Rat Model Of Neuropathy Research Articles

Computer-Assisted Histopathological Calculation Analysis of the Sciatic Nerve of Diabetic Neuropathy Rat Model

Histopathology is the science that studies the signs of disease by studying the structural and functional changes that occur in cells using certain types of dyes such as hematoxylin and eosin (H&E). Traditionally histopathological testing is carried out using semi-quantitative methods. A more advanced method is done by taking photos digitally, and then digital photos are quantified with the help of software such as ImageJ using plug-in tools. Recent advances in digital pathology require the development of more efficient computerized image analysis such as the Gaussian adaptive threshold method. This research aims to compare the calculation results of computer-assisted digitalization of histopathology using the ImageJ plugin manual method with automatic calculations using Gaussian adaptive threshold to quantify the amount of sciatic nerve cell damage in the Diabetic peripheral neuropathy (DPN) rat model. In this study, two image analysis methods were used to test their ability to measure the amount of cell damage in the sciatic nerve of normal rats using a model of diabetic neuropathy. The first method uses the ImageJ plugin manual. The second method is the Gaussian adaptive threshold method. The ImageJ plugin manual method obtained a cell abnormality value of 213 cells. Meanwhile, with the Gaussian adaptive threshold method, a value of 204 cells was obtained. The calculation results of the two methods show an insignificant difference between the methods p >0.05. This study presents a computerized morphometric image analysis method with the potential for pathology digitalization applications.

EFFECT OF MEMANTINE AS N-METHYL D-ASPARTATE RECEPTOR ANTAGONIST ON CASPASE-9 LEVEL OF RETINAL GANGLION CELL IN METHANOL TOXIC OPTIC NEUROPATHY RAT MODEL

Abstract
 Introduction & Objectives : Methanol toxic optic neuropathy (MTON) remains as a health issue in developing countries and there are no current definitive treatments. Accumulation of formic acid as metabolite of methanol causes mitochondrial dysfunction that can reduce ATP synthesis rate, disrupt axoplasmic transport, and elevate the reactive oxygen species (ROS). All of these mechanisms lead to the death of retinal ganglion cell (RGC) and optic nerve. RGC destruction in MTON has similar patterns with those that have been observed in glaucoma, ischemia, and trauma cases, that is through excessive activation of glutamate neurotransmitter via N-Methyl D-Aspartate receptors (NMDAR). Memantine is a NMDAR antagonist that inhibit the ion channel of NMDAR. This inhibitory effect of NMDAR by memantine is expected to reduce intracellular calcium level, prevent apoptosis of RGC, and prevent further mitochondrial dysfunction. Caspase-9 is essential to eliminate cells by executing apoptotic Objective: To observe the effect of Memantine on Caspase-9 level of RGC in Methanol-Intoxicated Rats.
 Methods : This experimental study was performed on 28 Methanol-Intoxicated Rats that are assigned into four treatment groups: K1 (MTON;enucleated day-3), K2 (MTON+Memantine; enucleated day-3), K3 (MTON; enucleated day-7), and K4 (MTON+Memantine; enucleated day-7). During the experiment, all groups were exposed to N2O:O2 gas and were given methanol orally. Caspase-9 level of RGC were measured immediately after enucleation.
 Results : The average of Caspase-9 level (ng/ml): K1=197,88±33,98; K2=205,64±63,66; K3=243,15±40,13; K4=150,08±119,60. The Caspase-9 level was significantly lower in K4 compared to K3 (p value =0.038).
 Conclusion : Memantine decrease the level of Caspase-9 of RGC in Methanol Toxic Optic Neuropathy rat model.

Protective effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve of rats with diabetic peripheral neuropathy.

Dyslipidemia has been considered a risk factor for diabetic peripheral neuropathy. Proprotein convertase subtilisin-like/Kexin 9 inhibitor (PCSK9) inhibitors are a new type of lipid-lowering drug currently in clinical use. The role of PCSK9 in diabetic peripheral neuropathy is still unclear. In this study, the effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve in rats with diabetic peripheral neuropathy and its underlying mechanisms were investigated. The diabetic peripheral neuropathy rat model was established by using a high-fat diet combined with streptozotocin injection, and experimental subjects were divided into normal, diabetic peripheral neuropathy, and alirocumab groups. The results showed that Alirocumab improved nerve conduction, morphological changes, and small fiber deficits in rats with DPN, possibly related to its amelioration of oxidative stress and the inflammatory response.

