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Background: Triptans are potent 5-HT 1B/1D/1F receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT 1B/1D/1F receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT 1B/1D/1F receptor occupancies at clinically relevant concentrations., Methods: Using the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (K p, uu, ROI ) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used K p, uu, ROI values to estimate unbound target-site concentrations and 5-HT 1B/1D/1F receptor occupancies in humans., Results: We observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (K p, uu, TG : eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (K p, uu, whole brain : eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT 1B receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations., Conclusions: This study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT 1B, 5-HT 1D , and 5-HT 1F receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan's antimigraine effect and/or side effects., (© 2024. The Author(s).)

As the field of cancer neuroscience expands, the strategic targeting of interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment, comparable to the advent of our current understanding of tumour immunology. Cancer cells actively release growth factors that stimulate tumour neo-neurogenesis, and accumulating evidence indicates that tumour neo-innervation propels tumour progression, inhibits tumour-related pro-inflammatory cytokines, promotes neovascularization, facilitates metastasis and regulates immune exhaustion and evasion. In this Review, we give an up-to-date overview of the dynamics of the tumour microenvironment with an emphasis on tumour innervation by the peripheral nervous system, as well as current preclinical and clinical evidence of the benefits of targeting the nervous system in cancer, laying a scientific foundation for further clinical trials. Combining empirical data with a biomarker-driven approach to identify and hone neuronal targets implicated in cancer and its spread can pave the way for swift clinical integration., (© 2024. Springer Nature Limited.)

Background and Purpose: After repeat administration of gadolinium-based contrast agents (GBCAs), the association between gadolinium retention in the central and peripheral nervous systems and the main manifestations of myelopathy and progressive neurologic symptoms remains unclear. We investigated the effects of the repeat administration of GBCAs on gadolinium retention in the central and peripheral nervous systems and the sensory, cognitive, and athletic implications., Materials and Methods: Forty-eight male Wistar rats (6 weeks of age) were randomly divided into 4 experimental groups (12 rats in each group): the gadodiamide group (linear and nonionic GBCAs), the gadopentetate dimeglumine group (linear and ionic GBCAs), the gadoterate meglumine group (macrocyclic and ionic GBCAs), and the control group (0.9% saline solution). The brains of the rats were scanned using 9.4T MRI. Sensory behavioral tests were performed to assess the effect of GBCAs on pain sensitivity function. Gadolinium deposition in the brain, spinal cord, and peripheral nerves was determined by inductively coupled plasma mass-spectrometry. Transmission electron microscopy was used to observe the microscopic distribution of gadolinium after deposition in the spinal cord. The histopathologic features in the spinal cord were analyzed by H&E staining, Nissl staining, glial fibrillary acidic protein staining, and neuron-specific enolase staining after administration of GBCAs., Results: All GBCAs resulted in gadolinium deposition in the central and peripheral nerve tissues, with the highest deposition in the sciatic nerve tissue (mean, 62.86 [SD, 12.56] nmol/g). Decreased muscle power, impairment of spatial cognitive function power, and pain hypersensitivity to thermal and mechanical stimuli were observed after exposure to gadodiamide. At the spinal cord, transmission electron microscopy found that the region of gadolinium depositions had a spheric structure similar to "sea urchins" and was mainly located near the vascular basement membrane., Conclusions: Multiple injections of GBCAs caused gadolinium deposition in the brain, spinal cord, and peripheral nerves, especially in the spinal cords of the gadodiamide group. Gadodiamide led to pain hypersensitivity and decreased muscle power and cognitive ability. For the patients who are hypersensitive to pain and need multiple MRI examinations, we recommend using macrocyclic GBCAs and the lowest dose possible., (© 2024 by American Journal of Neuroradiology.)

Background: Prenatal nicotine exposure (PNE) has been documented to cause numerous deleterious effects on fetal development. However, the epigenetic changes promoted by nicotine exposure on germ cells are still not well understood., Objectives: In this study, we focused on elucidating the impact of prenatal nicotine exposure on regulatory epigenetic mechanisms important for germ cell development., Methods: Sprague-Dawley rats were exposed to nicotine during pregnancy and male progeny was analyzed at 11 weeks of age. Testis morphology was analyzed using frozen testis sections and expression of germ cell markers was examined by RT-qPCR; histone modifications were assessed by Western Blot (WB). DNA methylation analysis was performed by methylation-specific PCR of bisulfite converted DNA. Genome-wide DNA methylation was analyzed using Methylated DNA immunoprecipitation (MeDIP)-seq. We also carried out transcriptomics analysis of pituitary glands by RNA-seq., Results: We show that gestational exposure to nicotine reduces germ cell numbers, perturbs meiosis, affects the expression of germ line reprogramming responsive genes, and impacts the DNA methylation of nervous system genes in the testis. PNE also causes perturbation of gene expression in the pituitary gland of the brain., Conclusions: Our data demonstrate that PNE leads to perturbation of male spermatogenesis, and the observed effects are associated with changes of peripheral nervous system signaling pathways. Alterations in the expression of genes associated with diverse biological activities such as cell migration, cell adhesion and GABA signaling in the pituitary gland underscore the complexity of the effects of nicotine exposure during pregnancy., (© 2024. The Author(s).)

