Peripheral Neuropathy In Mice Research Articles

Interferon-gamma Treatment of Human Umbilical Cord Mesenchymal Stem Cells can Significantly Reduce Damage Associated with Diabetic Peripheral Neuropathy in Mice.

Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin- 1β, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.

Nucleoside Reverse Transcriptase Inhibitors Are the Major Class of HIV Antiretroviral Therapeutics That Induce Neuropathic Pain in Mice.

The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies.

Front Cover: Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice (Chem. Biodiversity 4/2024)

Front Cover: Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice (Chem. Biodiversity 4/2024)

Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice.

Cannabidiol (CBD) is a substance that exerts several therapeutic actions, including analgesia. CBD is generally administered orally, but its poor water solubility and metabolism impair its bioavailability. Thus, the development of molecules with better pharmacokinetic profile from cannabidiol becomes an interesting strategy for the design of novel analgesic drugs for the relief of painful conditions that are difficult to manage clinically, such as neuropathic pain. In the present study, an unprecedented analogue of CBD (1) was synthesized and some of its physicochemical properties were evaluated in silico as well as its stability in an acid medium. Additionally, its effect was investigated in a model of neuropathic pain induced by the chemotherapy drug paclitaxel in mice, in comparison with cannabidiol itself. Cannabidiol (20 mg/kg), pregabalin (30 mg/kg), or analogue 1 (5, 10, and 20 mg/kg), administered on the 14th day after the first administration of paclitaxel, attenuated the mechanical allodynia of the sensitized animals. The antinociceptive activity of analogue 1 was attenuated by previous administration of a cannabinoid CB1 receptor antagonist, AM 251, which indicates that its mechanism of action is related to the activation of CB1 receptors. In conclusion, the CBD analogue 1 developed in this study shows great potential to be used in the treatment of neuropathic pain.

Octanol alleviates chronic constriction injury of sciatic nerve-induced peripheral neuropathy by regulating AKT/mTOR signaling.

Activation of gap junction channels can induce neuropathic pain. Octanol can limit the conductance of gap junctions containing connexin 43 proteins. Thus, this study focused on the roles of octanol in chronic constriction injury (CCI)-induced peripheral neuropathy in mice and its mechanisms of action. Male mice were assigned into control, sham, CCI, CCI + Octanol-20mg/kg, CCI + Octanol-40mg/kg and CCI + Octanol-80mg/kg groups. CCI was performed by applying three loose ligations to mouse sciatic nerve, and the mice with CCI was administered with 20mg/kg, 40mg/kg, or 80mg/kg octanol. The neuropathic pain development was examined by assessing thermal withdrawal latency, paw withdrawal mechanical threshold, and sciatic functional index. Histopathological changes were evaluated by hematoxylin and eosin staining. The phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) was examined by western blotting. The expression of Akt and mTOR was also evaluated by immunofluorescence staining. Octanol alleviated the CCI-induced mechanical and thermal hyperalgesia and sciatic functional loss. Additionally, octanol relieved the CCI-induced abnormal histopathological changes. Mechanistically, octanol inactivated the Akt/mTOR pathway in the mice with CCI. In conclusion, octanol can alleviate CCI-induced peripheral neuropathic by regulating the Akt/mTOR pathway and might be a novel pharmacological intervention for neuropathic pain.

Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN. CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation. Treatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16-22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype. Topically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.

Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Phlomidis Radix Extract Alleviates Paclitaxel-Induced Neuropathic Pain by Modulating Spinal TRPV1 in Mice.

Paclitaxel is a chemotherapeutic drug reported to have excellent activity against tumors; however, various side effects, including peripheral neuropathy, limit its use in some cases. In this study, the effect of Phlomidis radix (P.Radix) extract was assessed on paclitaxel-induced cold and mechanical peripheral neuropathy in mice. Multiple paclitaxel injections (accumulative dose of 8 mg/kg, i.p.) induced increased behavioral responses to cold and mechanical stimuli in mice from D10 to D21 after the first paclitaxel injection. Cold and mechanical stimuli were performed by acetone drop and von Frey filament, respectively. Oral administrations of 25% ethanol extract of P.Radix (300 and 500 mg/kg) relieved cold and mechanical pain in a dose-dependent manner. Furthermore, among the various transient receptor potential (TRP) cation channel subfamilies, paclitaxel upregulated the spinal gene expression of transient receptor potential vanilloid 1 (TRPV1) and melastatin 4 (TRPM4), but not ankyrin 1 (TRPA1). However, 500 mg/kg but not 300 mg/kg of P.Radix extract significantly downregulated the gene expression of TRPV1 but not TRPM4. Among the components of P.Radix, sesamoside was identified and quantified by high-performance liquid chromatography (HPLC), and the administration of sesamoside (7.5 mg/kg, i.p.) showed a similar analgesic effect to 300 mg/kg P.Radix. These results suggest that P.Radix and sesamoside should be considered when treating paclitaxel-induced neuropathic pain.

