Acetone Drop Research Articles

Harmaline attenuates chemotherapy-induced peripheral neuropathy: Modulation of Nrf-2 pathway and NK-1 receptor signaling

Peripheral neuropathy, resulting from damage to peripheral nerves, manifests as weakness, numbness, and pain, primarily affecting extremities and significantly impairing quality of life, especially in the elderly. Current treatments often entail severe side effects, necessitating the exploration of alternative therapies. Harmaline, a β-carboline alkaloid derived from Peganum harmala, exhibits promising antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of harmaline in a vincristine-induced mouse model of peripheral neuropathy. Swiss albino mice received vincristine (0.1 mg/kg, i.p.) for 10 days to induce neuropathy. Harmaline (5 and 10 mg/kg, i.p.) was administered 30 min before vincristine and continued until day 14 to evaluate its protective effects. Behavioral assessments were conducted on days 7 and 14. Vincristine treatment significantly heightened sensitivity to cold, measured by cold plate and acetone drop tests, and to heat, assessed via the hot plate test, while also impairing motor coordination. Biochemical analyses revealed decreased levels of GSH and Nrf-2, alongside elevated TBARS and IL-1β levels in sciatic nerve tissue. Harmaline administration markedly alleviated both behavioral and biochemical alterations induced by vincristine, with the 10 mg/kg dose exhibiting the most pronounced effects. Notably, harmaline treatment elevated GSH and Nrf-2 levels while reducing TBARS and IL-1β. Furthermore, substance-P treatment reversed the protective effects of harmaline, implicating the NK-1 receptor in its mechanism of action. In conclusion, harmaline demonstrates significant potential in mitigating vincristine-induced peripheral neuropathy by reducing oxidative stress through Nrf-2 activation and lowering IL-1β levels, likely via NK-1 receptor inhibition.

Pegylated nanoliposomal cisplatin ameliorates chemotherapy-induced peripheral neuropathy

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse effect of cisplatin. The current study aimed to determine whether PEGylated nanoliposomal cisplatin can limit CIPN in an animal model. MethodsCisplatin-loaded PEGylated liposome nanoparticles (Cis-PL) were produced as a combination of lecithin, cholesterol, and DSPE-mPEG2000 in a molar ratio of 50:45:5 and were characterized by polydispersity index (PDI), zeta potential, Field emission scanning electron microscopy (FESEM) analysis, as well as encapsulation efficiency (EE). Fifteen male rats were provided and randomly divided into 3 groups including Cis-PL group, cisplatin group, and control group. Behavioural tests (hot-plate test and acetone drop test) were used for evaluating CIPN. Moreover, oxidative stress markers and histopathological analysis were applied. Treatment-related toxicity was assessed by haematological analysis as well as liver and renal function tests. ResultsCis-PL had an average particle size of 125.4, PDI of 0.127, and zeta potential of −40.9 mV. Moreover, the Cis-PL exhibited a high EE as well as low levels of leakage rate at 25 °C. In a hot-plate test, paw withdrawal latency was longer in Cis-PL group in comparison to rats treated with cisplatin. A lower number of withdrawal responses was detected during acetone drop test in Cis-PL group than in cisplatin-treated rats. Assessment of oxidative stress markers showed that Cis-PL could improve oxidative stress. Additionally, histopathological assessment demonstrated that the number of satellite cells was significantly reduced in the dorsal root ganglion (DRG) of Cis-PL-treated rats compared with those treated with cisplatin. The cisplatin group had elevated white blood cells counts, reduced platelet counts, and higher levels of bilirubin, ALT (alanine aminotransferase, and AST (aspartate aminotransferase), and creatinine compared with the control group, which was ameliorated in Cis-PL group. ConclusionsData from the current study support the previous hypothesis that Cisplatin-loaded PEGylated liposome could be a promising solution for CIPN in the future by modulating oxidative stress and preventing glial cell activation in DRG, suggesting further clinical studies to investigate the efficacy of this agent and its potential application in clinical practice.

Polydatin attenuated neuropathic pain and motor dysfunction following spinal cord injury in rats by employing its anti-inflammatory and antioxidant effects.

Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3mg/kg). Over 4weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function.