Background: We recently reported that a 6-day continuous peripheral nerve block reduced established postamputation phantom pain 3 weeks after treatment ended. However, the immediate effects of perineural infusion (secondary outcomes) have yet to be reported., Methods: Participants from 5 enrolling academic centers with an upper or lower limb amputation and established phantom pain received a single-injection ropivacaine peripheral nerve block(s) and perineural catheter insertion(s). They were subsequently randomized to receive a 6-day ambulatory perineural infusion of either ropivacaine 0.5% or normal saline in a double-masked fashion. Participants were contacted by telephone 1, 7, 14, 21, and 28 days after the infusion started, with pain measured using the Numeric Rating Scale. Treatment effects were assessed using the Wilcoxon rank-sum test at each time point. Adjusting for 4 time points (days 1, 7, 14, and 21), P < .0125 was deemed statistically significant. Significance at 28 days was reported using methods from the original, previously published article., Results: Pretreatment average phantom and residual pain scores were balanced between the groups. The day after infusion initiation (day 1), average phantom, and residual limb pain intensity was lower in patients receiving local anesthetic (n = 71) versus placebo (n = 73): median [quartiles] of 0 [0-2.5] vs 3.3 [0-5.0], median difference (98.75% confidence interval [CI]) of -1.0 (-3.0 to 0) for phantom pain (P = .001) and 0 [0-0] vs 0 [0-4.3], and median difference 0.0 (-2.0 to 0.0) for residual limb pain (P < .001). Pain's interference with physical and emotional functioning as measured with the interference domain of the Brief Pain Inventory improved during the infusion on day 1 for patients receiving local anesthetic versus placebo: 0 [0-10] vs 10 [0-40], median difference (98.75% CI) of 0.0 (-16.0 to 0.0), P = .002. Following infusion discontinuation (day 6), a few differences were found between the active and placebo treatment groups between days 7 and 21. In general, sample medians for average phantom and residual limb pain scores gradually increased after catheter removal for both treatments, but to a greater degree in the control group until day 28, at which time the differences between the groups returned to statistical significance., Conclusions: This secondary analysis suggests that a continuous peripheral nerve block decreases phantom and residual limb pain during the infusion, although few improvements were again detected until day 28, 3 weeks following catheter removal., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems., (© 2021 International Society for Neurochemistry.)

Background: Peripheral nerve block (PNB) with perineural local anesthetic is used for anesthesia or analgesia with many benefits. To extend these benefits, various adjuvant drugs have been used to prolong the duration of analgesia. We aimed to evaluate the effectiveness of various adjuvants at prolonging the duration of sensory and motor blockade for PNB., Methods: A network meta-analysis of placebo-controlled and active randomized controlled trials was performed comparing 10 adjuvants. Embase, PubMed, Web of Science, and Cochrane library were searched, with articles before May 21, 2020 included. Two authors independently selected studies and extracted data. The primary outcomes were sensory block (SB) and motor block (MB) time, and the secondary outcome was time of first analgesia rescue (FAR). Effect size measures were described as mean differences (MD) with 95% confidence intervals (CIs). Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The study protocol was preregistered with the prospectively registered systematic reviews in health and social care international database (PROSPERO), as number CRD42020187866., Results: Overall 16,364 citations were identified, of which 53 studies were included with data for 3649 patients. In network meta-analyses, 4 of 7 included treatment strategies were associated with more efficacious analgesia compared with placebo therapy, including dexamethasone (SB time: 5.73 hours, 95% CI, 4.16-7.30; MB time: 4.20 hours, 95% CI, 2.51-5.89; time of FAR: 8.71 hours, 95% CI, 6.63-10.79), dexmedetomidine (SB time: 4.51 hours, 95% CI, 3.52-5.50; MB time: 4.04 hours, 95% CI, 2.98-5.11; time of FAR: 5.25 hours, 95% CI, 4.08-6.43), fentanyl (SB time: 3.59 hours, 95% CI, 0.11-7.06; MB time: 4.42 hours, 95% CI, 0.78-8.06), and clonidine (SB time: 2.75 hours, 95% CI, 1.46-4.04; MB time: 2.93 hours, 95% CI, 1.69-4.16; time of FAR: 3.35 hours, 95% CI, 1.82-4.87). In a subgroup analysis, addition of dexamethasone to ropivacaine significantly increased the time of FAR when compared to dexmedetomidine (time of FAR: 5.23 hours, 95% CI, 2.92-7.54) or clonidine (time of FAR: 6.61 hours, 95% CI, 4.29-8.92) with ropivacaine., Conclusions: These findings provide evidence for the consideration of dexmedetomidine, dexamethasone, and clonidine as adjuvants to prolong the duration of PNB. The addition of dexamethasone to ropivacaine has a longer time of FAR compared with clonidine or dexmedetomidine., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19., (© 2021 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes ( TAC1, tachykinin precursor 1; &nbsp; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; &nbsp; NPY2R, neuropeptide Y receptor Y2; &nbsp; GPR52, G protein-coupled receptor 52; &nbsp; SCN9A, sodium voltage-gated channel alpha subunit 9; &nbsp; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

Ethnopharmacological Relevance: Ophiorrhiza rugosa var. prostrata is a traditional medicinal plant used by the indigenous and local tribes (Chakma, Marma and Tanchangya) of Bangladesh for the management of chest pain, body ache, and earache. However, the knowledge of anti-nociceptive and anti-inflammatory potentials of this plant is scarce., Aim of the Study: Therefore, we scrutinized the anti-nociceptive and anti-inflammatory properties of O. rugosa leaves along with its possible mechanism(s) of action using chemical and heat-induced pain models., Methods and Materials: O. rugosa was extracted using 100% ethanol (EEOR) followed by exploring phytochemicals and assessing acute toxicity. To determine anti-nociceptive potentials, chemical-induced (acetic acid and formalin) and heat-induced (hot plate and tail immersion) nociceptive models were followed. To investigate the possible involvement of opioid receptors during formalin, hot plate, and tail immersion tests, naltrexone was administered whereas methylene blue and glibenclamide were used to explore cGMP involvement and ATP-sensitive K + channel pathways, respectively. Moreover, the anti-inflammatory potential was assessed using the carrageenan-induced paw edema test model. Motor behaviours of EEOR were assessed by the open-field test. Finally, bioactive constituents (identified by GC-MS) from O. rugosa were subjected to molecular docking and ADME/t analysis to evaluate its potency and safety., Results: During chemical-induced and heat-induced pain models, EEOR exhibited significant and effective nociception suppression at all experimental doses (200 and 400 mg/kg). Also, the administration of naltrexone corroborated the association of opioid receptors with the anti-nociceptive activity by EEOR. Similarly, cGMP and ATP-sensitive K + channel pathways were also found to be involved in the anti-nociceptive mechanism. Furthermore, significant and dose-dependent inhibition of inflammation induced by carrageenan was recorded for EEOR. Both doses of EEOR did not affect the animal's locomotor capacity in the open-field test. Besides, in silico test identified the key compounds (loliolide, harman, squalene, vitamin E, and gamma-sitosterol) that inhibited some particular receptors regarding pain and inflammation., Conclusion: This research exposes central and peripheral pain intervention as well as anti-inflammatory activity of O. rugosa. Also, the identified compounds from this plant support its activities by effectively inhibiting anti-nociceptive and anti-inflammatory receptors. Overall, these outcomes valorize the ethnomedicinal efficacy of O. rugosa in managing various painful conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hepatic encephalopathy (HE) is a debilitating and life-threatening disease. Results from acute or chronic liver failure and is characterized by abnormal cerebral and neurological alterations. This study aimed at investigating the effect of allicin, the major functional component in freshly crushed garlic extract, on thioacetamide (TAA)-induced HE in rats. Induction of HE by a single dose of TAA (300 mg/kg; I.P.) was associated with a marked elevation in the serum levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, total protein, blood urea nitrogen and serum ammonia besides reduction in the serum level of albumin. Moreover, it was accompanied with an increase in the hepatic and brain levels of inflammatory mediators; TNF-α and IL-1β as well as elevation of the hepatic and brain levels of oxidative stress biomarkers; reduced glutathione and lipid peroxidation evidenced by malondialdeyde. Oral administration of allicin (50, 100 and 200 mg/kg; P.O.) for 6 days prior to TAA injection restored the serum liver function, hepatic and brain levels of inflammatory mediators as well as oxidative stress biomarkers in a dose-dependent manner. From our results, it can be concluded that allicin has a protective effect on TAA-induced HE in rats in a dose-dependent manner due to its powerful antioxidant and anti-inflammatory properties., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively., (© 2021. The Author(s).)

