Neuropathy In Diabetic Rats Research Articles

Schefflera arboricola Tablets Relieve Diabetic Neuropathic Pain: Involvement of Oxidative Stress and Inflammation

Background Diabetic neuropathic pain (DNP) is a serious chronic complication of diabetes mellitus. Oxidative stress and inflammation are considered the central mechanisms of its pathogenesis. Schefflera arboricola (SA) is a Schefflera plant of the Araliaceae family that has the effect of pain relief. In this study, the effect of SA on DNP was first investigated. Materials and Methods Diabetic neuropathy in rats was induced by a single injection of streptozotocin (60 mg/kg). Three weeks later, SA (100 mg/kg, 300 mg/kg) or gabapentin (100 mg/kg) was given once a day for a week. Blood glucose, body weight, and thermal withdrawal latency in DNP rats were measured. The morphology of the sciatic nerve was observed by light microscopy and toluidine blue staining. Semiquantitative analysis of myelin basic protein (MBP) of the sciatic nerve was performed by immunohistochemistry. IL-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 were detected by enzyme-linked immunosorbent assay. Commercial reagent kits were used to detect inducible nitric oxide synthase, superoxide dismutase (SOD), and malondialdehyde (MDA). The expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) were detected by Western blot. Results DNP rat model was successfully constructed. SA and gabapentin could alleviate the thermal sting pain of DNP rats, increase the expression of MBP and SOD, and decrease the expression of proinflammatory agents and MDA. Moreover, SA could reverse the upregulation of NF-κB and the downregulation of Nrf2. Conclusion SA has a significant protective effect on DNP, manifesting in the improvement of allodynia and sciatic nerve pathology, inhibition of neuroinflammation, reduction of oxidative stress, enhancement of Nrf2, and inhibition of NF-κB.

Management of Neuropathic Pain Using Natural Products in Different Animal Models: A Review

The focus of this review is on how natural products and their bioactive ingredients can treat neuropathic pain disorders by acting as neuroprotective agents. which includes information about neuropathic pain and their types, namely central neuropathy and peripheral neuropathy with their mechanistic involvement of various pathways may contribute to the development of neuropathic pain. It also includes information about treatment modalities for peripheral neuropathy i.e., first-line therapy includes, tricyclic antidepressant, antiepileptic, anticonvulsants and serotonin- noradrenaline reuptake inhibitors (SNRIs) and second-line therapy (opioids, topical capsaicin, lidocaine patch). Several alternative remedies exist, includes non-pharmacological treatments that play a key part in the reduction of neuropathic pain. Bioactive ingredients, provide great efficacy with minimal side effects correlated with synthetic compounds. The main focus is on animal models utilised for the evaluation of neuropathic pain, Which include several animal models such as, Streptozotocin Induced diabetic neuropathy in rats and mice is a widely used animal model for assessment of neuropathic pain. Other animal models include, Alloxan-Induced Diabetic Neuropathy, the Spinal Cord Injury (SCI) model, the Chronic Construction Injury model (CCI), the Partial sciatic Nerve Injury model (PNI), Anticancer agents induced neuropathy (vincristine and paclitaxel and Oxaliplatin-induced Neuropathic pain and spinal nerve ligation (SNL) model of neuropathic pain.

Cucurbita pepo seeds improve peripheral neuropathy in diabetic rats by modulating the inflammation and oxidative stress in rats.

Cucurbita pepo (C. pepo) is cultivated and used traditionally as vegetable as well as medicine in different parts of the world. The aim of current study was to investigate the potential of C. pepo in attenuation of diabetic neuropathy via using streptozotocin (STZ)-induced diabetes model in male wistar rats. Diabetic neuropathy was induced by administration of STZ; 65mg/kg, i.p. and Nicotinamide (NAD; 230mg/kg i.p.) and assessed by measuring thermal hyperalgesia, mechanical hyperalgesia and motor nerve conduction velocity (MNCV) in experimental animals. Treatment with different doses of (100, 200 and 400mg/kg, p.o.) petroleum ether extract of C. pepo (CPE) and hydroethanolic extract of C. pepo (CHE) was started from the 60th day of STZ/NAD administration and continued upto 90th day. CPE and CHE significantly attenuated the behavioural changes including hyperalgesia, allodynia and MNCV linked to diabetic neuropathy. Moreover, the oxidative stress and level of TNF-α, TGF-β and IL-1β was found to be significantly attenuated in experimental animals. Thus C. pepo might ameliorate the progression of diabetic neuropathy via modulation of chronic hyperglycemia and therefore and have therapeutic potential for treatment of diabetic neuropathic pain.

Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy

BackgroundMorus alba Linn, referred to as white mulberry, is a potential traditional medicine for diabetes and neuroprotection. AimIsolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy. Material and methodsThe stem Bark of M. alba was peeled and subjected to extraction. A phytoconstituent was then isolated by column chromatography and characterized using Mass spectroscopy, FTIR, and NMR. The isolated phytoconstituent was used to formulate a nanoemulsion. Nanoemulsion was also characterized for viscosity, surface tension, refractive index, pH, and particle size. Selected nanoemulsion formulations were then tested for acute oral toxicity and diabetic neuropathy, including behavioral, hematological, histopathological, and biomarker examinations. ResultsThe spectral analysis affirmed that the isolated compound was found to be chrysin. A nanoemulsion formulation was made using the chrysin and was characterized and found to be stable during the stability testing and fulfilled all other testing parameters. Then acute oral toxicity study of the formulations was found to be safe. Formulations were found to possess significant results against diabetic neuropathy in rats. Biomarkers were analyzed for their mechanistic involvement in reducing neuropathy in rats, and it was found that the oxidative pathway was considerably restored, suggesting that chrysin causes these effects via this pathway. ConclusionsResults suggests that isolated phytoconstituent (chrysin) from the bark of Morus alba derived nanoemulsion has protective and beneficial effects by diminishing the oxidative damage against alloxan-induced diabetic neuropathy in rats.

Effect of Aerobic Exercise on IL-35 Anti-Inflammatory Cytokine and Behavioral Pain Responses in a Model of Diabetic Neuropathy Rats

Introduction: Nerve inflammation plays an important role in the occurrence and development of diabetic neuropathy pain. The aim of this study was to evaluate the effect of aerobic exercise on anti-inflammatory cytokine IL-35 and behavioral pain responses in a model of diabetic neuropathy rats.
 Methods: In this experimental study, twenty four 8-week-old male Wistar rats (weight range: 204 ± 11.3 grams) were randomly divided into three groups (n = 8): diabetic neuropathy, diabetic neuropathy exercise and control. After confirmation of diabetic neuropathy pain by hot plate behavioral tests and mechanical allodynia, the aerobic exercise protocol was implemented. IL-35 and NF-κB gene expression in spinal cord tissue was measured by real-time PCR. One-way analysis of variance and Tukey's post hoc test with SPSS version 16 software were used for statistical analysis (P <0.05).
 Results: Exercise reduced the response of behavioral tests of diabetic neuropathic pain in the exercise group compared to the diabetic neuropathy group (P <0.05). Induction of diabetes caused a significant decrease in IL-35 gene expression and a significant increase in NF-kB gene (P=0.001) (P=0.021).There was also a significant increase in IL-35 gene expression and a significant decrease in NF-κB gene expression in the exercise group compared to the diabetic neuropathy group (P=0.007) (P=0.034).
 Conclusion: It seems that aerobic training has reduced the sensitivity of nociceptors to pain agents by activating the anti-inflammatory cytokine IL-35 in spinal cord microglia. It is recommended to use aerobic exercise to reduce neuropathic pain.

Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats.

Diabetes mellitus (DM), a multifaceted metabolic disorder if not managed properly leads to secondary complications. Diabetic peripheral neuropathy (DPN) is one such complication caused by nerve damage that cannot be reversed but can be delayed. Recently, diabetes patients are using dietary supplements, although there remains a general skepticism about this practice. Curcumin (CUR), one such supplement can help prevent underlying low-grade inflammation in diabetes, but it is plagued by poor oral bioavailability. To better understand the role of bioavailability in clinical outcomes, we have tested double-headed nanosystems containing curcumin (nCUR) on DPN. Because CUR does not influence glucose levels, we have also tested the effects of nCUR combined with long-acting subcutaneous insulin (INS). nCUR with or without INS alleviates DPN at two times lower dose than unformulated CUR, as indicated by qualitative and quantitative analysis of the hind paw, sciatic nerve, spleen, and L4-6 spinal cord. In addition, nCUR and nCUR+INS preserve hind paw nerve axons as evident by the Bielschowsky silver stain and intraepidermal nerve fibers (IENF) density measured by immunofluorescence. The mechanistic studies further corroborated the results, where nCUR or nCUR+INS showed a significant decrease in TUNEL positive cells, mRNA expression of NLRP3, IL-1β, and macrophage infiltration while preserving nestin and NF200 expression in the sciatic nerve. Together, the data confirms that CUR bioavailability is proportional to clinical outcomes and INS alone may not be one of the solutions for DM. This study highlights the potential of nCUR with or without INS in alleviating DPN and warrants further investigation.