Mitotherapy prevents peripheral neuropathy induced by oxaliplatin in mice

Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.

Rutin-loaded chitosan nanoparticles alleviated Freund's adjuvant induced rheumatoid arthritis via modulating oxidative stress and inflammatory parameters in Wistar rats.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, primarily affecting the joints and with stromal tissue dysregulation causing chronic inflammation and joint destruction. Rutin is a natural flavonoid with potential therapeutic properties in chronic destructive conditions including rheumatoid diseases. In this study, the protective effects of rutin nanoformulation in an animal model of rheumatoid arthritis caused by Freund's complete adjuvant (FCA) were investigated. Sixty male rats were randomly divided into ten groups including normal, negative control, prednisolone 10 mg/kg (positive control), 3 doses of rutin (15, 30, 45mg/kg), rutin nanoparticles (15, 30, 45 mg/kg), and nanoparticle without rutin, for 28 days. Different behavioral parameters including the open field test, acetone drop test, hot plate test, Von Frey test, and inclined plane test were evaluated. Serum levels of glutathione (GSH), catalase, and nitric oxide as well as histopathological analyses were measured in different groups. Also, matrix metalloproteinase (MMP)-2 and MMP-9 activity were appraised by gelatin zymography. The injection of FCA prolonged the rats' immobility duration in comparison to the control group. Rheumatoid arthritis induction also increased nitric oxide and decreased GSH and catalase levels, while these effects were reversed in the groups that received nanoparticles containing rutin and prednisolone. Rutin nanoparticles suppressed MMP-9 and activated MMP-2. Also, this rutin drug delivery system plays a significant role in the improvement of histopathological symptoms. Considering the improvement of behavioral and tissue symptoms and the modulation of the level of inflammatory cytokines, nanoparticles containing rutin can be proposed as a suitable approach in the management of patients with rheumatoid arthritis.

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.

Thermo-hydraulic rating of a shell and tube heat exchanger for acetone cooling using bell-delaware method

Shell and tube heat exchangers are becoming the most popular devices for the transfer of heat in industrial process applications. In the present work, the thermo-hydraulic rating of a shell and tube heat exchanger proposed to cool an acetone stream was carried out using the Bell-Delaware methodology. An overall heat transfer coefficient value of 426.70 W/m2.K, a calculated heat transfer area of 121.46 m2, and a percent excess area of 20.83% were obtained. Both the pressure drop of acetone and water had values of 1,622.36 Pa and 3,020.46 Pa, respectively. The proposed shell and tube heat exchanger can be used satisfactorily for the required application, since the percent excess area does not exceed the 25%, and the pressure drops of both fluid streams are below the limit values established by the process.

Gallic acid attenuates the Chronic construction injury of sciatic nerve induced neuropathic pain in mice

Gallic acid (GA) is one of the natural flavonoids and it is known to protect the neuronal system from various endogenous neurodegenerative processes. The present study is focused on evaluating the role of GA in chronic construction injury (CCI) of sciatic nerve-induced neuropathic pain. The test compound i.e., gallic acid (20 and 40mg/kg), and reference compound i.e., pregabalin (PrG: 5mg/kg) were administered intravenously for 10 consecutive days. The sciatic nerve injury-induced neuralgic sensations were assessed with multiple test methods like acetone drop, pinprick, plantar, tail-flick, and tail pinch tests at different time points i.e., 0, 4th, 8th, 12th, and 16th days. The biochemical level changes i.e., thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide anion, calcium, myeloperoxidase (MPO), and tumor necrosis factor–α (TNF-α) were estimated in sciatic nerve samples. The administration of GA and PreG was shown a significant ameliorative effect against the CCI-induced pain response in a dose-dependent manner. Moreover, it also attenuated the tissue biochemical changes. The observed effects of GA were similar to reference drug PreG treated groups. Hence, GA has neuroprotective and pain relief effects against the CCI-induced neuralgia. It may be due to its natural free radical scavenging; regulation of inflammatory proteins; expression of antioxidant proteins, reduction of intracellular free calcium, and prevention of neuroinflammatory actions.