Monomethyl auristatin E (MMAE) is a potent anti-cancer microtubule-targeting agent (MTA) used as a payload in three approved MMAE-containing antibody drug conjugates (ADCs) and multiple ADCs in clinical development to treat different types of cancers. Unfortunately, MMAE-ADCs can induce peripheral neuropathy, a frequent adverse event leading to treatment dose reduction or discontinuation and subsequent clinical termination of many MMAE-ADCs. MMAE-ADC-induced peripheral neuropathy is attributed to non-specific uptake of the ADC in peripheral nerves and release of MMAE, disrupting microtubules (MTs) and causing neurodegeneration. However, molecular mechanisms underlying MMAE and MMAE-ADC effects on MTs remain unclear. Here, we characterized MMAE-tubulin/MT interactions in reconstituted in vitro soluble tubulin or MT systems and evaluated MMAE and vcMMAE-ADCs in cultured human MCF7 cells. MMAE bound to soluble tubulin heterodimers with a maximum stoichiometry of ~1:1, bound abundantly along the length of pre-assembled MTs and with high affinity at MT ends, introduced structural defects, suppressed MT dynamics, and reduced the kinetics and extent of MT assembly while promoting tubulin ring formation. In cells, MMAE and MMAE-ADC (via nonspecific uptake) suppressed proliferation, mitosis and MT dynamics, and disrupted the MT network. Comparing MMAE action to other MTAs supports the hypothesis that peripheral neuropathy severity is determined by the precise mechanism(s) of each individual drug-MT interaction (location of binding, affinity, effects on morphology and dynamics). This work demonstrates that MMAE binds extensively to tubulin and MTs and causes severe MT dysregulation, providing convincing evidence that MMAE-mediated inhibition of MT-dependent axonal transport leads to severe peripheral neuropathy., (Published by Elsevier Inc.)

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca 2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT 3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK 1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D 2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The role of peripheral adenosine receptors in pain is a controversial issue and seems to be quite different from the roles of spinal and central adenosine receptors. The present study is aimed at clarifying the role of these receptors in peripheral nociception. To clarify this, studies were done on Swiss mice with adenosine receptor agonists and antagonists. Nociceptive behavior was induced by subcutaneous injection of glutamate (10 μmol) into the ventral surface of the hind paw of mice. Statistical analyses were performed by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results showed that intraplantar (i.pl.) administration of N6-cyclohexyl-adenosine (CHA), an adenosine A1 receptor agonist, at 1 or 10 μg/paw significantly reduced glutamate-induced nociception (p<0.01 and p<0.001 vs. vehicle, respectively, n=8-10). In contrast, i.pl. injection of hydrochloride hydrate (CGS21680, an adenosine A2A receptor agonist) (1 μg/paw) induced a significant increase in glutamate-induced nociception compared to the vehicle (p<0.05, n=8), while 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, an adenosine A2A receptor antagonist) (20 μg/paw) caused a significant reduction (p<0.05, n=7-8). There were no significant effects on i.pl. administration of four additional adenosine receptor drugs-8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A1 antagonist, 1-10 μg/paw), N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA, an A2B agonist, 1-100 μg/paw), alloxazine (an A2B antagonist, 0.1-3 μg/paw), and 2-hexyn-1-yl-N(6)-methyladenosine (HEMADO) (an A3 agonist, 1-100 μg/paw) (p>0.05 vs. vehicle for all tests). We also found that prior administration of DPCPX (3 μg/paw) significantly blocked the anti-nociceptive effect of CHA (1 μg/paw) (p<0.05, n=7-9). Similarly, ZM241385 (20 μg/paw) administered prior to CGS21680 (1 μg/paw) significantly blocked CGS21680-induced exacerbation of nociception (p<0.05, n=8). Finally, inosine (10 and 100 μg/paw), a novel endogenous adenosine A1 receptor agonist recently reported by our research group, was also able to reduce glutamate-induced nociception (p<0.001 vs. vehicle, n=7-8). Interestingly, as an A1 adenosine receptor agonist, the inosine effect was significantly blocked by the A1 antagonist DPCPX (3 μg/paw) (p<0.05, n=7-9) but not by the A2A antagonist ZM241385 (10 μg/paw, p>0.05). In summary, these results demonstrate for the first time that i.pl administration of inosine induces an anti-nociceptive effect, similar to that elicited by CHA and possibly mediated by peripheral adenosine A1 receptor activation. Moreover, our results suggest that peripheral adenosine A2A receptor activation presents a pro-nociceptive effect, exacerbating glutamate-induced nociception independent of inosine-induced anti-nociceptive effects.