β-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation.

Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of β-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1β, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.

Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle, is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg-1·d-1, i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either β-Arrestin2 or β-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.

Intrathecal rapamycin attenuates the mechanical hyperalgesia of paclitaxel-induced peripheral neuropathy in mice.

Paclitaxel is an extensively used chemotherapy antitumor drug and paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common side effect. Rapamycin, originally used as an adjuvant drug for chemotherapy, has recently been found to possess potential neuroprotective activities. Our purposes of this study are to verify the effect of rapamycin on PIPN, which contributes to a new target for PIPN treatment. Mice were given paclitaxel or rapamycin with different injection methods. Paw withdrawal threshold was tested at different time points for mechanical sensitivity assessment. Administration of paclitaxel, both 2 mg/kg and 5 mg/kg, could induce mechanical hypersensitivity. 0.01 mg intrathecal injection of rapamycin showed the best effect on attenuate the mechanical hyperalgesia of PIPN. Intrathecal injection of only rapamycin would not induce the mechanical hyperalgesia while when rapamycin and paclitaxel were used together the mechanical hyperalgesia induced by paclitaxel could be attenuated. Paclitaxel could induce mechanical hyperalgesia in mice and rapamycin could attenuate such mechanical hyperalgesia of PIPN.

Hypericum perforatum ekstresinin siyatik sinir hasarı ile indüklenen periferik nöropati üzerindeki düzenleyici etkisi: fareler üzerinde deneysel bir çalışma

Purpose: The effect of Hypericum perforatum (HP), which is a medicinal plant, on sciatic nerve injury-induced peripheral neuropathy has been less studied so far. The current experimental study aimed to investigate the neuroprotective and antinociceptive effects of Hypericum perforatum (HP) extract on sciatic nerve injury-induced peripheral neuropathy in mice.
 Materials and Methods: In the present study, 18 Balb/C albino mice were allocated equally into three groups. The first group was determined as controls, and no procedure was performed on these mice. Neuropathy was generated by the partial sciatic nerve ligation method on mice allocated to the second and third groups. Mice in the third group received HP extract at a dose of 70 mg/kg per day for fourteen days. Nociception (cold allodynia) was evaluated using the cold plate test at the end of the experimental period. Tumor necrosis factor –αlpha (TNF-α) and interleukin-6 (IL-6) in plasma; inducible nitric oxide synthase (iNOS), phospholipase A2, cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-κB), caspase-3, Bcl-2, and Bax levels in sciatic nerve were measured by enzyme-linked immunosorbent assay test. 
 Results: Cold plate latencies (sec) of the neuropathy + HP, neuropathy, and control groups were 8.33 ± 0.67, 5.17 ± 0.60, and 13 ± 0.73, respectively. Plasma TNF-α, IL-6 levels, and sciatic nerve iNOS, COX-2, NF-κB, caspase-3, and Bax levels were significantly decreased after HP supplementation. Bcl-2 levels of the neuropathy + HP, neuropathy, and control groups were 9.92 ± 0.71, 5.37 ± 0.53, and 13.65 ± 0.68, respectively.
 Conclusion: HP has improved oxidative, inflammatory, and apoptotic responses, as well as cytokine levels in plasma and sciatic nerves of mice. It has been concluded that HP provided neuroprotective, anti-inflammatory, and antinociceptive effects in experimental mice with sciatic nerve injury models, which is suggested to guide future studies on neuropathic pain management.

3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors.

Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3', 4'-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3', 4'-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving KATP channels, adenosine and GABAA receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3', 4'-dihydroxyflavone at the above targets were also carried out. The test compound 3', 4'-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3', 4'-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of KATP channels, adenosine and GABAA receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3', 4'-dihydroxyflavone at these targets. The findings of the present study suggests that, 3', 4'-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve KATP channels, adenosine (A3) and GABAA (α2 subunit) receptors.

