MP-13, a novel chimeric peptide of morphiceptin and pepcan-9, produces potent antinociception with limited side effects.

Pharmacological investigations have substantiated the potential of bifunctional opioid/cannabinoid agonists in delivering potent analgesia while minimizing adverse reactions. Peptide modulators of cannabinoid receptors, known as pepcans, have been investigated before. In this study, we designed a series of chimeric peptides based on pepcans and morphiceptin (YPFP-NH2). Here, we combined injections of pepcans and morphiceptin to investigate the combination treatment of opioids and cannabis and compared the analgesic effect with chimeric compounds. Subsequently, we employed computational docking to screen the compounds against opioid and cannabinoid receptors, along with an acute pain model, to identify the most promising peptide. Among these peptides, MP-13, a morphiceptin and pepcan-9 (PVNFKLLSH) construct, exhibited superior supraspinal analgesic efficacy in the tail-flick test, with an ED50 value at 1.43 nmol/mouse, outperforming its parent peptides and other chimeric analogs. Additionally, MP-13 displayed potent analgesic activity mediated by mu-opioid receptor (MOR), delta-opioid receptor (DOR), and cannabinoid type 1 (CB1) receptor pathways. Furthermore, MP-13 did not induce psychological dependence and gastrointestinal motility inhibition at the effective analgesic doses, and it maintained non-tolerance-forming antinociception throughout a 7-day treatment regimen, with an unaltered count of microglial cells in the periaqueductal gray region, supporting this observation. Moreover, intracerebroventricular administration of MP-13 demonstrated dose-dependent antinociception in murine models of neuropathic, inflammatory, and visceral pain. Our findings provide promising insights for the development of opioid/cannabinoid peptide agonists, addressing a crucial gap in the field and holding significant potential for future research and development. PERSPECTIVE: This article offers insights into the combination treatment of pepcans with morphiceptin. Among the chimeric peptides, MP-13 exhibited potent analgesic effects in a series of preclinical pain models with a favorable side-effect profile.

Ameliorative activity of aqueous leaf extract from Madhuca longifolia against diclofenac-administered toxicity on rat stomach and intestine.

Madhuca longifolia, a tropical tree used as medicine and food, is known to have a beneficial effect against stomach gastric toxicity. Madhuca longifolia is used in treating cough, skin disease and nerve disorders. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), with overdosage and prolonged use, is known to cause gastric toxicity. Silymarin (SLY), a polyphenolic antioxidant flavonoid, is a derivative of Silybum marianum extracted from milk thistle seeds and fruits, has been widely used in the treatment of gastric ulcer. SLY was used as the standard drug to compare the effects with the Madhuca longifolia aqueous leaf extract treatment. The aim of the current study is to understand the effect of Madhuca longifolia aq. leaf extract on rat stomach and intestine against diclofenac-administered toxicity. Rats (n = 30) were divided into Group I normal control, Group II treated with diclofenac, Group III treated with diclofenac and Madhuca longifolia leaf extract, Group IV treated with diclofenac and silymarin, and Group V was treated with Madhuca longifolia leaf extract alone. After the study duration, rats were euthanized and tissue samples were analyzed for antioxidant, cytokine, protein expression levels and histopathological changes. Diclofenac treated rats had significant (p < 0.05) changes in levels of antioxidants, cytokines, protein expression and pathological changes as compared to rats treated with Madhuca longifolia. This study demonstrated that Madhuca longifolia leaf extract had gastroprotective activity in rats treated with diclofenac.

Protective effect of the ethanolic and methanolic leaf extracts of Madhuca longifolia against diclofenac-induced toxicity in female Wistar albino rats.

BACKGROUND: Diclofenac is commonly prescribed Non-Steroidal Anti-Inflammatory Drug (NSAIDs) as it has anti-inflammatory, analgesic and anti-pyretic properties. Long term usage and over-dosage of diclofenac is associated with adverse effects like drug-induced liver injury, gastrointestinal and renal toxicity. The therapeutic uses of medicinal plants have gained a prominent role in recent years. Madhuca longifolia is a tree found throughout India, which is known to have several pharmacological activities. The aim of our study is to investigate the potential effect of the ethanolic and methanolic leaf extracts of M. longifolia against diclofenac-induced toxicity. METHODS: The rats used for the experiment were divided into seven groups. Group-1 was the normal control. Group-2 was administered with diclofenac (50 mg/kg b.w./day/ip) on the 4th and the 5th day. Group-3 was treated with diclofenac and ELEML (500 mg/kg b.w./day/po) on all 5 days. Group-4 was treated with diclofenac and MLEML (500 mg/kg b.w./day/po) on all 5 days. Standard drug silymarin (25 mg/kg b.w./day/po) was given to the rats of group-5 along with diclofenac. Group-6 and group-7 were treated with ethanolic leaf extract and methanolic leaf extract of M. longifolia respectively. After the study period, the rats were evaluated for parameters like liver and renal markers, antioxidants and histopathological changes. RESULTS: This study has proved the beneficial effect of ethanolic and methanolic leaf extract of M. longifolia against diclofenac-induced toxicity wherein ethanolic leaf extract showed a better result than methanolic leaf extract. CONCLUSION: Our study has concluded the beneficial effect of ethanolic and methonolic leaf extract of Madhuca longifolia against DFC-induced toxicity. This study proves that it has potential effect on hepato, renal and gastro toxicity in female Wistar albino rats. It can further be studied to understand its mechanism in treating toxicity.