Oral proniosomal amitriptyline and liraglutide for management of diabetic neuropathy: Exceptional control over hyperglycemia and neuropathic pain

Exploitation of nanocarriers provides a compartment for enclosing drugs to protect them from degradation and potentiate their therapeutic efficiency. In the current study, amitriptyline- and liraglutide-loaded proniosomes were constructed for management of diabetic neuropathy, a serious complication associated with diabetes, that triggers spontaneous pain in patients and results in impaired quality of life. The developed therapeutic proniosomes were extensively characterized via dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and Fourier transform-infrared spectroscopy. High entrapment efficiency could be attained for both drugs in the proniosomes, and the reconstituted amitriptyline- and liraglutide-loaded niosomes possessed spherical morphology and particle sizes of 585.3 nm and 864.4 nm, respectively. In a diabetic neuropathy rat model, oral administration of the developed amitriptyline- and liraglutide-loaded proniosomes significantly controlled blood glucose levels, reduced neuropathic pain, oxidative stress and inflammatory markers, and improved histological structure of the sciatic nerve as compared to the oral and subcutaneous administration of amitriptyline and liraglutide, respectively. Loading of the tricyclic antidepressant amitriptyline and the antidiabetic peptide liraglutide into proniosomes resulted in exceptional control over hyperglycemia and neuropathic pain, and thus could provide an auspicious delivery system for management of neuropathic pain and control of blood glucose levels.

Effect of Aescin on Inflammatory Responses in a Diabetic Peripheral Neuropathy Rat Model by Modulating HMGB1 and RAGE Levels

Effect of Aescin on Inflammatory Responses in a Diabetic Peripheral Neuropathy Rat Model by Modulating HMGB1 and RAGE Levels

Phytochemical Screening and Evaluation of Protective Effect of Methanolic Extract of Cleodendrum viscosum Leaves in Rat Model of Vincristine Induced Peripheral Neuropathy

Chemotherapy induced peripheral neuropathy is a disabling pain condition resulting from cancer therapy. However, no scientific data available for many herbal drugs which are locally used and evaluating these drugs would be worth to have scientific approach of using them. In this study an indigenous plant called Clerodendrum viscosum leaves have been used to evaluate the effect of plant in vincristine induced peripheral neuropathy in rat model. Vincristine sulfate was administered to Male sprague dawley rats to induce neuropathy. Pain behavior was assessed by Hot plate, Cold plate, sciatic function index and formalin test were also estimated. Animals were sacrificed and the sciatic nerve excised for histopathological studies. The whole preclinical studies revealed that the aforementioned plant extract exhibited less neuronal damage. The study concluded that methanolic extract of Cleodendrum Viscosum leaves can used against chemotherapy induced peripheral neuropathy.

Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis.The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3–100μM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor β1, mostly produced by astrocytes.In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die−1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype.Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.

Protective effects of Labisia pumila against neuropathy in a diabetic rat model.