Tridax procumbens Ameliorates Streptozotocin-Induced Diabetic Neuropathy in Rats via Modulating Angiogenic, Inflammatory, and Oxidative Pathways.

Tridax procumbens (TP) is a traditional Indian therapeutic plant and was evaluated for its blood glucose lowering abilities, as well as for its ability to curb diabetic neuropathy (DN). Administrating 45 mg/kg body weight of streptozotocin (STZ) intraperitoneally for four weeks, DN was induced in Wistar rats. After the rats' tails were clipped, the blood glucose levels were measured. Body weight and urine volume were also assessed. Oxidative stress makers such as superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), catalase (CAT), inflammatory cytokines for instance tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were estimated. Further, protein kinase C (PKC-β) and vascular endothelial growth factor (VEGF) were also estimated as angiogenic markers. Behavioral parameters were also evaluated by using cold allodynia using acetone test, hot allodynia using Eddy's hot plate, grip strength test using Rota rod, and hyperalgesia test using Tail flick technique. The statistical assessment of findings was done employing one-way (ANOVA) analysis of variance, and subsequently Turkey as post hoc with GraphPad Prism software package. The ingestion of TP for 1 month in DN rats stemmed in a substantial decline in blood glucose concentrations matched to nontreated rats with DN. There had been a considerable improvement in DN as evident from the finding from biochemical markers. The serum level of antioxidant defense enzymes was significantly increased, while the activities of TBARS had been substantially reduced in the TP treated rats with DN. TP averted DN-triggered surge levels of TNF-α and IL-6 in the serum. Further, PKC-β and VEGF concentrations had been also reduced by the treatment TP. The findings of this research demonstrated that the restorative impact of TP on DN rats might be linked to the anti-inflammatory and antioxidative antiangiogenic retorts.

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 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.

Neuroprotective and Hypoglycemic Effects of the Nanoemulsion and Nettle Aqueous Extract on Streptozotocin-Induced Diabetic Neuropathy in Rats: Molecular, Biochemical, and Histological Evidence

Neuroprotective and Hypoglycemic Effects of the Nanoemulsion and Nettle Aqueous Extract on Streptozotocin-Induced Diabetic Neuropathy in Rats: Molecular, Biochemical, and Histological Evidence

Lower Formalin-Induced Pain Responses in Painless Diabetic Neuropathy Rat Correlate with the Reduced Spinal Cord NR2B Subunit of N-Methyl-D-Aspartate Receptor Activation.

Diabetic neuropathy (DN) is a late complication of diabetic mellitus and may rise into painful and painless variants. Limited studies have looked at nociceptive mechanisms of painless DN variant. The study aimed to determine phosphorylation and total NR2B subunit of N-methyl-D-aspartate receptor in the spinal cord of painless DN rat during early phase following formalin injection. Thirty-six Sprague-Dawley male rats were randomly assigned into three groups: control, painful, and painless DN (n = 12). The rats were developed into the early phase of DN for 2weeks following diabetic induction. Two weeks later, the rats were injected with 5% formalin solution and flinching and licking responses were recorded for 60min. The rats were sacrificed 3days later, and the spinal cord enlargement region was collected. Immunohistochemistry and Western blot procedures were conducted to determine the phosphorylated and total NR2B subunit expressions. The results showed reduced flinching and licking responses in painless DN rats compared to control and painful DN groups, followed by a significant reduction in phosphorylated and total NR2B expression at both ipsilateral and contralateral regions of the spinal cord. In conclusion, reduced pain behavior responses in painless DN rats following formalin injection is possibly contributed by the reduced expression of phosphorylated and total NR2B subunit in the spinal cord.

The Role of the Inflammatory and the Vascular Pathogenesis in a Model of Streptozotocin Induced Diabetic Neuropathy in Rats