Purpose: Hypertensive lesions induce alterations at hemodynamic, peripheral, and central levels. Anandamide (N-arachidonoylethanolamine; AEA) protects neurons from inflammatory damage, but its free administration may cause central adverse effects. AEA controlled release by nanoformulations could reduce/eliminate its side effects. The present study aimed to evaluate the effects of nanoformulated AEA (nf-AEA) on systolic blood pressure (SBP), behavior, and central/peripheral inflammatory, oxidative, and apoptotic state in spontaneously hypertensive rats (SHR)., Materials/methods: Male rats were used, both Wistar Kyoto (WKY) and SHR (n ​= ​10 per group), with/without treatment with nf-AEA (obtained by electrospraying) at a weekly dose of 5 ​mg/kg IP for 4 weeks. SBP was measured and behavioral tests were performed. Inflammatory/oxidative markers were quantified at the central (brain cortex) and peripheral (serum) level., Results: SHR showed hyperactivity, low anxiety, and high concentrations of central/peripheral inflammatory/oxidative markers, also higher apoptosis of brain cortical cells compared to WKY. As opposed to this group, treatment with nf-AEA in SHR significantly reduced SBP, peripheral/central inflammatory/oxidative makers, and central apoptosis. Nf-AEA also increased neuroprotective mechanisms mediated by intracellular heat shock protein 70 (Hsp70), which were attenuated in untreated SHR. Additionally, nf-AEA reversed the abnormal behaviors observed in SHR without producing central adverse effects., Conclusions: Our results suggest protective properties of nf-AEA, both peripherally and centrally, through a signaling pathway that would involve the type I angiotensin II receptor, Wilms tumor transcription factor 1, Hsp70, and iNOS. Considering non-nf-AEA limitations, this nanoformulation could contribute to the development of new antihypertensive and behavioral disorder treatments associated with neuroinflammation., Competing Interests: Declaration of competing interest The author(s) declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD., Competing Interests: The authors have declared that no competing interests exist.

Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.

Citicoline is a chemical compound involved in the synthesis of cell membranes. It also has other, not yet explained functions. Research on the use of citicoline is conducted in neurology, ophthalmology, and psychiatry. Citicoline is widely available as a dietary supplement. It is often used to enhance cognitive functions. In our article, accessible databases were searched for articles regarding citicoline use in neurological diseases. This article has a systemic review form. After rejecting non-eligible reports, 47 remaining articles were reviewed. The review found that citicoline has been proven to be a useful compound in preventing dementia progression. It also enhances cognitive functions among healthy individuals and improves prognosis after stroke. In an animal model of nerve damage and neuropathy, citicoline stimulated regeneration and lessened pain. Among patients who underwent brain trauma, citicoline has an unclear clinical effect. Citicoline has a wide range of effects and could be an essential substance in the treatment of many neurological diseases. Its positive impact on learning and cognitive functions among the healthy population is also worth noting., Competing Interests: The authors declare no conflict of interest.

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.

Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons., (© 2020 Marshall-Phelps et al.)

Context: Peripheral nerve damage can occur in a variety of systemic conditions and can have a profound impact on functional and psychological health. Currently, therapeutic interventions for peripheral nerve damage are limited., Objective: The aim of this systematic review, conducted in accordance with the Cochrane Collaboration's handbook and reported according to the PRISMA checklist, was to evaluate the efficacy and safety of omega-3 oral supplements for improving peripheral nerve structure and function., Data Sources: PubMed, Embase, and Cochrane databases, along with clinical trial registries, were searched from inception to February 2019. Evidence was identified, critically appraised, and synthesized, and the certainty of evidence was appraised using the Grading of Recommendations Assessment, Development and Evaluation approach., Study Selection: Randomized controlled trials assessing the effects of omega-3 oral supplementation on outcomes of peripheral nerve structure, peripheral nerve function, or both were eligible for inclusion. Titles and abstracts of identified articles were independently assessed for potential eligibility by 2 review authors. For studies judged as eligible or potentially eligible, full text articles were retrieved and independently assessed by 2 review authors to determine eligibility; disagreements were resolved by consensus., Data Extraction: Fifteen trials were included. Two clinically similar studies that investigated the effect of omega-3 supplementation in individuals receiving chemotherapy were meta-analyzed. Pooled data showed a reduced incidence of peripheral neuropathy (RR = 0.58; 95%CI, 0.43-0.77) and a preservation of sensory nerve action potential amplitudes with omega-3 supplementation compared with placebo (MD = 4.19 µV; 95%CI; 2.19-6.19)., Conclusion: This review finds, with low certainty, that omega-3 supplementation attenuates sensory loss and reduces the incidence of neuropathy secondary to oxaliplatin and paclitaxel treatment relative to placebo. There is currently limited evidence to ascertain whether omega-3 supplementation is beneficial in other systemic conditions characterized by peripheral nerve damage., Systematic Review Registration: PROSPERO registration number CRD 42018086297., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pseudorabies virus (PRV), an alphaherpesvirus closely related to Varicella-Zoster virus (VZV) and Herpes simplex type 1 (HSV1) infects mucosa epithelia and the peripheral nervous system (PNS) of its host. We previously demonstrated that PRV infection induces a specific and lethal inflammatory response, contributing to severe neuropathy in mice. So far, the mechanisms that initiate this neuroinflammation remain unknown. Using a mouse footpad inoculation model, we found that PRV infection rapidly and simultaneously induces high G-CSF and IL-6 levels in several mouse tissues, including the footpad, PNS and central nervous system (CNS) tissues. Interestingly, this global increase occurred before PRV had replicated in dorsal root ganglia (DRGs) neurons and also was independent of systemic inflammation. These high G-CSF and IL-6 levels were not caused by neutrophil infiltration in PRV infected tissues, as we did not detect any neutrophils. Efficient PRV replication and spread in the footpad was sufficient to activate DRGs to produce cytokines. Finally, by using knockout mice, we demonstrated that TLR2 and IFN type I play crucial roles in modulating the early neuroinflammatory response and clinical outcome of PRV infection in mice. Overall, these results give new insights into the initiation of virus-induced neuroinflammation during herpesvirus infections., Competing Interests: The authors have declared that no competing interests exist.