Diabetes accelerates peripheral, distal symmetric polyneuropathy, small fiber predominant neuropathy, radiculoplexopathy, and autonomic neuropathy. This study investigated the neuroprotective effects of gallic acid and myricetin-richLabisia pumila extractin a diabetic neuropathy rat model and evaluated the neuropathy correlationship with serum inflammatory biomarkers. Thirty male rats were divided into 5 groups (n = 6), namely: healthy control; non-treated diabetic control; and diabetic-rats treated with 200mg/kg metformin; Labisia pumila ethanol extract (LP) at 150mg/kg or 300mg/kg doses. Diabetes was induced by 60mg streptozotocin /kg intraperitoneal injection. Rats were orally treated daily for ten weeks. Their fasting blood glucose (FBG), neurological functions (hot plate and tail immersion; thermal hyperalgesia; cold allodynia; motor walking function), biomarkers for inflammation and oxidative stress, the neuro-histopathological changes, and brain somatic indexwere measured. The extract significantly prevented abnormal increases in FBG and decreases in body weight gain. It attenuated behavioral dysfunctions (hot plate and tail immersion; thermal hyperalgesia; cold allodynia; motor walking function), systemic inflammation (serum TNF-α, prostaglandin-E2) oxidative tension (malondialdehyde), histological brain and sciatic nerve injuries in the diabetic-rats, better than Metformin. LP mitigated neural dysfunction better than metformin partly by amending diabetic systemic inflammation, oxidative tension, and diabetic abnormalities. The nerve injuries were strongly correlated to serum prostaglandin-E2, TNF-α levels, and walking functions. The motor function was correlated to sensory neuronal functions, inflammation, and oxidation. The sensory neuronal functions were more affected by TNF-α than prostaglandin-E2 or oxidation. Diabetic brain and sciatic nerve deteriorations were influenced by serum TNF-α, PGE2, and MDA levels. The online version contains supplementary material available at 10.1007/s40200-021-00905-0.

Neuroprotective role of Tinospora cordifolia extract in streptozotocin induced neuropathic pain

Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.

Neuroprotective effect of Canthium parviflorum on streptozotocin induced diabetic neuropathy in rats

In traditional system to cure diabetes and related complications, Canthium parviflorum Lam plant leaves are used. Ethanolic extract of leaves were considered to investigate its neuroprotective property in streptozotocin elicited diabetic neuropathy rat model. Streptozotocin (60 mg/kg body weight) given by intraperitoneal injection to induce diabetes, with no treatment given, was intended to develop diabetic neuropathy. Fourteen days after induction, animals were given the extract (100 and 200 mg/kg) once daily for thirty five days. Hypersensitivity to temperature in diabetic neuropathy was assessed by tail immersion and eddy’s hot plate tests. Nerve growth factor, blood glucose, and pro-inflammatory cytokines involved in pathological pain were measured in sciatic nerve. Neuropathy which is also associated with oxidative stress was assessed by measuring bio-markers in sciatic tissue. Diabetic induced neuropathic animals exhibited significant decrease in the paw and tail withdraw time thus signifying diabetic neuropathy. Extract treatment prevented diabetic neuropathy in animals thus showing normalized response to hot and cold. These actions in extract treatment groups are supported evidently by normal blood glucose, significant low levels of pro-inflammatory cytokines, oxidative stress bio-markers, and high nerve growth factor in sciatic nerve tissue. C. parviflorum leaves ethanolic extract display neuroprotective effect in STZ-induced diabetic neuropathy in rats.

Vitamin D and rosuvastatin obliterate peripheral neuropathy in a type-2 diabetes model through modulating Notch1, Wnt-10α, TGF-β and NRF-1 crosstalk

AimsVitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model. Main methodsDiabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways. Key findingsTwo-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function. SignificanceVitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.

Protective Effects of Oxytocin and Progesterone on Paclitaxel-Induced Neuropathy in Rats

Objective: Paclitaxel (Ptx), used to treat cancer, still causes neuropathic pain and peripheral neuropathy today. This study was conducted to evaluate the effects of progesterone (Pg) and oxytocin (Oxy) on peripheral neuropathy rat model induced by Ptx. Materials and Methods: A total of 38 male Sprague–Dawley rats were randomly divided into five groups, e.g., control (n = 6), Ptx (n = 8), Ptx + Oxy (n = 8), Ptx + Pg (n = 8), and Ptx + Oxy + Pg (n = 8). The rats were monitored daily for body weight change throughout the experiment. To evaluate peripheral neuropathy, electroneuromyography measurements (latency, amplitude, and motor nerve conduction velocity (MNCV)) were recorded from the sciatic nerve innervating the gastrocnemius muscle. Sciatic nerve tissue samples were collected for histopathological evaluation. Results: Ptx led to significant reductions in body weight from day 6 (P < 0.05). There was no difference between groups in the distal latency and amplitudes (P > 0.05). Proximal latency was prolonged in Ptx group rats than in other groups (P < 0.05). Importantly, it was found that MNCV was higher in the Ptx + Pg group than Ptx, Ptx + Oxy, and Ptx + Oxy + Pg groups (P < 0.05). Furthermore, Pg-administered rats had the lowest nerve degeneration compared to rats administered Oxy and Oxy + Pg (P < 0.05). Conclusions: The present findings suggest that Pg has a protective effect on peripheral neuropathy induced by Ptx in rat.