Abstract Background Peripheral diabetic neuropathy (DN) is one of the major health problems facing the whole world. There is no treatment that could completely reverse or prevent progression of DN except for good glycemic control. The inflammatory and vascular pathways are two main domains that are incorporated in the pathogenesis of diabetic neuropathic pain (DNP) and DN. Thus, targeting both of them could be an appropriate way to delay progression of DN. Aim To investigate the role of the inflammatory and the vascular pathogenesis in diabetic mechanical allodynia. Method Twenty male Wistar rats were divided randomly into naïve and diabetic groups (n = 10). Diabetes was induced through i.p injection of single dose of streptozotocin (STZ) (50mg/kg), then 8 weeks after induction of diabetes, the sciatic content of tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) was assessed using ELISA technique. Additionally, the number of intercellular adhesion molecule-1 (ICAM-1) as well as CD31, the most specific vascular marker, positively stained vessels was counted manually in sciatic nerves cross sections. Whereas, DNP was assessed weekly throughout the experiment using 60%mechanical threshold of paw withdrawal test. Results There was a significant increase in the sciatic content of TNFα, VEGF and ICAM-1 positively stained vessels and a significant decrease in CD31 positively stained vessels in the diabetic group as compared to the naïve group. There was a correlation between TNFα, VEGF, ICAM-1, CD31 positively stained vessels in one side and the 60% mechanical threshold on the other side (r=-0.8, -0.9, -0.8 and 0.7 respectively). Conclusion The diabetic mechanical allodynia is negatively correlated to the sciatic nerve content TNFα, VEGF, ICAM-1 and positively correlated to the CD31.

Fullerene C60 nanoparticle attenuates pain and tumor necrosis factor-α protein expression in hippocampus following diabetic neuropathy in rats

Fullerene C60 nanoparticle attenuates pain and tumor necrosis factor-α protein expression in hippocampus following diabetic neuropathy in rats

Triphala Churna-A Traditional Formulation in Ayurveda Mitigates Diabetic Neuropathy in Rats.

Neuropathy is a common complication of diabetes affecting a large number of people worldwide. Triphala churna is a formulation mentioned in Ayurveda-a traditional system of medicine. It is a simple powder formulation consisting of powders of three fruits, Emblica officinalis L., Terminalia bellirica (Gaertn.) Roxb. and Terminalia chebula Retz. Individual components of Triphala churna have anti-diabetic and antioxidant activities. Hence, this study was designed to evaluate the effect of Triphala churna on diabetic neuropathy. Diabetes was induced with streptozotocin (STZ, 55 mg/kg, i. p.) in rats. Animals were grouped and treated orally with Triphala churna at a dose of 250, 500, and 1,000 mg/kg after 6 weeks of diabetes induction for the next 4 weeks. At the end of study, parameters such as body weight, plasma glucose level, motor nerve conduction velocity were determined. The effect of Triphala churna on thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia was also determined at the end of study. The plasma cytokine levels like TGF-β1, TNF-α, and IL-1β were determined by ELISA assay. Histopathology study of the sciatic nerve was studied. Western blotting was performed to study the expression of neuronal growth factor.Treatment with Triphala churna showed a significant reduction in plasma glucose and a significant rise in body weight. Triphala treatment significantly increased the motor nerve conduction velocity and decreased the thermal and mechanical hyperalgesia, as well as mechanical allodynia. The treatment significantly inhibited levels of circulatory cytokines like TGF-β1, TNF-α, and IL-1β. Histopathology study confirmed the neuroprotective effect of Triphala churna. The expression of NGF was significantly increased in sciatic nerves after treatment with Triphala churna. From the results, it can be concluded that Triphala churna delays the progression of neuropathy in diabetic rats.

Carvedilol Exerts Neuroprotective Effect on Rat Model of Diabetic Neuropathy

Diabetic neuropathy (DN) commonly occurs in diabetics, affecting approximately 50% of both type 1 and 2 diabetic patients. It is a leading cause of non-traumatic amputations. Oxidative stress could play a key role in the pathophysiology of DN. This study aimed to investigate the potential neuroprotective effect of carvedilol on STZ-induced DN in rats. Thirty male Sprague Dawley rats (weighing 200–250 g) were randomly divided into five groups (six/group), where group 1 (negative control) received only the vehicle (0.5% of carboxymethyl cellulose orally 1 ml/kg). DN was induced by a single injection of remaining rats with streptozotocin (STZ; 50 mg/kg, i.p.). After diabetes induction, group 2 served as the diabetic untreated animals; while groups 3 and 4 were treated with carvedilol (1 and 10 mg/kg/d, orally, respectively). Group 5 received a-lipoic acid as a reference neuroprotective (100 mg/kg/d, orally). All treatments were continued for 45 days after diabetes induction, followed by behavioural tests. After sacrificing the animals, dorsal root ganglia, and sciatic nerves were collected for histopathological examination and biochemical assessments. Briefly, STZ administration caused cold allodynia, induced oxidative stress, and increased nerve growth factor (NGF) concentration. Nevertheless, carvedilol improved the behavioural tests, ameliorated the oxidative imbalance as manifested by reducing malondialdehyde, restoring glutathione content, and superoxide dismutase activity. Carvedilol also decreased NGF concentration in DRG homogenate. In conclusion, this study demonstrates the neuroprotective effect of carvedilol in an experimentally induced DN rat model through–at least partly–its antioxidant effect and reduced NGF concentration in DRG.