Key Points: Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non-5-HT 3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5-HT. Whilst 5-HT 3 receptors were not detected in mouse urothelium, 5-HT 3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5-HT 3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders., Abstract: Serotonin (5-HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut-brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross-sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5-HT in bladder afferent signalling and its role in colon-bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5-HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid-induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5-HT receptor subtypes, the serotonin transporter (SERT) and 5-HT-producing enzymes was determined in the urothelium using RT-PCR. Retrograde labelling of bladder-projecting dorsal root ganglion neurons was used to investigate expression of 5-HT 3 receptors using single cell RT-PCR, while sensory neuronal and urothelial responses to 5-HT were determined by live cell calcium imaging. 5-HT elicited bladder afferent firing predominantly via 5-HT 3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5-HT bioavailability. Granisetron, a 5-HT 3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5-HT exerts a direct effect on bladder afferents to enhance signalling. 5-HT 3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

The restoration of voluntary muscle activity in posttraumatic paraplegia in both animal experiments and other clinical applications requires reproducibility of a technically-demanding microsurgical procedure, limited by physicians' understanding of Brunelli's spinal cord grafting paradigm. The insufficient clinical investigation of the long-term benefits of the CNS-PNS graft application warrants additional inquiry. The objective of this study is to explore the potential benefits of the first replicated, graft-induced neuroregeneration of denervated skeletal muscle regarding long-term clinical outcomes and to investigate the effect of Cerebrolysin on neuromodulation. A randomized study evaluating 30 rats, approved by the National Animal Ethics Advisory Committee was performed. The medication was administered postoperatively. For 14 days, 12 rats received Cerebrolysin (serum), 11 received NaCl 0.9% (shams), and 7 were controls. For microsurgery, the lateral corticospinal tract T10 was grafted to the denervated internal obliquus abdominal muscle. On day 90, intraoperative proof of reinnervation was observed. On day 100, 15 rats were euthanized for fixation, organ removal, and extensive histology-morphology examination, and the Wei-Lachin statistical procedure was employed. After an open revision of 16 rats, 8 were CMAP positive. After intravenous Vecuronium application, two (Cerebrolysin, NaCl) out of two rats showed an incomplete compound muscle action potential (CMAP) loss due to glutamatergic and cholinergic co-transmission, while two others showed a complete loss of amplitude. Cerebrolysin medication initiated larger restored muscle fiber diameters and less scarring. FB+ neurons were not observed in the brain but were observed in the Rexed laminae. Brunelli's concept was successfully replicated, demonstrating the first graft induced existence of cholinergic and glutamatergic neurotransmission in denervated grafted muscles. Statistics of the histometric count of muscle fibers revealed larger fiber diameters after Cerebrolysin. Brunelli's CNS-PNS experimental concept is suitable to analyze graft-neuroplasticity focused on the voluntary restoration of denervated skeletal muscles in spinal cord injury. Neuroprotection by Cerebrolysin is demonstrated., (©Carol Davila University Press.)

Fingolimod (FTY) is known to have multiple effects on the immune system and the central nervous system (CNS) in patients with multiple sclerosis (MS). In this study, we evaluated the immunological and neurobiological effects of FTY in MS. Blood and cerebrospinal fluid (CSF) samples were collected from 15 MS patients before first FTY administration and after 4 months of FTY therapy. Immunophenotyping and evaluation of sphingosine-1-phosphate (S1P), neurofilament light chain (NFL), S-100 and neuron-specific enolase (NSE) levels were conducted. After 4 months of FTY therapy, absolute cell count in CSF was decreased from 6.33 to 2.43 MPt/l, accompanied by decreases of CD3+ (2.22 to 0.65 MPt/l) and of CD4+ counts (1.60 to 0.39 MPt/l). In blood, CD3+ (1.05 to 0.09 GPt/l), CD4+ (0.80 to 0.02 GPt/l), CD8+ (0.23 to 0.04 GPt/l) and CD19+ (0.21 to 0.01GPt/l) cell counts were as well reduced. CD14+ cell count remained stable over the same period (0.24 to 0.26GPt/l). NFL and S1P levels in CSF and blood were reduced over time (NFL: CSF 1759 to 1359 pg/l, blood 8.42 to 7.36 pg/l; S1P: CSF 2.12 to 0.71 nmol/l, blood 392.1 to 312.9 nmol/l). Strong correlations between CSF and blood NFL levels were observed. Neuronal damage markers such as S-100 (1.86 to 1.69 μg/l) and NSE (9.53 to 8.67 μg/l) were reduced to a lesser degree than other markers. FTY exerted significant effects on immunological and neurobiological markers in the central and peripheral compartment. Decreases in levels of neuroinflammatory and neurodegenerative markers were already evident after 4 months of treatment. Four-month serum NFL level appears to be a useful marker for FTY efficacy that correlates well with changes in the CNS compartment. KEY MESSAGES: FTY has important immunological effects in both central and peripheral compartments. Cellular effects of FTY effects are more pronounced in the blood than in the CSF. FTY reduces S1P and NFL levels in CSF and serum. Serum NFL appears to be a useful marker for FTY therapy.

Increased bile acids in the colon can evoke increased epithelial secretion resulting in diarrhea, but little is known about whether colonic bile acids contribute to abdominal pain. This study aimed to investigate the mechanisms underlying activation of colonic extrinsic afferent nerves and their neuronal cell bodies by a major secondary bile acid, deoxycholic acid (DCA). All experiments were performed on male C57BL/6 mice. Afferent sensitivity was evaluated using in vitro extracellular recordings from mesenteric nerves in the proximal colon (innervated by vagal and spinal afferents) and distal colon (spinal afferents only). Neuronal excitability of cultured dorsal root ganglion (DRG) and nodose ganglion (NG) neurons was examined with perforated patch clamp. Colonic 5-HT release was assessed using ELISA, and 5-HT immunoreactive enterochromaffin (EC) cells were quantified. Intraluminal DCA increased afferent nerve firing rate concentration dependently in both proximal and distal colon. This DCA-elicited increase was significantly inhibited by a 5-HT 3 antagonist in the proximal colon but not in the distal colon, which may be in part due to lower 5-HT immunoreactive EC cell density and lower 5-HT levels in the distal colon following DCA stimulation. DCA increased the excitability of DRG neurons, whereas it decreased the excitability of NG neurons. DCA potentiated mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. Together, this study suggests that DCA can excite colonic afferents via direct and indirect mechanisms but the predominant mechanism may differ between vagal and spinal afferents. Furthermore, DCA increased mechanosensitivity of high-threshold spinal afferents and may be a mechanism of visceral hypersensitivity. NEW & NOTEWORTHY Deoxycholic acid (DCA) directly excites spinal afferents and, to a lesser extent, indirectly via mucosal 5-HT release. DCA potentiates mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. DCA increases vagal afferent firing in proximal colon via 5-HT release but directly inhibits the excitability of their cell bodies.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant and debilitating side effect. However, there have been no studies of the relative risk of CIPN with known causative agents. We examined the risk of CIPN in patients taking such agents as a part of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program-sponsored phase I trials., Methods: CIPN events in each patient were graded according to the Clinical Terminology of Common Adverse Effects and compared among several high-risk chemotherapeutic agent groups, adjusting for possible confounding factors. Patients receiving tubulin-targeted agents were analysed separately for specific background factors associated with CIPN., Results: In 135 phase I clinical trials, 259 of 3614 patients were identified as developing CIPN during chemotherapy. Tubulin-targeting agents and proteasome inhibitors were identified as high-risk agents (hazard ratio 9.04 and 5.01, respectively) for CIPN, whereas platinum-complex agents and thalidomide analogues imparted lower risk (hazard ratio 1.52 and 1.11, respectively). Age, sex and medical history of diabetes were not significantly related to CIPN. CIPN developed over time as the number of chemotherapy cycles increased. Among patients with CIPN, treatment with tubulin-targeting agents resulted in a significantly higher rate of chemotherapy schedule modification compared with treatments with other chemotherapeutic agents., Conclusions: Tubulin-targeting agents and proteasome inhibitors were associated with a greatly increased risk of CIPN compared with other agents. CIPN tended to develop in later chemotherapy cycles. These findings will help to minimise the risk of CIPN by encouraging increased surveillance and earlier dose adjustment of high-risk agents in phase I trials., (Published by Elsevier Ltd.)

Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design., Competing Interests: ED, SB, Ad, AA, CH, LA, VG, GW No competing interests declared, TW Reviewing editor, eLife, (© 2019, Diamantopoulou et al.)

Introduction : Acute and preventive treatment of primary headache disorders is not completely resolved with regard to efficacy, safety, and tolerability. Hence, peripheral and central neuromodulation can provide therapeutic alternatives in drug-resistant cases. Peripheral targets of neuromodulation include invasive and non-invasive neurostimulation and electrical and chemical nerve and ganglion blockades. Areas covered : A PubMed search of papers published from January 2012 to October 2018 was conducted. The goal of this review was to analyze the efficacy and safety of invasive (implantable) peripheral neurostimulation methods (the occipital nerve, the cervical branch of vagal nerve, the sphenopalatine ganglion) and non-invasive (transcutaneous) peripheral neurostimulation methods (the occipital nerve, the supraorbital nerve, and the cervical and auricular branches of the vagal nerve), based on the results of published clinical trials and case series. Acting also on the peripheral nervous system, peripheral nerve (i.e. greater occipital nerve) and ganglion (i.e. sphenopalatine ganglion) blockades, botulinum neurotoxin type A-hemagglutinin complex therapies, and calcitonin gene-related peptide-related monoclonal antibody treatments in this patient population are also discussed. Expert opinion : This review summarizes the latest results on the therapeutic strategies acting on the periphery in primary headache disorders. These therapeutic options are minimally invasive or non-invasive, efficacious, safe, and well tolerated.

Acrylamide (ACR) is extensively used in industrial areas and has been demonstrated to induce neurotoxicity via oxidative stress and apoptosis. In this study, we assessed the probable protective effects of thymoquinone (TQ), an active constituent of Nigella sativa, against ACR-induced neurotoxicity. ACR (50 mg/kg, i.p., for 11 days) and TQ (2.5, 5 and 10 mg/kg, i.p., for 11 days) were administered to rats. On 12th day, gait score was examined and rats were sacrificed. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined in sciatic nerve. Furthermore, western blotting was conducted. The exposure of rats to ACR caused severe gait disabilities. The MDA and GSH contents were increased and decreased, respectively. ACR decreased P-ERK/ERK ratio and myelin basic protein (MBP) content, but significantly increased P-JNK/JNK, P-P38/P38, Bax/Bcl-2 ratios and caspase 3 and 9 levels. Concurrently administration of TQ (5 and 10 mg/kg) with ACR, prevented gait abnormalities and meaningfully reduced MDA and elevated the GSH contents. Furthermore, TQ (5 mg/kg) elevated the P-ERK/ERK ratio and MBP content while reduced the P-JNK/JNK, P-P38/P38 ratios and apoptotic markers. MAP kinase and apoptosis signaling pathways were involved in ACR-induced neurotoxicity in rat sciatic nerve and TQ significantly reduced ACR neurotoxicity. TQ afforded neuroprotection, in part, due to its anti-oxidative stress and anti-apoptotic mechanisms.

Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings. A single dose of ≥1 mg/kg fulranumab administered subcutaneously (SC) caused a decrease in neuron and sympathetic ganglion size (superior cervical ganglion), observed morphologically and stereologically, with a resulting appearance of increased glial cell density. Similar results were observed in repeat-dose (15 to 52 weeks) toxicity studies at ≤50 mg/kg/wk fulranumab SC. These effects recovered after a 3-month treatment-free period. Fulranumab did not cause any neuronal death, necrosis, apoptosis, or any apparent decrease in function of sympathetic neurons/ganglia at any time point examined. A no observed effect level (NOEL) was established at 0.25 mg/kg fulranumab SC every 4 weeks for 28 weeks.

Histological evidence points to the presence of dopamine (DA) in the cephalic sensory organs of multiple gastropod molluscs, suggesting a possible sensory role for the neurotransmitter. We investigated the sensory function of DA in the nudipleuran Pleurobranchaea californica, in which the central neural correlates of sensation and foraging behavior have been well characterized. Tyrosine hydroxylase-like immunoreactivity (THli), a signature of the dopamine synthetic pathway, was similar to that found in two other opisthobranchs and two pulmonates previously studied: 1) relatively few (<100) THli neuronal somata were observed in the central ganglia, with those observed found in locations similar to those documented in the other snails but varying in number, and 2) the vast majority of THli somata were located in the peripheral nervous system, were associated with ciliated, putative primary sensory cells, and were highly concentrated in chemotactile sensory organs, giving rise to afferent axons projecting to the central nervous system. We extended these findings by observing that applying a selective D2/D3 receptor antagonist to the chemo- and mechanosensory oral veil-tentacle complex of behaving animals significantly delayed feeding behavior in response to an appetitive stimulus. A D1 blocker had no effect. Recordings of the two major cephalic sensory nerves, the tentacle and large oral veil nerves, in a deganglionated head preparation revealed a decrease of stimulus-evoked activity in the former nerve following application of the same D2/D3 antagonist. Broadly, our results implicate DA in sensation and engender speculation regarding the foraging-based decisions the neurotransmitter may serve in the nervous system of Pleurobranchaea and, by extension, other gastropods., Competing Interests: The authors have declared that no competing interests exist.

