scholarly journals Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
L. Di Cesare Mannelli ◽  
G. D'Agostino ◽  
A. Pacini ◽  
R. Russo ◽  
M. Zanardelli ◽  
...  
Keyword(s):  
Pain Relief ◽  
Sciatic Nerve ◽  
Pain Threshold ◽  
Chronic Constriction Injury ◽  
Axon Diameter ◽  
Ppar Alpha ◽  
Axonal Diameter ◽  
Antinociceptive Effects ◽  
Myelin Thickness ◽  
Tissue Alterations

Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect.N-Palmitoylethanolamine (PEA) exerts antinociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Aimed to evaluate the antineuropathic properties of PEA, a damage of the sciatic nerve was induced in mice by chronic constriction injury (CCI) and a subcutaneous daily treatment with 30 mg kg−1PEA was performed. On the day 14, PEA prevented pain threshold alterations. Histological studies highlighted that CCI induced oedema and an important infiltrate of CD86 positive cells in the sciatic nerve. Moreover, osmicated preparations revealed a decrease in axon diameter and myelin thickness. Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR-αnull mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR-α-mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration.

scholarly journals Effects of 660 nm Low Level Laser Therapy on Neuropathic Pain Relief Following Chronic Constriction Injury in Rat Sciatic Nerve

2013 ◽  
Vol 1 (2) ◽  
pp. 76-81 ◽  
Author(s):  
Masoume Masoumipoor ◽  
Seyed Behnam Jameie ◽  
Atusa Janzadeh ◽  
Farinaz Nasirinezhad ◽  
Mahdie Kerdari ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Relief ◽  
Sciatic Nerve ◽  
Laser Therapy ◽  
Chronic Constriction Injury ◽  
Low Level Laser Therapy ◽  
Low Level ◽  
Rat Sciatic Nerve ◽  
Low Level Laser ◽  
Level Laser

Neurofilaments and pathologies of the Peripheral Nervous System

2014 ◽  
Author(s):  
◽  
Jeffrey Dale
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Conduction Velocity ◽  
Radial Growth ◽  
Stride Length ◽  
Wild Type ◽  
Axon Diameter ◽  
Internodal Length ◽  
Axonal Diameter ◽  
Myelin Thickness

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The efficiency of signal propagation in the peripheral nervous system (PNS) is maximized by myelination and axon diameter. Myelination induces axonal expansion through radial growth. Radial growth is dependent on neurofilaments (NFs) that can be made up of the neurofilament light (NF-L) subunit in association with either the neurofilament medium (NF-M) or neurofilament heavy (NF-H) subunit. Myelin thickness and length (internodal) are established proportional to axon diameter for optimal conduction velocity. Myelin thickness is regulated by total neuregulin I type III (Nrg1 type III) levels present on the axon whereas the mechanisms that control the establishment of internodal length are less understood. My work expands on previous data demonstrating that myelin thickness does not respond to alterations in axonal diameter. In contrast to the previous study, my work describes myelin thickness in the context of decreased axonal diameters. NF subunit mutants that result in varying degrees of altered axonal diameter were used as a tool to study the response of myelin thickness to larger reductions in axonal diameter. At two and six months, g-ratios corresponded to the degree of axonal diameter change. At two months, the size of axons arranged into the following order: wild type > NF-H[superscript [[delta]]Tail] > NF-M[superscript [[delta]]Tail]>NF-(M/H) [superscript [[delta]]Tail]. Correspondingly, g-ratios arranged into the same order indicating the larger the decrease in axon diameter, the greater the proportional increase in myelin thickness. At six months, axon diameters grouped into "wild type" sizes and "NFM?Tail" sizes. Similarly, g-ratios grouped into "wild type" ratios and "NF-M?Tail" ratios indicating that myelin thickness did not respond to increased radial growth. At six months NF-M?Tail mice demonstrated decreased internodal length suggesting that internodal length responded to alterations in axon diameter. My work provides the first evidence of the consequence of altered myelin thickness in isolation. Mice with hypomyelination, alone, demonstrated reduced swing speed and stride length in all limbs. Mutations in proteins specific to myelin result CMT1 that display uniform slowing of conduction velocity. In contrast, CMT2E arises from mutations to axonal proteins resulting in non-uniform slowing of conduction velocity. We generated a mouse model of CMT2E by expressing a hNF-L[superscript E397K] transgene. hNF-L[superscript E397K] expression causes inherent defects to the neurofilament network. As a result, our CMT2E model demonstrates altered myelin thickness in motor and sensory nerves and unilateral gait alterations that include decreased stride length, increased foot drags, and altered coordination of coupled limbs. The correlation between defects observed in our hypomyelination model and our CMT2E model suggest that altered myelin thickness may play a role in CMT2E phenotype. NF accumulations first appear at the NMJs of the diaphragm in SMA?7 mice. Motor axon loss and decreased axonal diameter is observed in the cervical spinal cord which is responsible for innervating the diaphragm. Taken together, these data suggest that inherent NF defects may be present in SMA?7 mice. My work provides a comprehensive analysis of the NF network in a cell, sciatic nerve, where analyses wouldn't be confounded by axonal loss. My analyses demonstrated that total NF levels, trafficking, and deposition were unaffected in SMA?7 mice suggesting that the NF network was uncompromised. Therefore, NF accumulations at the NMJ are most likely due to local alterations to NF dynamics. Furthermore, my work demonstrates that alterations to the transport of retrograde motors and anterograde transport of vital synaptic vesicle proteins coincide with the appearance of NF accumulations.