Magnolin Inhibits Paclitaxel-Induced Cold Allodynia and ERK1/2 Activation in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anti-cancer drugs. The main symptoms often include sensory disturbances and neuropathic pain, and currently there is no effective treatment for this condition. This study aimed to investigate the suppressive effects of magnolin, an extracellular signal-regulated kinase (ERK) inhibitor substance derived from a 95% EtOH extract of the seeds of Magnolia denudata, on the symptoms of CIPN. A taxol-based anti-cancer drug paclitaxel (PTX) was repeatedly injected (2 mg/kg/day, total 8 mg/kg) into mice to induce CIPN. A neuropathic pain symptom was assessed using a cold allodynia test that scores behaviors of licking and shaking paw after plantar administration of acetone drop. Magnolin was administered intraperitoneally (0.1, 1, or 10 mg/kg) and behavioral changes to acetone drop were measured. The effect of magnolin administration on ERK expression in the dorsal root ganglion (DRG) was investigated using western blot analysis. The results showed that the repeated injections of PTX induced cold allodynia in mice. Magnolin administration exerted an analgesic effect on the PTX-induced cold allodynia and inhibited the ERK phosphorylation in the DRG. These results suggest that magnolin could be developed as an alternative treatment to suppress paclitaxel-induced neuropathic pain symptoms.

The potential of esculin in ameliorating Type-2 diabetes mellitus induced neuropathy in Wistar rats and probing its inhibitory mechanism of insulin aggregation

Diabetic neuropathy encompasses multiple pathological disturbances, many of which coincide with the pathophysiological mechanisms of neurodegenerative disorders. In the present study, various biophysical techniques like Rayleigh light scattering assay, Thioflavin T assay, far-UV Circular Dichroism spectroscopy, Transmission electron microscopy have unveiled the anti-fibrillatory effect of esculin upon human insulin fibrillation. MTT cytotoxicity assay demonstrated the biocompatibility of esculin and in-vivo studies such as behavioral tests like hot plate test, tail immersion test, acetone drop test, plantar test were performed for validating diabetic neuropathy. Assessment of levels of serum biochemical parameters, oxidative stress parameters, pro-inflammatory cytokines as well as neuron specific markers was done in the current study. Rat brains were subjected to histopathology and their sciatic nerves were subjected to transmission electron microscopy to analyze myelin structure alterations. All these results reveal that esculin ameliorates diabetic neuropathy in experimental diabetic rats. Conclusively, our study demonstrates the anti-amyloidogenic potential of esculin in the form of inhibition of human insulin fibrillation, making it a promising candidate in combating neurodegenerative disorders in the near future and the results of various behavioral, biochemical, and molecular studies reveal that esculin possesses anti-lipidemic, anti-inflammatory, anti-oxidative and neuroprotective properties which help in ameliorating diabetic neuropathy in streptozotocin induced diabetic Wistar rats.

A consistent volume-of-fluid approach for direct numerical simulation of the aerodynamic breakup of a vaporizing drop

A novel simulation framework has been developed in this study for the direct numerical simulation of the aerodynamic breakup of a vaporizing drop. The interfacial multiphase flow with phase change is resolved using a consistent geometric volume-of-fluid method. The bulk fluids are viscous and incompressible with surface tension at the interface. The newly-developed numerical methods have been implemented in the Basilisk solver, in which the adaptive octree/quadtree mesh is used for spatial discretization, allowing flexibility in dynamically refining the mesh in a user-defined region. The simulation framework is extensively validated by a series of benchmark cases, including the 1D Stefan and sucking problems, the growth of a 3D spherical bubble in a superheated liquid, and a 2D film boiling problem. The simulation results agree very well with the exact solution and previous numerical studies. 2D axisymmetric simulations were performed to resolve the vaporization of a moving drop with a low Weber number in a high-temperature free stream. The computed rate of volume loss agrees well with the empirical model of drop evaporation. Finally, the validated solver is used to simulate the aerodynamic breakup of an acetone drop at a high Weber number. A fully 3D simulation is performed and the morphological evolution of the drop is accurately resolved. The rate of vaporization is found to be significantly enhanced due to the drop deformation and breakup. The drop volume decreases nonlinearly in time and at a much higher rate than the empirical correlation for a spherical drop.