Chronic Treatment With Hydrogen Sulfide Donor GYY4137 Mitigates Microglial and Astrocyte Activation in the Spinal Cord of Streptozotocin-Induced Diabetic Rats.

Long-term diabetic patients suffer immensely from diabetic neuropathy. This study was designed to investigate the effects of hydrogen sulfide (H2S) on peripheral neuropathy, activation of microglia, astrocytes, and the cascade secretion of proinflammatory cytokines in the streptozotocin (STZ)-induced peripheral diabetic neuropathy rat model. STZ-induced diabetic rats were treated with the water-soluble, slow-releasing H2S donor GYY4137 (50 mg/kg; i.p.) daily for 4 weeks. Antiallodynic/antihyperalgesic activities were evaluated using different tests and histopathological changes and the expression of proinflammatory cytokines in the spinal cord were examined. GYY4137 treatment produced neuroprotective effects in the spinal cord of diabetic animals and modulated their sensory deficits. The treatment decreased allodynia (p < 0.05) and mechanical hyperalgesia (p < 0.01) and restored thermal hyperalgesia (p < 0.001) compared with diabetic rats. The treatment decreased the microglial response and increased astrocyte counts in spinal cord gray and white matter compared with untreated diabetic rats. Proinflammatory cytokines were reduced in the treated group compared with diabetic rats. These results suggest that H2S has a potentially ameliorative effect on the neuropathic pain through the control of astrocyte activation and microglia-mediated inflammation, which may be considered as a possible treatment of peripheral nerve hypersensitivity in diabetic patients.

Optimized monitoring of peripheral neuropathy on preclinical studies in a drug-induced rat model of neuropathy

Optimized monitoring of peripheral neuropathy on preclinical studies in a drug-induced rat model of neuropathy

The bone marrow-derived mesenchymal stem cells (BMSCs) alleviate diabetic peripheral neuropathy induced by STZ via activating GSK-3β/β-catenin signaling pathway

BackgroundDiabetic peripheral neuropathy, a common complication of diabetic mellitus, has brought a threaten on patients’ health. The bone marrow-derived mesenchymal stem cells (BMSCs) were reported to play an important role in diverse diseases. Nevertheless, the specific function of BMSCs in diabetic peripheral neuropathy remained uncharacterized. MethodsA wide range of experiments including RT-qPCR, western blot, H&E staining, oxidative stress assessment, measurement of thermal sensitivity, ELISA, urine protein and CCK-8 assays were implemented to explore the function and mechanism of BMSCs in vivo and vitro. ResultsThe experimental results displayed that BMSCs improve STZ-induced diabetes symptoms in rats by decreasing blood glucose and urinary protein. Functionally, BMSCs ameliorate oxidative stress, painful diabetic neuropathy, neurotrophic status and angiogenesis in STZ-induced rats. Moreover, BMSCs participate in the regulation of sciatic neuro morphology in diabetic neuropathy rat model. In mechanism, BMSCs alleviate diabetic peripheral neuropathy via activating GSK-3β/β-catenin signaling pathway in rats and improve Schwann's cells viability by activating GSK-3β/β-catenin signaling pathway under high glucose. ConclusionsWe verified that BMSCs alleviate diabetic peripheral neuropathy of rats induced by STZ via activating GSK-3β/β-catenin signaling pathway, which implied a novel biomarker for diabetic peripheral neuropathy treatment.

