Suppression of MAPK/NF-kB and activation of Nrf2 signaling by Ajugarin-I in EAE model of multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neurodegenerative autoimmune disease of the central nervous system (CNS). The current study aimed to investigate the neuroprotective properties of Ajugarin-I (Aju-I) against the experimental autoimmune encephalomyelitis (EAE) model of MS and explored the underlying mechanism involved. The protective potential of Aju-I was first confirmed against glutamate-induced HT22 cells and hydrogen peroxide (H2 O2 )-induced BV2 cells. Next, an EAE model has been established to investigate the mechanisms of MS and identify potential candidates for MS treatment. The behavioral results demonstrated that Aju-I post-immunization treatment markedly reduced the EAE-associated clinical score, motor impairment, and neuropathic pain. Evans blue and fluorescein isothiocyanate extravasation in the brain were markedly reduced by Aju-I. It effectively restored the EAE-associated histopathological changes in the brain and spinal cord. It markedly attenuated EAE-induced inflammation in the CNS by reducing the expression levels of p-38/JNK/NF-κB but increased the expression of IkB-α. It suppressed oxidative stress by increasing the expression of Nrf2 but decreasing the expression of keap-1. It suppressed EAE-induced apoptosis in the CNS by regulating Bax/Bcl-2 and Caspase-3 expression. Taken together, this study suggests that Aju-I treatment exhibits neuroprotective properties in the EAE model of MS via regulation of MAPK/NF-κB, Nrf2/Keap-1, and Bcl2/Bax signaling.

Anti-epileptic activity of daidzin in PTZ-induced mice model by targeting oxidative stress and BDNF/VEGF signaling.

Epilepsy is a complex and multifactorial neurodegenerative disease described by recurrent seizures. Oxidative stress and dysregulation of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are critical factors for the development of epilepsy. Daidzin is well-known for its effective anti-inflammatory and antioxidant potential for centuries. The present study was focused on exploring the anti-epileptic potential of daidzin in the pentylenetetrazole-induced mice model. Daidzin (1, 5, and 10 mg/kg) was administered in the acute study and the dose was optimized. Pretreatment with daidzin remarkably reduced the severity of epileptogenesis in a dose-dependent manner. Moreover, chronic epilepsy was induced in mice by administration of PTZ (35 mg/kg, i.p) every alternative day for 21 days. Results demonstrated that daidzin significantly prevented epileptogenesis and reversed histopathological changes in the hippocampus. It remarkably improved antioxidant (glutathione, glutathione sulfotransferase, superoxide dismutase, and catalase) levels while decreased MDA (malondialdehyde) and nitrite production in the brain. It remarkably improved the expressions of heme oxygenase-1 (HO-1) and BDNF while reduced the expression of VEGF. It remarkably prevented the neuronal apoptosis in the brain tissue. Additionally, spectroscopic analysis such as FTIR (Fourier transform infrared spectroscopy) and DSC (differential scanning calorimetry) revealed that daidzin remarkably prevented PTZ-induced protein damage. HPLC-UV spectrophotometry results demonstrated that there was no peak of aglycone daidzin (metabolite) in the brain sample which specify that the anticonvulsant effect of the compound is due to its direct entry into the brain tissue. Moreover, the molecular docking results showed that daidzin possesses a better binding affinity for ALDH2, estrogen receptor-ß, P13k, AKT2, mTORC1, and HIF-1-α proteins. Taken together, the results of the present study showed that daidzin has remarkable neuroprotective and anti-epileptic properties through modulation of oxidative stress, BDNF/VEGF, and apoptotic signaling in the brain tissue of PTZ-kindled mice.

N-Pyrazoloyl and N-thiopheneacetyl hydrazone of isatin exhibited potent anti-inflammatory and anti-nociceptive properties through suppression of NF-κB, MAPK and oxidative stress signaling in animal models of inflammation.

BACKGROUND: Hydrazide derivatives constitute an important class of compounds for new drug development as they are reported to possess good anti-inflammatory and analgesic activity. The present study was aimed to investigate the role of newly synthesized hydrazide derivatives N-pyrazoloyl hydrazone of isatin (PHI) and N-thiopheneacetyl hydrazone of isatin (THI) in acute and chronic inflammatory pain models induced by carrageenan and complete Freud's adjuvant (CFA). MATERIALS: PHI and THI (0.1, 1 and 10 mg/kg) pretreatments were provided intraperitoneally to male BALB/c mice prior to inflammatory inducers. Behavioral responses to inflammation and pain were evaluated by assessment of paw edema, mechanical allodynia, mechanical and thermal hyperalgesia. Cytokines production and NF-κB levels were evaluated by ELISA. Western blot analysis was performed for the detection of IκBα, p38, JNK and ERK. Hematoxylin and eosin (H&E) staining and radiographic analysis were performed to evaluate the effect of PHI and THI treatment on bone and soft tissues. Oxidative stress was determined by reduced glutathione, glutathione-S-transferase and catalase assays. Evans blue dye was used to monitor vascular protein leakage. RESULT: PHI and THI dose dependently (0.1, 1 and 10 mg/kg) reduced inflammation and pain in mice, however, the dose of 10 mg/kg exhibited significant activity. The anti-inflammatory and analgesic effects were attributed to suppression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) production levels. PHI and THI significantly blocked CFA-induced activation of NF-κB and MAPK signaling pathways. Oxidative stress and plasma nitrite levels were reduced remarkably. The PHI and THI (10 mg/kg) treatment did not exhibit any apparent toxicity on the liver, kidney, muscles strength, and motor co-ordination in mice. CONCLUSION: Both PHI and THI possess significant anti-inflammatory and analgesic activity via inhibition of inflammatory mediators.