Pregabalin can interact synergistically with Kv7 channel openers to exert antinociception in mice

Chronic pain is a common public health problem and remains an unmet medical need. Currently available analgesics usually have limited efficacy for the treatment of chronic pain, including neuropathic pain and persistent inflammatory pain, or they are accompanied by many adverse side effects. The voltage-gated calcium channel blocker (pregabalin) and potassium channel openers (flupirtine and retigabine) have been widely used for the management of chronic pain, but their effectiveness in combination is unclear. In this research, we evaluated the antinociceptive effects of pregabalin in combination with flupirtine or retigabine in carrageenan-induced inflammatory pain and paclitaxel-induced peripheral neuropathy in mice using the von Frey test. Isobolographic analysis indicated that pregabalin exerted synergistic antinociceptive effects when combined with flupirtine or retigabine in neuropathic and inflammatory pain models. Furthermore, the antinociceptive effects of pregabalin, flupirtine/retigabine, and their combinations were significantly attenuated by the Kv7 channel blocker XE991. The favored dose ratio between pregabalin and flupirtine/retigabine in combinations was also investigated. Finally, we evaluated the motor coordination of their combinations using the rotarod test, and the outcomes underpinned their safety. Collectively, our results support the potential use of pregabalin in combination with flupirtine or retigabine to alleviate chronic pain.

Human IAPP is a contributor to painful diabetic peripheral neuropathy.

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.

Khellin as a selective monoamine oxidase B inhibitor ameliorated paclitaxel-induced peripheral neuropathy in mice

BackgroundTreatment of paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is full of challenges because of the unclear pathogenesis of PIPN. Herbal folk medicine Khellin (Khe) is a natural compound extracted from Ammi visnaga for treatment of renal colics and muscle spasms. PurposeHere, we aimed to assess the potential of Khe in ameliorating PIPN-like pathology in mice and investigate the underlying mechanisms. MethodsPIPN model mice were conducted by injection of PTX based on the published approach. The capability of Khe in ameliorating the PTX-induced neurological dysfunctions was assayed by detection of nociceptive hypersensitivities including mechanical hyperalgesia, thermal hypersensitivity, and cold allodynia in mice. The underlying mechanisms were investigated by assays against the PIPN mice with MAOB-specific knockdown in spinal cord and dorsal root ganglion (DRG) tissues by injection of adeno-associated virus (AAV)-MAOB-shRNA. ResultsWe determined that MAOB not MAOA is highly overexpressed in the spinal cord and DRG tissues of PIPN mice and Khe as a selective MAOB inhibitor improved PIPN-like pathology in mice. Khe promoted neurite outgrowth, alleviated apoptosis, and improved mitochondrial dysfunction of DRG neurons by targeting MAOB. Moreover, Khe inhibited spinal astrocytes activation and suppressed neuroinflammation of spinal astrocytes via MAOB/NF-κB/NLRP3/ASC/Caspase1/IL-1β pathway. ConclusionOur work might be the first to report that MAOB not MAOA is selectively overexpressed in the spinal cord and DRG tissues of PIPN mice, and all findings have highly addressed the potency of selective MAOB inhibitor in the amelioration of PIPN-like pathology and highlighted the potential of Khe in treating PTX-induced side effects.

The Ameliorative Effect of Thymoquinone on Vincristine-Induced Peripheral Neuropathy in Mice by Modulating Cellular Oxidative Stress and Cytokine.

Thymoquinone (TQ), an active constituent of Nigella sativa, has been reported to exert a broad spectrum of pharmacological effects, including neuroprotective, anticancer, anti-inflammatory, antidiabetic, antiepileptic, antioxidant, and other modulatory roles in inflammation in experimental studies. The present study aims to evaluate the potential effects of TQ on vincristine-induced neuropathy in mice, as well as the possible role of oxidative stress, and pro- and anti-inflammatory cytokine in neuropathy development. A Swiss strain of male albino mice were randomly divided into seven groups, comprising of five animals each. Vincristine sulfate (0.1 mg/kg, i.p.) was administered for 10 consecutive days for the induction of peripheral neuropathy. The animals received their respective treatment of TQ (2.5, 5, and 10 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) concurrently with vincristine for 10 days followed by 4 days post treatment. The animals were assessed for pain and related behavior on day 7 and 14 using hot and cold plates, and a rotarod test. TQ preventive treatment attenuated vincristine induced neuropathy in a dose dependent manner evidenced as a significant (p < 0.001) increase in reaction time on the hot plate and the cold plate, and a fall off time on the rotarod test. Further, TQ preventive treatment resulted in a significant (p < 0.001) reduction in the number of flinches and duration of paw elevation in a formalin test. Preventative treatment with TQ abolished the vincristine-induced rise in malondialdehyde and glutathione depletion in sciatic nerve tissue, as well as the blood IL-6 levels. In conclusion, TQ at 2.5, 5, and 10 mg/kg dose produced significant attenuation of neuropathic pain induced by vincristine which may be due to its antinociceptive, antioxidant, and anti-proinflammatory activity.

