doi.org/10.3390/ijms222212273 - 12 Nov 2021

Cited by 9 | Viewed by 3368

Abstract

Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit [...] Read more.

Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1β gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1β mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14–22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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13 pages, 33620 KiB

Open AccessArticle

Increased Expression of Thymic Stromal Lymphopoietin in Chronic Constriction Injury of Rat Nerve

by Chieh-Hsin Wu, Chun-Ching Lu, Chao-Lan Huang, Ming-Kung Wu and Ying-Yi Lu

Int. J. Mol. Sci. 2021, 22(13), 7105; https://doi.org/10.3390/ijms22137105 - 1 Jul 2021

Cited by 5 | Viewed by 2850

Abstract

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron–glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP [...] Read more.

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron–glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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12 pages, 1379 KiB

Open AccessArticle

Functional Coupling between the P2X₇ Receptor and Pannexin-1 Channel in Rat Trigeminal Ganglion Neurons

by Hiroyuki Inoue, Hidetaka Kuroda, Wataru Ofusa, Sadao Oyama, Maki Kimura, Tatsuya Ichinohe and Yoshiyuki Shibukawa

Int. J. Mol. Sci. 2021, 22(11), 5978; https://doi.org/10.3390/ijms22115978 - 1 Jun 2021

Cited by 7 | Viewed by 3130

Abstract

The ionotropic P2X receptor, P2X₇, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X₇ receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) [...] Read more.

The ionotropic P2X receptor, P2X₇, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X₇ receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X₇ receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X₇ receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X₇ receptor antagonists, while only the second component was inhibited by P2X_{1, 3,} and ₄ receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X₇-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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18 pages, 2900 KiB

Open AccessArticle

Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing

by Ruirui Lu, Katharina Metzner, Fangyuan Zhou, Cathrin Flauaus, Annika Balzulat, Patrick Engel, Jonas Petersen, Rebekka Ehinger, Anne Bausch, Peter Ruth, Robert Lukowski and Achim Schmidtko

Int. J. Mol. Sci. 2021, 22(1), 405; https://doi.org/10.3390/ijms22010405 - 2 Jan 2021

Cited by 10 | Viewed by 4295

Abstract

The sodium-activated potassium channel Slack (K_Na1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I_KNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing [...] Read more.

The sodium-activated potassium channel Slack (K_Na1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I_KNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I_KNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I_KNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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19 pages, 4299 KiB

Open AccessArticle

Irisin Gene Delivery Ameliorates Burn-Induced Sensory and Motor Neuropathy

by Shu-Hung Huang, Shih-Ming Yang, Jing-Jou Lo, Sheng-Hua Wu and Ming-Hong Tai

Int. J. Mol. Sci. 2020, 21(20), 7798; https://doi.org/10.3390/ijms21207798 - 21 Oct 2020

Cited by 10 | Viewed by 4013

Abstract

Burn-related neuropathy is common and often involves pain, paresthesia, or muscle weakness. Irisin, an exercise-induced myokine after cleavage from its membrane precursor fibronectin type III domain-containing 5 (FNDC5), exhibits neuroprotective and anti-inflammatory activities. A rat model of third-degree burn on the right hind [...] Read more.

Burn-related neuropathy is common and often involves pain, paresthesia, or muscle weakness. Irisin, an exercise-induced myokine after cleavage from its membrane precursor fibronectin type III domain-containing 5 (FNDC5), exhibits neuroprotective and anti-inflammatory activities. A rat model of third-degree burn on the right hind paw was used to investigate the therapeutic role of irisin/FNDC5. Rats received burn injury and were treated with intrathecal recombinant adenovirus containing the irisin sequence (Ad-irisin) at 3 weeks postburn. One week later, mechanical allodynia was examined. The expression of irisin in cerebrospinal fluid (CSF) was detected. Ipsilateral gastrocnemius muscle and lumbar spinal cord were also obtained for further investigation. Furthermore, the anti-apoptotic effect of recombinant irisin in SH-SY5Y cells was evaluated through tumor necrosis factor alpha (TNFα) stimulus to mimic burn injury. We noted intrathecal Ad-irisin attenuated pain sensitization and gastrocnemius muscle atrophy by modulating the level of irisin in CSF, and the expression of neuronal FNDC5/irisin and TNFα in the spinal cord. Ad-irisin also ameliorated neuronal apoptosis in both dorsal and ventral horns. Furthermore, recombinant irisin attenuated TNFα-induced SH-SY5Y cell apoptosis. In summary, irisin attenuated allodynia and muscle wasting by ameliorating neuroinflammation-induced neuronal apoptosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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15 pages, 54142 KiB