The retinoic acid (RA) signaling pathway regulates axial patterning and neurogenesis in the developing central nervous system (CNS) of chordates, but little is known about its roles during peripheral nervous system (PNS) formation and about how these roles might have evolved. This study assesses the requirement of RA signaling for establishing a functional PNS in the cephalochordate amphioxus, the best available stand-in for the ancestral chordate condition. Pharmacological manipulation of RA signaling levels during embryogenesis reduces the ability of amphioxus larvae to respond to sensory stimulation and alters the number and distribution of ectodermal sensory neurons (ESNs) in a stage- and context-dependent manner. Using gene expression assays combined with immunohistochemistry, we show that this is because RA signaling specifically acts on a small population of soxb1c-expressing ESN progenitors, which form a neurogenic niche in the trunk ectoderm, to modulate ESN production during elongation of the larval body. Our findings reveal an important role for RA signaling in regulating neurogenic niche activity in the larval amphioxus PNS. Although only few studies have addressed this issue so far, comparable RA signaling functions have been reported for neurogenic niches in the CNS and in certain neurogenic placode derivatives of vertebrates. Accordingly, the here-described mechanism is likely a conserved feature of chordate embryonic and adult neural development.

Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology "best practice" recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve. If somatic PNS neurotoxicity is suspected (situation 2), analysis minimally should include three spinal nerves, multiple dorsal root ganglia, and a trigeminal ganglion. If autonomic PNS neuropathy is suspected (situation 3), parasympathetic and sympathetic ganglia should be assessed. For dedicated neurotoxicity studies where a neurotoxic effect is expected (situation 4), PNS sampling follows the strategy for situations 2 and/or 3, as dictated by functional or other compound/target-specific data. For all situations, bilateral sampling with unilateral processing is acceptable. For situations 1-3, PNS is processed conventionally (immersion in buffered formalin, paraffin embedding, and hematoxylin and eosin staining). For situation 4 (and situations 2 and 3 if resources and timing permit), perfusion fixation with methanol-free fixative is recommended. Where PNS neurotoxicity is suspected or likely, at least one (situations 2 and 3) or two (situation 4) nerve cross sections should be postfixed with glutaraldehyde and osmium before hard plastic resin embedding; soft plastic embedding is not a suitable substitute for hard plastic. Special methods may be used if warranted to further characterize PNS findings. Initial PNS analysis should be informed, not masked ("blinded"). Institutions may adapt these recommendations to fit their specific programmatic requirements but may need to explain in project documentation the rationale for their chosen PNS sampling, processing, and evaluation strategy.

Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl 3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl 3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neuropathic Pain (NP) is a painful condition which is a direct consequence of a lesion or disease affecting the somatosensory system with symptoms like allodynia, hyperalgesia. It has complex pathogenesis as it involves several molecular signaling pathways, thus numerous reliable animal models are crucial to understand the underlying mechanism of NP and formulate effective management therapy. Some models like spinal cord injury, chronic constriction injury, spinal nerve ligation, chemotherapy induced peripheral neuropathy, diabetes-induced NP and many more are discussed. This review contains an overview of the procedures followed to induce neuropathy and specific characteristics of that particular model. Some new techniques like spared nerve ligation, have omitted the limitation of methods not presently used where complete nerve damage occurs. Since animal models provide a window to experienced symptoms and physiology and impact the translation of bench discoveries to the bedside, the reporting, interpretation and comparison of these models is necessary because slight variation in procedure of model generation can drastically alter the results. The development of novel, but rational analgesic drugs to alleviate this intractable pain demands elucidation of molecular mechanisms of NP for which different types of animal models have been established., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of ralfinamide on cardiovascular function and locomotor activity. Oral ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin-induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to ralfinamide., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Peripheral neuropathy affects about 50% of the diabetic population. The manifestations range from pain, numbness, paresthesia and ulceration in the extremities and it is the major cause of non-traumatic amputations. Currently there is no effective treatment for peripheral neuropathy. With the prevalence of obesity and type 2 diabetes and associated complications reaching epidemic levels, there is a critical need for finding a treatment to preserve nerve function., Introduction: This article will review the potential for fish oil as a treatment for diabetic peripheral neuropathy., Methods: A through search of the PubMed database was performed and relevant articles on the topic were included in this review., Results: Many studies support a role for fish oil in cardiovascular health. However, less information is available regarding the effect of fish oil on diabetes complications including neuropathy. Pre-clinical studies from my laboratory using diabetic rodent models have demonstrated that fish oil can slow progression and reverse diabetic neuropathy as determined by examining multiple endpoints. Mechanistically fish oil has been shown to have anti-inflammatory properties. Lowering the omega-6/omega-3 fatty acid ratio has been shown to be anti-thrombotic. Moreover, metabolites of eicosapentaenoic and docosahexaenoic acids, the main polyunsaturated fatty acids found in fish oil, commonly referred to as resolvins and neuroprotectin have been shown to be neuroprotective and can stimulate neuron outgrowth in vitro., Conclusion: Additional studies are required but existing data suggests that dietary enrichment with omega-3 fatty acids contained in fish oil may be beneficial treatment for diabetic neuropathy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Hantaviruses are a group of single-stranded RNA viruses of the Bunyaviridae family. "New World" hantaviruses cause hantavirus cardiopulmonary syndrome (HCPS) in North America. HCPS carries with it significant mortality and those patients who survive the disease are often left with substantial morbidity. Neurologic complications of hantavirus infections are rare, with only sparse cases of central nervous system involvement having been documented in the literature. To our knowledge, there are no reports of hantavirus infection contributing to peripheral nervous system dysfunction. Here we report a case of possible small fiber neuropathy associated with hantavirus infection, in a patient who survived HCPS. Persistent and treatment-resistant neuropathic pain may be a prominent feature in hantavirus-associated peripheral neuropathy.

Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.