Antinociceptive effects of lead acetate in sciatic nerve chronic constriction injury model of peripheral neuropathy in male Wistar rats

2020 ◽  
Vol 394 (1) ◽  
pp. 117-125
Author(s):  
Bamidele Victor Owoyele ◽  
Ahmed Olalekan Bakare ◽  
Maryam Tayo Ayinla ◽  
Kehinde Ahmed Adeshina ◽  
Damilola Onietan ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Lead Acetate ◽  
Wistar Rats ◽  
Chronic Constriction Injury ◽  
Injury Model ◽  
Antinociceptive Effects ◽  
Male Wistar Rats ◽  
Chronic Constriction Injury Model

scholarly journals Nauclea latifolia Smith (Rubiaceae) exerts antinociceptive effects in neuropathic pain induced by chronic constriction injury of the sciatic nerve

2014 ◽  
Vol 151 (1) ◽  
pp. 445-451 ◽  
Author(s):  
Germain Sotoing Taïwe ◽  
Elisabeth Ngo Bum ◽  
Emmanuel Talla ◽  
Théophile Dimo ◽  
Amadou Dawe ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Antinociceptive Effects ◽  
Nauclea Latifolia

scholarly journals Ninjin'yoeito Alleviates Neuropathic Pain Induced by Chronic Constriction Injury in Rats

2021 ◽  
Vol 8 ◽  
Author(s):  
Risa Takemoto ◽  
Seiwa Michihara ◽  
Li-Kun Han ◽  
Nina Fujita ◽  
Ryuji Takahashi
Keyword(s):  
Neuropathic Pain ◽  
Pain Relief ◽  
Contact Area ◽  
Pain Threshold ◽  
Chronic Constriction Injury ◽  
Weight Bearing ◽  
Repeated Administration ◽  
Control Group ◽  
Spontaneous Pain ◽  
Serum Samples

Kampo medicines are frequently used empirically to treat pain in clinical practice. Ninjin'yoeito (NYT), which is associated with few adverse effects, is often used to treat the elderly, but has not yet been examined in detail. We herein investigated the effects of NYT, at 500 and 1,000 mg/kg p.o. (NYT500/NYT1000 group) in single and repeated administrations for 14 days, on pain in rats with peripheral neuropathy induced by loose ligation of the sciatic nerve (chronic constriction injury: CCI). Untreated CCI rats given distilled water were used as a control group. To assess induced pain, the pain threshold was measured using the von Frey test. To evaluate spontaneous pain, the ground-contact area of the paw with neuropathic pain was measured using the Dynamic Weight Bearing test. Serum samples were collected after the test to elucidate the mechanism of action of NYT, and brain-derived neurotrophic factor (BDNF) and corticosterone protein levels, which have been reported to change due to chronic pain, were analyzed. After single administration of NYT, the pain threshold rose in the NYT500 and NYT1000 groups. The pain threshold tended to rise on day 14 of repeated administration in the NYT500 group (p = 0.08) and it significantly rose at NYT1000 group (p < 0.05) compared to Control group. In addition, the foot contact area increased (p = 0.09). Therefore, CCI-induced pain was significantly remitted and spontaneous pain was remitted after repeated administration of NYT. Serum BDNF levels were higher in untreated CCI rats than in normal rats (p = 0.05), but decreased after the repeated administration of NYT (NYT1000, p = 0.15), while serum corticosterone levels were lower (p = 0.12) than those in normal rats and increased after the repeated administration of NYT (NYT1000, p = 0.07). The blood BDNF level has been suggested to influence pain intensity. The findings demonstrated NYT effectively treats neuropathic pain, suggesting that a NYT-induced decrease in blood BDNF contributed to the mechanism of pain relief. In addition, the variation of corticosterone was observed, suggesting that normalization of responsiveness to stress by NYT contributed to the pain relief.