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice.

Chemotherapy-provoked peripheral neuropathy and its linked comorbidities severely reduce the quality of a patient's life. Its therapy is not completely resolved and has become an important clinical challenge. The protective actions of molecular hydrogen (H2) in many neurological disorders have been described, but its effects on memory and the emotional deficits accompanying neuropathic pain induced by chemotherapy remain unknown. In this study, using male mice injected with paclitaxel (PTX), we examined the effects of systemic treatment with hydrogen-rich water (HRW) in: (i) the mechanical and thermal allodynia provoked by PTX and the pathways involved; (ii) the memory deficits, anxiety- and depressive-like behaviors associated with PTX-induced peripheral neuropathy (PIPN); and (iii) the plasticity (p-extracellular signal-regulated protein kinase; p-ERK ½), nociceptive (p-protein kinase B, p-Akt), inflammatory (p-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; p-IKBα), and oxidative (4-hydroxynonenal: 4-HNE) alterations provoked by PIPN in the prefrontal cortex (PFC). The results revealed: (1) the antiallodynic actions of HRW administered at one or two times per day during 7 and 3 consecutive days; (2) the participation of Kv7 potassium channels and the Nrf2-heme oxygenase 1-NAD(P)H: quinone oxidoreductase 1 pathway in the painkiller effects of HRW; (3) the inhibition of memory deficits and the anxiodepressive-like behaviors related with PIPN induced by HRW; and (4) the normalization of p-ERK ½, p-Akt and 4-HNE up-regulation and the activation of antioxidant enzymes produced by this treatment in PFC. This study proposes HRW as a possible effective and safe therapy for PIPN and its associated cognitive and emotional deficits.

Oral Administration of Glutathione Trisulfide Increases Reactive Sulfur Levels in Dorsal Root Ganglion and Ameliorates Paclitaxel-Induced Peripheral Neuropathy in Mice.

Peripheral neuropathy is a dose-limiting side effect of chemotherapy with paclitaxel. Paclitaxel-induced peripheral neuropathy (PIPN) is typically characterized by a predominantly sensory neuropathy presenting with allodynia, hyperalgesia and spontaneous pain. Oxidative mitochondrial damage in peripheral sensory neurons is implicated in the pathogenesis of PIPN. Reactive sulfur species, including persulfides (RSSH) and polysulfides (RSnH), are strong nucleophilic and electrophilic compounds that exert antioxidant effects and protect mitochondria. Here, we examined the potential neuroprotective effects of glutathione trisulfide (GSSSG) in a mouse model of PIPN. Intraperitoneal administration of paclitaxel at 4 mg/kg/day for 4 days induced mechanical allodynia and thermal hyperalgesia in mice. Oral administration of GSSSG at 50 mg/kg/day for 28 days ameliorated mechanical allodynia, but not thermal hyperalgesia. Two hours after oral administration, 34S-labeled GSSSG was detected in lumber dorsal root ganglia (DRG) and in the lumber spinal cord. In mice treated with paclitaxel, GSSSG upregulated expression of genes encoding antioxidant proteins in lumber DRG, prevented loss of unmyelinated axons and inhibited degeneration of mitochondria in the sciatic nerve. In cultured primary neurons from cortex and DRG, GSSSG mitigated paclitaxel-induced superoxide production, loss of axonal mitochondria, and axonal degeneration. These results indicate that oral administration of GSSSG mitigates PIPN by preventing axonal degeneration and mitochondria damage in peripheral sensory nerves. The findings suggest that administration of GSSSG may be an approach to the treatment or prevention of PIPN and other peripheral neuropathies.