Neurotoxicity is a relevant side effect of bortezomib treatment. Previous reports have shown that the development of peripheral neuropathy caused by anti-neoplastic agents may be a result of reduced axonal transport. Based on evidence from prior studies that the kinesin-5 inhibitor monastrol enhances axonal transport and improves neuronal regeneration, we focused on the neuroprotective role of monastrol during the chemotherapeutic treatment with bortezomib. Prolonged treatment of C57BL/6 mice with bortezomib induced a length-dependent small-fiber neuropathy with axonal atrophy and loss of sensory nerve fibers. The administration of monastrol substantially alleviated morphological features of axonal injury and functional measures of sensory neuropathy. Cytotoxicity studies in leukemia and multiple myeloma cell lines showed no interference of monastrol with the cytostatic effects of bortezomib. Our data indicate that the novel approach of targeting microtubule turnover by monastrol provides protection against bortezomib-induced neurotoxicity. The favorable cytotoxic profile of monastrol makes it an interesting candidate as neuroprotective agent in combined chemotherapy regimens that warrants further consideration.

In recent years, several studies have reported a relatively high frequency of polyneuropathy in patients with Parkinson's disease (PD), in particular, in patients receiving levodopa-carbidopa intestinal gel (LCIG) infusion. In spite of the several patients investigated with nerve conduction studies, no study has prospectively explored a possible central nervous system involvement of patients receiving LCIG infusion. We prospectively evaluated eight PD patients receiving LCIG infusion, who underwent neurophysiological evaluations with nerve conduction studies, visual, somatosensory and motor evoked potentials before LCIG infusion, and 1 and 6 months after. At 6 months follow-up, we found significant reduction in sural nerve SNAP amplitude, increase of central sensory conduction time N22-P40, and increases of central motor conduction time recorded from I dorsal interosseous and tibialis anterior. In PD patients with LCIG infusion, we found a subclinical neurophysiological impairment of both peripheral and central nervous system.

An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined.

Background.: Quantitative sensory testing (QST) has been used to predict the outcome of epidural steroid injections in lumbosacral radicular pain and has the potential to be an important tool in the selection of appropriate treatment (such as epidural steroid injections vs surgery) for patients with chronic radicular pain. In addition, QST assists in identification of the pain pathways of peripheral and central sensitization in selected groups of patients., Methods.: Twenty-three patients were given dorsal root ganglion (DRG) infiltration with local anaesthesia and steroid ('DRG block'), and those who demonstrated at least 50% pain relief were offered pulsed radiofrequency (PRF) to the DRG. Questionnaires and QST scores were measured before the DRG blocks and at 1 week and 3 months after their procedure. Those who received PRF also answered questionnaires and underwent QST measurements at 1 week and 3 months after their procedure., Results.: There was a significant increase in pressure pain threshold scores after DRG blocks. A reduced conditioned pain modulation response was seen before DRG, which increased after the procedure. Ten out of 23 patients underwent PRF to the DRG, and an increase in pressure pain threshold scores after PRF was observed. The conditioned pain modulation response was maintained in this group and increased after PRF., Conclusions.: The study demonstrates that patients with unilateral radicular low back pain who receive dorsal root ganglion interventions show changes in pressure pain thresholds and conditioned pain modulation that are consistent with a 'normalization' of peripheral and central sensitization., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: and purpose: The peptide PnPP-19, derived from the spider toxin PnTx2-6 (renamed as δ-CNTX-Pn1c), potentiates erectile function by activating the nitrergic system. Since NO has been studied as an antinociceptive molecule and PnPP-19 is known to induce peripheral antinociception, we intended to evaluate whether PnPP-19 could induce peripheral antinociception through activation of this pathway., Experimental Approach: Nociceptive thresholds were measured by paw pressure test. PGE 2 (2 μg/paw) was administered intraplantarly together with PnPP-19 and inhibitors/blockers of NOS, guanylyl cyclase and K ATP channels. The nitrite concentration was accessed by Griess test. The expression and phosphorylation of eNOS and nNOS were determined by western blot., Key Results: PnPP-19 (5, 10 and 20 μg/paw) induced peripheral antinociception in rats. Administration of NOS inhibitor (L-NOarg), selective nNOS inhibitor (L-NPA), guanylyl cyclase inhibitor (ODQ) and the blocker of K ATP (glibenclamide) partially inhibited the antinociceptive effect of PnPP-19 (10 μg/paw). Tissue nitrite concentration increased after PnPP-19 (10 μg/paw) administration. Expression of eNOS and nNOS remained the same in all tested groups, however the phosphorylation of nNOS Ser852 (inactivation site) increased and phosphorylation of eNOS Ser1177 (activation site) decreased after PGE 2 injection. Administration of PnPP-19 reverted this PGE 2 -induced effect., Conclusions and Implications: The peripheral antinociceptive effect induced by PnPP-19 is resulting from activation of NO-cGMP-K ATP pathway. Activation of eNOS and nNOS might be required for such effect. Our results suggest PnPP-19 as a new drug candidate to treat pain and reinforce the importance of nNOS and eNOS activation, as well as endogenous NO release, for induction of peripheral antinociception., (Copyright © 2017 Elsevier Inc. All rights reserved.)

See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1.2) at the juxtaparanode. Expression of type III neuregulin-1 (TIIINRG1) in induced pluripotent stem cell-derived sensory neurons strongly enhances myelination, while conversely pharmacological blockade of the NRG1-ErbB pathway prevents myelination, providing direct evidence for the ability of this pathway to promote the myelination of human sensory axons. The β-secretase, BACE1 is a protease needed to generate active NRG1 from the full-length form. Due to the fact that it also cleaves amyloid precursor protein, BACE1 is a therapeutic target in Alzheimer's disease, however, consistent with its role in NRG1 processing we find that BACE1 inhibition significantly impairs myelination in our co-culture system. In order to exploit co-cultures to address other clinically relevant problems, they were exposed to anti-disialosyl ganglioside antibodies, including those derived from a patient with a sensory predominant, inflammatory neuropathy with mixed axonal and demyelinating electrophysiology. The co-cultures reveal that both mouse and human disialosyl antibodies target the nodal axolemma, induce acute axonal degeneration in the presence of complement, and impair myelination. The human, neuropathy-associated IgM antibody is also shown to induce complement-independent demyelination. Myelinating co-cultures using human induced pluripotent stem cell-derived sensory neurons thus provide insights into the cellular and molecular specialization of axoglial signalling, how pharmacological agents may promote or impede such signalling and the pathogenic effects of ganglioside antibodies.awx012media15372351982001., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)