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Objectives: We aimed to investigate the protective potential of Punica granatum L. fruit rind extract (PFE) containing punicalagin (10.3% W/W), ellagic acid (EA) (2.7%W/W) in vincristine (75 µg/kg ...

In the present experimental work, we investigate the protective potential of standardized Momordica charantia L fruit extract [gallic acid (GA) 6%; > 8% bitters {momordicosides K (3%) and L (2%); and momordicines I (2%) and II (3%)}] (MC) comparable to its marker compound gallic acid in chemo-toxic neuropathy induced by vincristine [75 μg/kg intra-peritoneal (i.p.) for 10 consecutive days] in rats. An array of behavioral examinations was carried out on days 1st, 12th and 21st, followed by various biochemical and histopathological studies at the end. Vincristine significantly induced cold and dynamic mechanical allodynia, mechanical and heat hyperalgesia; functional deficit in walking and a rise in the levels of TNF-α, IL 6, mitochondrial complexes, myeloperoxidase (MPO), thio-barbituric acid reactive substances (TBARS), and nitrite along with decrease in glutathione (GSH). Administration of MC [400 and 800 mg/kg, per oral (p.o.)], GA (30 mg/kg, p.o.) and gabapentin (100 mg/kg, p.o.) attenuated the vincristine induced behavioral and biochemical changes. MC demonstrated superior antinociceptive activity in comparison to GA. Histopathological evaluation also divulged defending the effects of MC. Pretreatment of saclofen (1 mg/kg, i.p.), picrotoxin (1 mg/kg, i.p.) upturned the antinociceptive action of MC, but ingestion of GABA (100 mg/kg, i.p.) potentiated the action of MC. Additionally, pretreatment with l -arginine [nitric oxide (NO) donor; 100 mg/kg, i.p.] inverted the antinociceptive action of MC; whereas, aminoguanidine (iNOS inhibitor) and 7-nitroindazole (nNOS inhibitor) potentiated it. Besides this a PPARγ antagonist BADGE did not amend the effect of MC. Corroboratively, the attenuating effect of MC in vincristine induced neuropathy is attributed to its modulating action on GABAergic system along with antimitotoxic, NOS inhibition, anti-inflammatory and anti oxidative activities.

Inclusion of metabolic considerations in the drug design process leads to significant development in the field of chemical drug targeting and the design of safer drugs during past few years which is a part of an approach now designated as Retro metabolic drug design (RMDD). This approach represents systematic methodologies that integrate structure–activity and structure–metabolism relationships and are aimed to design safe, locally active compounds with an improved therapeutic index. It embraces two distinct methods, chemical delivery systems and a soft drug approach. Present review recapitulates an impression of RMDD giving reflections on the chemical delivery system and the soft drug approach and provides a variety of examples to embody its concepts. Successful application of such design principles has already been applied to a number of marketed drugs like esmolol; loteprednol etc., and many other candidates like beta blockers, ACE inhibitors, alkylating agents, antimicrobials etc., are also under investigation.

Background Injury to a nerve is the most common reason of acquired peripheral neuropathy. Therefore, searching for effective substance to recover of nerve after injury is need of present era. The current study investigates the protective potential of Standardized Fruit Extract of Punica granatum L (PFE) [Ellagic acid (41.6%), Punicalagins (10%), Granatin (5.1%)] in Tibial & Sural Nerve Transection (TST) induced neuropathic pain in rats. Methods TST was performed by sectioning tibial and sural nerve portions of the sciatic nerve and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint brush & Walking Track tests were performed to assess cold allodynia; mechanical heat, hyperalgesia and dynamic mechanical allodynia & tibial functional index respectively. The levels of TNF-α, TBARS, GSH and Nitrite were measured in the sciatic nerve as an index of inflammation & oxidative stress. Results TST led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; functional deficit in walking along with rise in the levels of TBARS, TNF-α, GSH and Nitrite. Administrations of PFE (100 & 300 mg/kg oral), significantly attenuate TST induced behavioral & biochemical changes. Pretreatments of BADGE (120 mg/kg IP) a PPAR-γ antagonist and nitric oxide precursor L-arginine (100 mg/kg IP) abolished the protective effect of PFE. Whereas, pretreatment of L-NAME (5 mg/kg IP) a NOS inhibitor significantly potentiated PFE’s protective effect of PFE. Conclusion PFE shown to have attenuating effect in TST induced neuropathic pain which may be attributed to potential PPAR-gamma agonistic activity, nitric oxide inhibitory, anti-inflammatory and anti oxidative actions.