Molsidomine ameliorates diabetic peripheral neuropathy complications in Wistar rats.

Diabetic neuropathy is a disorder that affects various regions of the nervous system and there is no specific treatment available for it. This study evaluated the protective effect of molsidomine in diabetic neuropathy in rats. Diabetes was induced in male Wistar rats by administrating streptozotocin (52 mg/kg ip). Diabetic rats were treated with molsidomine 5 mg/kg po and 10 mg/kg po. After 8 weeks of treatment, motor coordination, mechanical allodynia, mechanical hyperalgesia, nerve conduction velocity, and glycosylated hemoglobin were assessed. Thereafter, animals were killed and the sciatic nerve was isolated for measurement of reduced glutathione and lipid peroxidation, and histopathological analysis. Treatment with molsidomine significantly improved motor coordination, paw withdrawal threshold, mechanical threshold, and nerve conduction velocity. Furthermore, molsidomine treatment also reduced malondialdehyde levels and prevented depletion of reduced glutathione in the sciatic nerve homogenate. Histopathology revealed that molsidomine treatment maintained normal architecture of the sciatic nerve. The results of our study strengthen the alternative use of molsidomine in diabetic neuropathy.

Effect of xylopic acid on alloxan-induced diabetic neuropathy in rats

Background: Neuropathic pain is a very disturbing condition commonly found in diabetic patients. This study investigated xylopic acid (XA), the major constituent of Xylopia aethiopica in diabetic neuropathy as well as established possible toxicity of the compound on some selected tissues.Methods: Diabetes was induced in six groups of male rats with 120 mg/kg alloxan monohydrate. Diabetes was confirmed as a blood glucose level >15 mmol/dl. Neuropathic pain was confirmed on day three post-diabetes induction and treatment with 10 mg/kg, 30 mg/kg or 100 mg/kg xylopic acid, 10 mg/kg glibenclamide, 10 mg/kg morphine, and 10 ml/kg normal saline were initiated and continued for the next 15 days. The effects of the treatments on cold allodynia (cold water at 4°C) and thermal hyperalgesia (hot water at 55 ± 1°C) were evaluated within the duration of treatments. Histology of the liver and kidney, as well as haematological, serum biochemical, and semen analyses, were done after the fifteenth day of the experiment.Results: Xylopic acid produced significant anti-hyperglycaemic and analgesic effects in the cold allodynia and thermal hyperalgesia tests. Sperm motility, viability and count were significantly restored at 10 mg/kg XA as compared higher doses and negative control. The outcome of haematological analysis revealed a protective effect of XA although histological damage liver and kidney due to alloxan treatment was observable.Conclusions: Xylopic acid ameliorates diabetic neuropathy in rats and does not exert detrimental effects at low doses.

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction.

Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, Western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.

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.

Protective effect of Curculigo orchioides in streptozotocin and nicotinamide-induced diabetic neuropathic pain in Wistar rats

Pain, paraesthesia, sensory loss, and associated high morbidity and mortality are typically characterized by diabetic neuropathy (DN). Curculigo orchioides (CO) is a herbal medicine that is rich in flavonoids, glycosides, and polyphenols which are known for potential antioxidant activity. Moreover, the anti-hyperglycemic potential of CO paved the way for pharmacological investigation in the treatment of diabetic complications since the regulation of hyperglycemia is considered as a major factor in the treatment of diabetes. The current study was designed to evaluate the neuroprotective effect of CO extract in DN. DN was induced in rats using streptozotocin (STZ) (65 mg/kg, i.p.) after 15 minutes of nicotinamide (NAD; 230 mg/kg, i.p.). Diabetic rats showed significant mechanical, thermal hyperalgesia, and allodynia. Diabetic rats also showed increased oxidative stress parameters and advanced glycation end products (AGEs) formation. Oral treatment was started on 60th day after STZ–NAD administration and continued for the next 30 days, with different doses (150, 300, and 600 mg/kg) of CO extracts (ethanolic and hydroalcoholic) and standard drug gabapentin (30 mg/kg). The results of the study revealed that both extracts reduced hyperglycemia and inhibited the pain response partially via reduction of oxidative stress and AGEs formation in DN rats. Both the extracts reduced the neuropathic pain in diabetic rats at dose dependent manner.