Open AccessArticle

Microglia–Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury

by Sayaka Asano, Yoshinori Hayashi, Koichi Iwata, Akiko Okada-Ogawa, Suzuro Hitomi, Ikuko Shibuta, Yoshiki Imamura and Masamichi Shinoda

Int. J. Mol. Sci. 2020, 21(18), 6834; https://doi.org/10.3390/ijms21186834 - 17 Sep 2020

Cited by 30 | Viewed by 4148

Abstract

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which [...] Read more.

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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Review

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16 pages, 1445 KiB

Open AccessReview

Calcium in Neuronal and Glial Response to Axotomy

by Andrey Khaitin

Int. J. Mol. Sci. 2021, 22(24), 13344; https://doi.org/10.3390/ijms222413344 - 12 Dec 2021

Cited by 10 | Viewed by 3366

Abstract

Neurotrauma assumes an instant or delayed disconnection of axons (axotomy), which affects not only neurons, but surrounding glia as well. Not only mechanically injured glia near the site of disconnection, especially transection, is subjected to the damage, but also glia that is remote [...] Read more.

Neurotrauma assumes an instant or delayed disconnection of axons (axotomy), which affects not only neurons, but surrounding glia as well. Not only mechanically injured glia near the site of disconnection, especially transection, is subjected to the damage, but also glia that is remote from the lesion site. Glial cells, which surround the neuronal body, in turn, support neuron survival, so there is a mutual protection between neuron and glia. Calcium signaling is a central mediator of all post-axotomy events, both in neuron and glia, playing a critical role in their survival/regeneration or death/degeneration. The involvement of calcium in post-axotomy survival of the remote, mechanically intact glia is poorly studied. The purpose of this review is to sum up the calcium-involving mechanisms in responses of neurons and glial cells to axotomy to show their importance and to give some suggestions for future research of remote glia in this context. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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24 pages, 1759 KiB

Open AccessReview

Potential Therapeutic Strategies and Substances for Facial Nerve Regeneration Based on Preclinical Studies

by Myung Chul Yoo, Jinmann Chon, Junyang Jung, Sung Su Kim, Seonhwan Bae, Sang Hoon Kim and Seung Geun Yeo

Int. J. Mol. Sci. 2021, 22(9), 4926; https://doi.org/10.3390/ijms22094926 - 6 May 2021

Cited by 10 | Viewed by 4201

Abstract

Despite advances in microsurgical technology and an improved understanding of nerve regeneration, obtaining satisfactory results after facial nerve injury remains a difficult clinical problem. Among existing peripheral nerve regeneration studies, relatively few have focused on the facial nerve, particularly how experimental studies of [...] Read more.

Despite advances in microsurgical technology and an improved understanding of nerve regeneration, obtaining satisfactory results after facial nerve injury remains a difficult clinical problem. Among existing peripheral nerve regeneration studies, relatively few have focused on the facial nerve, particularly how experimental studies of the facial nerve using animal models play an essential role in understanding functional outcomes and how such studies can lead to improved axon regeneration after nerve injury. The purpose of this article is to review current perspectives on strategies for applying potential therapeutic methods for facial nerve regeneration. To this end, we searched Embase, PubMed, and the Cochrane library using keywords, and after applying exclusion criteria, obtained a total of 31 qualifying experimental studies. We then summarize the fundamental experimental studies on facial nerve regeneration, highlighting recent bioengineering studies employing various strategies for supporting facial nerve regeneration, including nerve conduits with stem cells, neurotrophic factors, and/or other therapeutics. Our summary of the methods and results of these previous reports reveal a common feature among studies, showing that various neurotrophic factors arising from injured nerves contribute to a microenvironment that plays an important role in functional recovery. In most cases, histological examinations showed that this microenvironmental influence increased axonal diameter as well as myelination thickness. Such an analysis of available research on facial nerve injury and regeneration represents the first step toward future therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)

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