Naringin Attenuates the Diabetic Neuropathy in STZ-Induced Type 2 Diabetic Wistar Rats.

The application of traditional medicines for the treatment of diseases, including diabetic neuropathy (DN), has received great attention. The aim of this study was to investigate the ameliorative potential of naringin, a flavanone, to treat streptozotocin-induced DN in rat models. After the successful induction of diabetes, DN complications were measured by various behavioral tests after 4 weeks of post-induction of diabetes with or without treatment with naringin. Serum biochemical assays such as fasting blood glucose, HbA1c%, insulin, lipid profile, and oxidative stress parameters were determined. Proinflammatory cytokines such as TNF-α and IL-6, and neuron-specific markers such as BDNF and NGF, were also assessed. In addition, pancreatic and brain tissues were subjected to histopathology to analyze structural alterations. The diabetic rats exhibited increased paw withdrawal frequencies for the acetone drop test and decreased frequencies for the plantar test, hot plate test, and tail flick test. The diabetic rats also showed an altered level of proinflammatory cytokines and oxidative stress parameters, as well as altered levels of proinflammatory cytokines and oxidative stress parameters. Naringin treatment significantly improved these parameters and helped in restoring the normal architecture of the brain and pancreatic tissues. The findings show that naringin's neuroprotective properties may be linked to its ability to suppress the overactivation of inflammatory molecules and mediators of oxidative stress.

Mechanistic efficacy assessment of selected novel methanimine derivatives against vincristine induced Neuropathy: In-vivo, Ex-vivo and In-silico correlates

Vincristine induced peripheral neuropathy (VIPN) is a serious untoward side effect suffered by cancer patients, which still lacks an adequate therapeutic approach. This study examined the alleviating potential of novel methanimine derivatives i.e. (E)-N-(4-nitrobenzylidene)-4-chloro-2-iodobenzamine (KB 9) and (E)-N-(2-methylbenzylidene)-4-chloro-2-iodobenzamine (KB 10) in VIPN. Vincristine was injected in BALB/c mice for 10 days to instigate nociceptive neuropathy. Dynamic and static allodynia, thermal (hot and cold) hyperalgesia were evaluated at 0, 5, 10 and 14 days using cotton brush, Von Frey filament application, hot plate test, acetone drop and cold water respectively. Tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), lipid peroxide (LPO), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) assays were performed to assess the efficacy of KB9 and KB10 against neuroinflammation and oxidative stress utilizing ELISA, immunohistochemistry and western blot analysis in brain and sciatic nerve tissues. Computational studies were executed to determine the stable binding conformation of both compounds with respect to COX-2 and NF-κB. Interestingly, both compounds substantially reduced protein expression related to neuroinflammation, oxidative stress (LPO, GST, SOD, CAT) and pain (NF-κB, COX-2, IL-1β and TNF-α). This molecular analysis suggested that the neuroprotective effect of KB9 and KB10 was mediated via regulation of inflammatory signaling pathways. Overall, this study demonstrated that KB9 and KB10 ameliorated vincristine induced neuropathy, through anti-inflammatory, anti-nociceptive and antioxidant mechanisms.

Exploring the Pain Attenuating Potential of Imatinib in Chronic Constriction Injury Model of Neuropathic Pain

Background: Preclinical studies have identified three members of tyrosine kinase receptor family (Trk), TrkA, TrkB, and TrkC in dorsal root of ganglia (DRG), which carry sensory neural signals to the central nervous system from the peripheral nervous system in neuropathic pain. Imatinib is a selective tyrosine kinase inhibitor and widely employed as anti-cancer drug in myeloid leukemia and gastrointestinal stromal tumor. The present study was designed to investigate the potential of imatinib in neuropathic pain. Method: Neuropathic pain was induced by chronic constriction injury in rats by putting four loose ligatures around sciatic nerve. The extent of neuropathic pain was assessed by noting paw withdrawal threshold (mechanical hyperalgesia) in pin prick test, paw withdrawal latency in hot plate test (heat hyperalgesia) and paw withdrawal duration in acetone drop test (cold allodynia) before surgery and on 14th day post surgery. Result: There was a significant development of cold allodynia, mechanical and heat hyperalgesia on 14th day in CCI-subjected rats. Administration of imatinib (25 mg/kg and 50 mg/kg) significantly abolished the behavioural deficits (hyperalgesia and allodynia) induced by CCI in a dose-dependent manner. Conclusion: The observed beneficial effects of imatinib in reduction of behavioral deficits in CCI-subjected rats may be possibly attributed to tyrosine kinase inhibition in dorsal root ganglia neurons associated with the neuropathic pain.

Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activities.

BackgroundSpinal cord injury (SCI) is one of the most debilitating disorders throughout the world, causing persistent sensory-motor dysfunction, with no effective treatment. Oxidative stress and inflammatory responses play key roles in the secondary phase of SCI. Naringenin (NAR) is a natural flavonoid with known anti-inflammatory and antioxidative properties. This study aims at evaluating the effects of intrathecal NAR administration on sensory-motor disability after SCI.MethodsAnimals underwent a severe compression injury using an aneurysm clip. About 30 minutes after surgery, NAR was injected intrathecally at the doses of 5, 10, and 15 mM in 20 µL volumes. For the assessment of neuropathic pain and locomotor function, acetone drop, hot plate, inclined plane, and Basso, Beattie, Bresnahan tests were carried out weekly till day 28 post-SCI. Effects of NAR on matrix metalloproteinase (MMP)-2 and MMP-9 activity was appraised by gelatin zymography. Also, histopathological analyses and serum levels of glutathione (GSH), catalase and nitrite were measured in different groups.ResultsNAR reduced neuropathic pain, improved locomotor function, and also attenuated SCI-induced weight loss weekly till day 28 post-SCI. Zymography analysis showed that NAR suppressed MMP-9 activity, whereas it increased that of MMP-2, indicating its anti-neuroinflammatory effects. Also, intrathecal NAR modified oxidative stress related markers GSH, catalase, and nitrite levels. Besides, the neuroprotective effect of NAR was corroborated through increased survival of sensory and motor neurons after SCI.ConclusionsThese results suggest intrathecal NAR as a promising candidate for medical therapeutics for SCI-induced sensory and motor dysfunction.

6]-Shogaol Attenuates Oxaliplatin-Induced Allodynia through Serotonergic Receptors and GABA in the Spinal Cord in Mice.

Although oxaliplatin is a well-known anti-cancer agent used for the treatment of colorectal cancer, treated patients often experience acute cold and mechanical allodynia as side effects. Unfortunately, no optimal treatment has been developed yet. In this study, [6]-shogaol (10 mg/kg, i.p.), which is one of the major bioactive components of Zingiber officinale roscoe (Z. officinale), significantly alleviated allodynia induced by oxaliplatin (6 mg/kg, i.p.) injection. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. The analgesic effect of [6]-shogaol was blocked by the intrathecal injection of 5-HT1A, 5-HT3, and GABAB receptor antagonists, NAN-190 (1 μg), MDL-72222 (15 μg), and CGP 55845 (10 μg), respectively. Furthermore, oxaliplatin injection lowered the GABA concentration in the superficial laminae of the spinal dorsal horn, whereas [6]-shogaol injection significantly elevated it. The GAD (glutamic acid decarboxylase) 65 concentration also increased after [6]-shogaol administration. However, pre-treatment of NAN-190 completely inhibited the increased GABA induced by [6]-shogaol in the spinal dorsal horn, whereas MDL-72222 partially blocked the effect. Altogether, these results suggest that [6]-shogaol could attenuate oxaliplatin-induced cold and mechanical allodynia through 5-HT1A and 5-HT3 receptor antagonists located in the GABAergic neurons in the spinal dorsal horn in mice.