Vincristine increased spinal cord substance P levels in a peripheral neuropathy rat model

Chemotherapy-induced peripheral neuropathy has an important impact on the quality of life of cancer patients. Vincristine-induced neuropathy is a major dose-limiting side effect. Symptoms of peripheral neuropathy are spontaneous pain, allodynia, and hyperalgesia. To analyze the contribution of substance P to the development of vincristine-induced mechanical allodynia/hyperalgesia, substance P levels in the rat spinal dorsal horn were analyzed after vincristine treatment. Mechanical allodynia/hyperalgesia was tested with the von Frey filaments 14 days after intraperitoneal (i.p.) administration of vincristine 0.1 mg/kg/day in rats. Vincristine-induced mechanical allodynia/hyperalgesia after day 14 was significantly inhibited by the neurokinin 1 receptor antagonist, aprepitant (20 mg/kg, s.c.). Immunohistochemistry showed that vincristine treatment significantly increased substance P expression (30.3% ± 2.4%) compared to saline treatment in the superficial layers of the spinal dorsal horn. Moreover, vincristine treatment significantly increased the substance P level in the spinal cord. These results suggest that vincristine treatment increases substance P in the spinal dorsal horn, and that aprepitant attenuates mechanical allodynia/hyperalgesia in vincristine-induced neuropathic rats.

Approach to creating early diabetic peripheral neuropathy rat model

To create the early diabetic peripheral neuropathy (DPN) rat model. After one-week adaption, 26 male Sprague-Dawley (SD) rats were divided into two groups, the control group (n=6) and the model group (n=20). High-sucrose/high-fat diet (D12451, 35% of energy from carbohydrate, 45% of energy from fat) was given to the model group for six weeks to induce insulin resistance, meanwhile normal diet was given to the control group. Afterwards, streptozocin (STZ) buffer solution (35 mg/kg bodyweight) was injected into abdomen of the model group to induce specific pancreatic injury, meanwhile an equal amount of buffer solution was given to the control group. Then 48 h later, type 2 diabetes mellitus (T2DM) was supposed to be successfully induced according to the random blood glucose more than 16.7 mmol/L in the model group. Then the basic features of the T2DM rats were evaluated, including body weight, fasting blood glucose (FBG), glucose tolerance (oral glucose tolerance test, OGTT), and insulin tolerance (intraperitoneal insulin tolerance test, IPITT). Subsequently, withdrawal thermal latency (WTL) was measured regularly to determine when the early DPN occurred. Once confirmed, sciatic nerve conduction velocity (NCV) of all the rats was conducted. The T2DM rats were successfully induced in the model group through high-sucrose/high-fat diet for six weeks along with STZ intraperitoneal injection (35 mg/kg bodyweight). When compared to the control group, the T2DM rats had higher FBG (P<0.001), and the glucose tolerance and insulin tolerance were both damaged (P<0.001 in OGTT, P=0.002 in IPITT). It was on the 17th day when the T2DM rats became much more sensitive to heat stimulus compared to the control group (P=0.004). Meanwhile, the sciatic NCV was conducted. There was no significant difference between the early DPN group and the control group (P=0.196). High-sucrose/high-fat diet for six weeks along with STZ intraperitoneal injection (35 mg/kg bodyweight) could successfully induce T2DM rat model, manifested by a certain extent of insulin resistance and deficiency of insulin secretion. It was about 17 days later when the early DPN emerged. In the early DPN, small fiber neuropathy came out earlier than large fiber neuropathy.

Notch activation enhances microglial CX3CR1/P38 MAPK pathway in rats model of vincristine-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) has a adverse impact to the living quality of cancer patients. This side effect of CIPN limit the dose of drug used in many chemotherapies, such as vincristine (VCR). The activation of microglia in the spinal dorsal horn is involved in the occurrence and development of neuropathic pain induced by VCR. Recent study has demonstrated that hypoxia induced microglia activation depends on Notch signaling, and it is involved in the release of many inflammatory related factors in microglia. In this work, we aimed to study that the role of Notch signaling pathway in microglia activation on a VCR-induced neuropathy rat model. Our results showed that the mechanical, thermal and cold pain threshold of rats was decreased by treatment of VCR, but N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, relieved the hyperalgesia. Molecular analysis showed that activation of Notch signaling pathway increased after nerve injury and that DAPT could significantly inhibit the upregulation of Notch signaling pathway, the activation of microglia, and the release of pro-inflammatory cytokines in the spinal. Taking together, Notch signaling pathway could be a potential therapeutic target to alleviate neuropathic pain.