scholarly journals Possible role of antioxidative capacity of (−)-epigallocatechin-3-gallate treatment in morphological and neurobehavioral recovery after sciatic nerve crush injury

2017 ◽  
Vol 27 (5) ◽  
pp. 593-613 ◽  
Author(s):  
Waleed M. Renno ◽  
Ludmil Benov ◽  
Khalid M. Khan
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Diameter Ratio ◽  
Crush Injury ◽  
Sciatic Nerve Crush ◽  
Axon Diameter ◽  
Nerve Crush ◽  
Myelin Thickness ◽  
Nerve Crush Injury

OBJECTIVEThis study examined the capacity of the major polyphenolic green tea extract (−)-epigallocatechin-3-gallate (EGCG) to suppress oxidative stress and stimulate the recovery and prompt the regeneration of sciatic nerve after crush injury.METHODSAdult male Wistar rats were randomly assigned to one of 4 groups: 1) Naïve, 2) Sham (sham injury, surgical control group), 3) Crush (sciatic nerve crush injury treated with saline), and 4) Crush+EGCG (sciatic nerve crush injury treated with intraperitoneally administered EGCG, 50 mg/kg). All animals were tested for motor and sensory neurobehavioral parameters throughout the study. Sciatic nerve and spinal cord tissues were harvested and processed for morphometric and stereological analysis. For the biochemical assays, the time points were Day 1, Day 7, Day 14, and Day 28 after nerve injury.RESULTSAfter sciatic nerve crush injury, the EGCG-treated animals (Crush+EGCG group) showed significantly better recovery of foot position and toe spread and 50% greater improvement in motor recovery than the saline-treated animals (Crush group). The Crush+EGCG group displayed an early hopping response at the beginning of the 3rd week postinjury. Animals in the Crush+EGCG group also showed a significant reduction in mechanical allodynia and hyperalgesia latencies and significant improvement in recovery from nociception deficits in both heat withdrawal and tail flick withdrawal latencies compared with the Crush group. In both the Crush+EGCG and Crush groups, quantitative evaluation revealed significant morphological evidence of neuroregeneration according to the following parameters: mean cross-sectional area of axons, myelin thickness in the sciatic nerve (from Week 4 to Week 8), increase of myelin basic protein concentration and gene expression in both the injured sciatic nerve and spinal cord, and fiber diameter to axon diameter ratio and myelin thickness to axon diameter ratio at Week 2 after sciatic nerve injury. However, the axon area remained much smaller in both the Crush+EGCG and Crush groups compared with the Sham and Naïve groups. The number of axons per unit area was significantly decreased in the Crush+EGCG and Crush groups compared with controls. Sciatic nerve injury produced generalized oxidative stress manifested as a significant increase of isoprostanes in the urine and decrease of the total antioxidant capacity (TAC) of the blood from Day 7 until Day 14. EGCG-treated rats showed significantly less increase of isoprostanes than saline-treated animals and also showed full recovery of TAC levels by Day 14 after nerve injury. In spinal cord tissue analysis, EGCG-treated animals showed induced glutathione reductase and suppressed induction of heme oxygenase 1 gene expression compared with nontreated animals.CONCLUSIONSEGCG treatment suppressed the crush-induced production of isoprostanes and stimulated the recovery of the TAC and was associated with remarkable alleviation of motor and sensory impairment and significant histomorphological evidence of neuronal regeneration following sciatic nerve crush injury in rats. The findings of this study suggest that EGCG can be used as an adjunctive therapeutic remedy for nerve injury. However, further investigations are needed to establish the antioxidative mechanism involved in the regenerative process after nerve injury. Only upregulation of glutathione reductase supports the idea that EGCG is acting indirectly via induction of enzymes or transcription factors.