Exploring the role of cAMP in gabapentin- mediated pain attenuating effects in chronic constriction injury model in rats

It has been shown that an increase in cAMP leads to pain sensitization and gabapentin is shown to decrease cAMP levels. However, the impact of drugs modulating cAMP levels on analgesic actions of gabapentin is not studied. The present study investigates the effect of milrinone on pain attenuating effects of gabapentin in chronic constriction injury (CCI). Neuropathic pain was induced by putting four loose ligatures around the sciatic nerve. The pain assessment was done by noting the paw withdrawal threshold in the pinprick test, paw withdrawal latency in hot plate test and paw withdrawal duration in acetone drop test before surgery and on 14th- day post-surgery. There was a significant development of cold allodynia, mechanical and heat hyperalgesia on 14th day in CCI rats. Gabapentin (100 mg/kg) treatment for 14 days significantly attenuated pain, while milrinone (50 mg/kg) treatment for 14 days significantly exacerbated neuropathic pain in CCI-subjected rats. Milrinone (30 and 50 mg/kg) also attenuated analgesic actions of gabapentin in CCI-subjected rats, suggests that gabapentin may abolish neuropathic pain by increasing the intracellular levels of cAMP in CCI-subjected rats.

5-HT1A receptors mediate the analgesic effect of rosavin in a mouse model of oxaliplatin-induced peripheral neuropathic pain

Oxaliplatin, a third-generation platinum derivative, is the mainstay of current antineoplastic medications for advanced colorectal cancer therapy. However, peripheral neuropathic complications, especially cold allodynia, undermine the life-prolonging outcome of this anti-cancer agent. Rosavin, a phenylpropanoid derived originally from Rhodiola rosea, exhibits a wide range of therapeutic properties. The present study explored whether and how rosavin alleviates oxaliplatin-induced cold hypersensitivity in mice. In the acetone drop test, cold allodynia behavior was observed from days 3 to 5 after a single injection of oxaliplatin (6 mg/kg, i.p.). Cold allodynia was significantly attenuated following rosavin treatment (10 mg/kg, i.p.). Specific endogenous 5-HT depletion by three consecutive pretreatments with para-chlorophenylalanine (150 mg/kg/day, i.p.) abolished the analgesic action of rosavin; this effect was not observed following pretreatment with naloxone (opioid receptor antagonist, 10 mg/kg, i.p.). Furthermore, 5-HT1A receptor antagonist WAY-100635 (0.16 mg/kg, i.p.), but not 5-HT3 receptor antagonist MDL-72222 (1 mg/kg, i.p.), blocked rosavin-induced analgesia. These results suggest that rosavin may provide a novel approach to alleviate oxaliplatin-induced cold allodynia by recruiting the activity of 5-HT1A receptors.

Intrathecal Administration of Melatonin Ameliorates the Neuroinflammation- Mediated Sensory and Motor Dysfunction in A Rat Model of Compression Spinal Cord Injury.

Spinal cord injury (SCI), often characterized by sensory-motor dysfunction, is a major debilitating disorder of the central nervous system. As no useful treatment for post- SCI complications has been approved thus far, finding novel treatments is of great importance. Considering the promising effects of melatonin (MEL) against destructive mechanisms in other models of brain damage, in the current study, we evaluated its ameliorative effects on sensory- motor outcomes, inflammatory mediators, histological changes and other post-SCI complications. Rats in SCI and MEL groups underwent laminectomy followed by a severe compression injury by an aneurysm clip. Then, intrathecal treatment with vehicle (5% dimethyl sulfoxide) or MEL was carried out post-injury. Acetone drop, von Frey, inclined plane, and BBB tests as well as weight changes and auricle temperature, were used to evaluate the neuropathic pain, motor function, and other post-SCI complications. The effects of MEL on the activity of MMP-2 and MMP-9 were assessed using the gelatin zymography method every week till day 28 post-SCI. Histopathological assessments were performed on days 14, 21, and 28. MEL treatment resulted in decreased motor dysfunction, mechanical and cold allodynia, auricle temperature, and also ameliorated weight loss. Moreover, MEL suppressed MMP-9 activity while increasing that of MMP-2 post-SCI, indicating its anti-neuroinflammatory effects. Also, MEL significantly preserved white matter myelinated areas and the number of sensory neurons post-SCI. The results suggest MEL as a promising candidate for medical therapies with advantageous effects on improving functional recovery through suppressing inflammatory mediators, and attenuating spinal tissue damages.

Sex Differences in a Rat Model of Peripheral Neuropathic Pain and Associated Levels of Endogenous Cannabinoid Ligands

Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.