Aqueous leaves extract of Madhuca longifolia attenuate diclofenac-induced hepatotoxicity: Impact on oxidative stress, inflammation, and cytokines.

Diclofenac is a Non-Steroidal Anti-inflammatory drug which is used as an analgesic. It is known to cause heptotoxicity on over dose and long term usage. Madhuca longifolia is an evergreen tree found widely in India that is known to have several ethnomedical uses. The aim of our study is to evaluate the beneficial effect of the aqueous leaf extract of M. longifolia against diclofenac-induced toxicity. Rats were dived into five groups of six rats each. Group-I was normal control. Group-II was administered with diclofenac (50 mg/kg. b.w./day, i.p) on 4th and 5th day. Group-III rats were treated with aqueous leaf extract of M. longifolia (500 mg/kg b.w./day, oral) for 5 consecutive days and diclofenac (50 mg/kg. b.w./day, i.p) was given on 4th and 5th day. Silymarin (25 mg/kg. b.w./day, oral) was used as standard drug which was given to the rats of group-IV along with diclofenac on 4th and 5th day. Aqueous leaf extract of M. longifolia (500 mg/kg b.w./day, oral) alone was administered in group-V. After the study period, the rats were evaluated for liver enzyme markers, antioxidant parameters, histopathological changes, and cytokines levels. The hepatic proinflammatory mediator cytokines like TNF-α, IL-6, and IL-1ß were evaluated through ELISA. The protein expression of Caspase-3, COX-2, and NF-κB were analysed through Western blotting techniques. Aqueous leaves extract of M. longifolia was able to normalize the changes caused by diclofenac. Current study indicatesthe protective effect of the aqueous leaves extract of M. longifolia against diclofenac-induced toxicity.

Evidence of antidiabetic activity of Spirulina fusiformis against streptozotocin-induced diabetic Wistar albino rats.

The aim of our study is to investigate the protective effect of Spirulina fusiformis against streptozotocin-induced diabetes in Wistar albino rats. Rats were divided into five groups: group I was normal control, group II was diabetic control (50 mg/kg b.w. of streptozotocin, i.p.), group III was Spirulina fusiformis (400 mg/kg b.w., p.o.) treated diabetic rats; group IV was Glibenclamide (0. 6 mg/kg b.w., p.o.) treated diabetic rats and group V was treated with Spirulina fusiformis (400 mg/kg b.w., p.o.) alone. There was significant elevation in the levels of blood glucose, serum lipid profile and serum renal markers (total protein, urea, creatinine and uric acid) in the diabetic rats. Also, diabetic rats showed significantly (P < 0.05) reduced antioxidant status (reduced levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione; increased levels of TBARS), impaired oral glucose tolerance and elevated HbA1C. Spirulina fusiformis was able to normalize the above mentioned parameters. Significant histopathological changes were found in the pancreas, liver and kidney sections of the diabetic control group while treatment with Spirulina fusiformis was able to minimize the extent of tissue damage. Current study shows that Spirulina fusiformis possesses significant antidiabetic and antihyperlipidemic effects in streptozotocin-induced diabetic rats by effectively reducing the rise in blood glucose levels and lipid profile.

Natural remedies for non-steroidal anti-inflammatory drug-induced toxicity.

The liver is an important organ of the body, which has a vital role in metabolic functions. The non-steroidal anti-inflammatory drug (NSAID), diclofenac causes hepato-renal toxicity and gastric ulcers. NSAIDs are noted to be an agent for the toxicity of body organs. This review has elaborated various scientific perspectives of the toxicity caused by diclofenac and its mechanistic action in affecting the vital organ. This review suggests natural products are better remedies than current clinical drugs against the toxicity caused by NSAIDs. Natural products are known for their minimal side effects, low cost and availability. On the other hand, synthetic drugs pose the danger of adverse effects if used frequently or over a long period. Copyright © 2016 John Wiley & Sons, Ltd.