A new cationic palladium(II) dithiocarbamate exhibits anti-inflammatory, analgesic, and antipyretic activities through inhibition of inflammatory mediators in in vivo models.

Inflammation is being a protective mechanism of the body towards the injury. However, chronic and progressive inflammation may lead to some chronic diseases. Due to the serious unwanted effects associated with available drugs, new and safe anti-inflammatory agents are still required. Therefore, the present study was designed to investigate the anti-inflammatory, analgesics, and antipyretic properties of a new compound (4-benzylpiperidine-1-carbodithioato-κ2S,S')(1,4-bis-(diphenylphosphino)butane)palladium(II)chloride monohydrate (compound-1) in albino mice models. Compound-1 was characterized by elemental analysis, FT-IR, and multinuclear NMR spectroscopy. Initially, compound-1 was evaluated for cytotoxicity, anti-inflammatory, and analgesic activities by performing MTT assay, carrageenan-, histamine-, serotonin-, and CFA-induced paw edema, mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia (0.1, 1, and 10 mg/kg, b.w). Antipyretic activity was evaluated in brewer's yeast-induced model. The pro-inflammatory cytokines were measured by using commercially available ELISA kits. Additionally, nitrite production, antioxidant enzymes, H&E staining, muscle activity and motor coordination, and kidney and liver function tests were also determined. The results demonstrated that compound-1 significantly inhibited inflammation, pain, and febrile responses in all models at a dose of 10 mg/kg without effecting viability of cells in vitro at concentrations up to 100 µM. Similarly, the data clearly demonstrated significant reduction in the pro-inflammatory cytokines and nitrite production while enhancing antioxidant enzymes. Furthermore, pretreatment with compound-1 did not produce any prominent side effect on kidney, liver, stomach, and muscles. These findings suggest that compound-1 has potent anti-inflammatory-, pain-, and pyrexia-relieving properties. Hence, compound-1 might be a potential candidate for the therapeutic management of chronic inflammation and pain.

Diadzein ameliorates 5-fluorouracil-induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents.

5-Fluorouracil (5-FU) is one of the most commonly prescribed anti-cancer agent. However, its use is associated with several debilitating adverse effects such as intestinal mucositis (IM) and myelosuppression. Oxidative stress and inflammation are major contributors in the development of mucositis. Diadzein is known for its potent anti-inflammatory and anti-oxidative activities from decades. The present study focused on investigating the effects of diadzein on intestinal mucositis induced by 5-FU by mainly focusing on oxidative stress and inflammatory markers in mice. Mucositis was induced in mice by administration of 5-FU (50 mg/kg, i.p.), once daily for three days and diadzein (1, 5, 10 mg/kg) was administered once daily for seven days. Diadzein pretreatment was found to reduce the severity of mucosal injury in a dose-dependent manner. Diadzein significantly reversed weight loss, relieved diarrhea, and improved histopathological deformities associated with inflammation. Moreover, diadzein remarkably improved the intestinal wall histopathology by reducing inflammatory mediators infiltration and prevented suppression of antioxidants (glutathione, glutathione sulfo-transferase, and catalase) by 5-FU administration. Furthermore, nitrite production in intestinal tissue was reduced by diadzein consistent with the observed modulation of inflammatory markers. Additionally, diadzein also improved the amended microflora profile, by reducing the number of pathogenic bacteria and increasing the abundance of probiotics. Taken together, the behavioral, biochemical and histological outcomes of the present study demonstrates that diadzein has significant anti-mucositis properties in 5-FU induced mucositis model, and the attenuative potential of diadzein might be due to inhibition of oxidative stress and inflammatory mediators.

Cinnamomum cassia: an implication of serotonin reuptake inhibition in animal models of depression.

The aim of the study was to explore the traditional use of Cinnamomum cassia against depression. The standardised methanolic extract of the bark of C. cassia was evaluated for antidepressant activity using various behavioural tests, i.e. tail suspension test (TST), forced swim test (FST) and locomotor activity test. The serotonergic and noradrenergic modulation was assessed using 5-hydroxytryptophan (5-HTP)-induced head twitches and yohimbine potentiation tests, respectively. The fluoxetine and phenelzine were used as positive controls in the study. The C. cassia extract significantly decreased the immobility time in TST (maximum effective dose tested was 50 mg/kg) while no effect was observed in FST and locomotor activity test. The extract significantly increased the 5-HTP-induced head twitches while yohimbine-induced lethality remained unaltered. The aforementioned results are similar to that caused by fluoxetine. The standardised methanolic extract of C. cassia demonstrated antidepressant activity that can be attributed to rise in serotonin levels.