Functional interaction between N-methyl-D-aspartate receptor and ascorbic acid during neuropathic pain induced by chronic constriction injury of the sciatic nerve

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Sepideh Saffarpour ◽  
Farinaz Nasirinezhad
Keyword(s):  
Ascorbic Acid ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nmda Receptors ◽  
Pain Threshold ◽  
Chronic Constriction Injury ◽  
Single Injection ◽  
Antinociceptive Effect ◽  
Pain Condition

AbstractBackground:Neuropathic pain is a chronic pain condition, which is resistant to therapy. Ascorbate was released because of the activation of glutaminergic neurons. Due to the important role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of neuropathic pain, this study investigated the analgesic efficacy of ascorbic acid (AA) in neuropathic pain condition and the role of NMDA receptors in this effect.Methods:For this purpose, adult male rats were randomly allocated to experimental groups (n=8 in each group). Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. During the second week after CCI, animals received a single injection of 1, 3, 5, or 10 mg/kg of AA intraperitoneally and pain threshold was determined 15 and 60 min later. The antinociceptive effect of chronic administration was also evaluated by intraperitoneal injection (IP) of 3 mg/kg AA for 3 weeks. To determine the role of NMDA receptors, separate groups of animals 30 min after single injection of AA (1 mg/kg) animals received i.p. injection of ketamine (5 mg/kg), MK-801 (0.01 mg/kg), or glutamate (1000 nmol) and were tested 20 min afterwards. Data analyzed by ANOVA and Newman-Keuls tests and p<0.05 were considered as significant.Results:IP of 3, 5 and 10 mg/kg increased the pain threshold during the second week after CCI (p<0.05,Conclusions:The results indicated that AA produced a dose-dependent antinociceptive effect that seems to mediate through its interaction with NMDA receptors.

scholarly journals Curcumin Diglutaric Acid, a Prodrug of Curcumin Reduces Pain Hypersensitivity in Chronic Constriction Injury of Sciatic Nerve Induced-Neuropathy in Mice

2020 ◽  
Vol 13 (9) ◽  
pp. 212
Author(s):  
Thanchanok Limcharoen ◽  
Peththa Wadu Dasuni Wasana ◽  
Hasriadi Hasriadi ◽  
Chawanphat Muangnoi ◽  
Opa Vajragupta ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Analgesic Effect ◽  
Water Solubility ◽  
Chronic Constriction Injury ◽  
Repeated Administration ◽  
Tnf Α ◽  
Antinociceptive Effects ◽  
Low Solubility

The drug treatment for neuropathic pain remains a challenge due to poor efficacy and patient satisfaction. Curcumin has been reported to alleviate neuropathic pain, but its clinical application is hindered by its low solubility and poor oral bioavailability. Curcumin diglutaric acid (CurDG) is a curcumin prodrug with improved water solubility and in vivo antinociceptive effects. In this study, we investigated the anti-inflammatory mechanisms underlying the analgesic effect of CurDG in the chronic constriction injury (CCI)-induced neuropathy mouse model. Repeated oral administration of CurDG at a low dose equivalent to 25 mg/kg/day produced a significant analgesic effect in this model, both anti-allodynic activity and anti-hyperalgesic activity appearing at day 3 and persisting until day 14 post-CCI surgery (p < 0.001) while having no significant effect on the motor performance. Moreover, the repeated administration of CurDG diminished the increased levels of the pro-inflammatory cytokines: TNF-α and IL-6 in the sciatic nerve and the spinal cord at the lowest tested dose (equimolar to 25 mg/kg curcumin). This study provided pre-clinical evidence to substantiate the potential of pursuing the development of CurDG as an analgesic agent for the treatment of neuropathic pain.

scholarly journals Differential Expression of Neuroinflammatory mRNAs in the Rat Sciatic Nerve Following Chronic Constriction Injury and Pain-Relieving Nanoemulsion NSAID Delivery to Infiltrating Macrophages

2019 ◽  
Vol 20 (21) ◽  
pp. 5269 ◽  
Author(s):  
Andrea M. Stevens ◽  
Lu Liu ◽  
Dylan Bertovich ◽  
Jelena M. Janjic ◽  
John A. Pollock
Keyword(s):  
Gene Expression ◽  
Chronic Pain ◽  
Pain Relief ◽  
Sciatic Nerve ◽  
Mrna Expression ◽  
Chronic Constriction Injury ◽  
Expression Profiles ◽  
Nerve Tissue ◽  
Rat Sciatic Nerve ◽  
The Impact

The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.

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