Sphingosine-1-phosphate receptor 2 modulates pain sensitivity by suppressing the ROS-RUNX3 pathway in a rat model of neuropathy.

Neuropathic pain correlates with a lesion or other dysfunction in the nervous system. Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in the central nervous system and modulates synaptic plasticity. The present study aimed to investigate the role of S1P2 in neuropathic pain caused by chronic constriction injury (CCI). Sprague-Dawley rats were allocated into eight groups (n = 15 for each group): sham, CCI, CCI + green fluorescent protein, CCI + S1P2, CCI + Ctrl-short hairpin RNA (shRNA), CCI + S1P2 shRNA, CCI + S1P2 + CYM-5442, and CCI + S1P2 shRNA + CYM-5442. The CCI model was established via sciatic nerve ligation. S1P2 was overexpressed or knocked down by intrathecal injection of adeno-associated virus-S1P2 (AAV-S1P2) or AAV-S1P2 shRNA. The S1P1 agonist, CYM-5442 (1 mg/kg), was injected intraperitoneally after surgery. S1P2 expression, pain thresholds, apoptosis signaling, inflammation, and oxidative stress in rats were then examined. We found that sciatic nerve injury downregulated S1P2 expression in the spinal cords of rats. S1P2 overexpression enhanced pain thresholds. In contrast, S1P2 knockdown decreased pain thresholds in rats exposed to CCI. CCI and S1P2 silencing increased secretion of interleukin-1β (IL-1β), IL-6, and CCL2, whereas S1P2 overexpression decreased. S1P2 impeded CCI-induced reactive oxygen species (ROS) production and runt-related transcription factors 3 (RUNX3) downregulation, and S1P2 knockdown had the opposite effect. S1P2 overexpression suppressed Bax and active caspase 3 expression and promoted Bcl-2 expression, whereas loss of S1P2 reversed their expression. Additionally, S1P1 activation counteracted the effect of S1P2 on pain sensitivity. In conclusion, S1P2 is downregulated in CCI rats and may help modulate neuropathic pain via the ROS/RUNX3 pathway.

Effect of Vitis vinifera hydroalcoholic extract against oxaliplatin neurotoxicity: in vitro and in vivo evidence

Oxaliplatin treatment is associated with the development of a dose-limiting painful neuropathy impairing patient’s quality of life. Since oxidative unbalance is a relevant mechanism of oxaliplatin neurotoxicity, we assessed the potential antioxidant properties of Vitis vinifera extract in reducing oxaliplatin-induced neuropathy as a valuable therapeutic opportunity. A hydroalcoholic extract of Vitis vinifera red leaf was characterized and tested in primary rat astrocyte cells treated with oxaliplatin (100 μM). Oxaliplatin lethality in the human adenocarcinoma cell line HT-29 was evaluated in the absence and presence of the extract. In vivo, pain hypersensitivity was measured in a rat model of neuropathy induced by oxaliplatin and ex vivo molecular targets of redox balance were studied. Vitis vinifera extract (50 μg mL−1, 4 h incubation) significantly reduced the oxaliplatin-dependent superoxide anion increase and lipid peroxidation in rat astrocytes but did not interfere with the mortality elicited by oxaliplatin in HT-29 cancer cells. In oxaliplatin-treated rats, a repeated daily administration of the Vitis vinifera extract (300 mg kg−1, p.o.) significantly prevented mechanical and thermal hypersensitivity to noxious and non noxious stimuli. mRNA and protein levels of Nrf2 were normalized in spinal cord and DRGs. Moreover, in the spinal cord, the extract significantly decreased the activation of astrocytes. Vitis vinifera reduced oxidative damages and relieved pain without influencing oxaliplatin anti-cancer activity.